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David Martin

Publications and source records attributed to David Martin.

At least 73 records · Page 4Linked to original sources
PubMed2004

Transplantation of a combination of CD133+ and CD34+ selected progenitor cells from alternative donors.

Positive selected haematopoietic stem cells are increasingly used for allogeneic transplantation with the CD34 antigen employed in most separation techniques. However, the recently described pentaspan molecule CD133 appears to be a marker of more primitive haematopoietic progenitors. Here we report our experience with a new CD133-based selection method in 10 paediatric patients with matched unrelated (n = 2) or mismatched-related donors (n = 8). These patients received a combination of stem cells (median = 29.3 x 10(6)/kg), selected with either anti-CD34 or anti-CD133 coated microbeads. The proportion of CD133+ selected cells was gradually increased from patient to patient from 10% to 100%. Comparison of CD133+ and CD34+ separation procedures revealed similar purity and recovery of target populations but a lower depletion of T cells by CD133+ selection (3.7 log vs. 4.1 log, P < 0.001). Both separation procedures produced >90% CD34+/CD133+ double positive target cells. Engraftment occurred in all patients (sustained primary, n = 8; after reconditioning, n = 2). No primary acute graft versus host disease (GvHD) >/= grade II or chronic GvHD was observed. The patients showed a rapid platelet recovery (median time to independence from substitution = 13.5 d), whereas T cell regeneration was variable. Five patients are alive with a median follow-up of 10 months. Our data demonstrates the feasibility of CD133+ selection for transplantation from alternative donors and encourages further trials with total CD133+ separated grafts.

AC133 Antigen↗
PubMed2004

[Prediction of transcription and genomic sequences].

Technological developments have enhanced DNA sequencing at genomic scale. On the basis of the resulting sequences, computational biologists now attempt to localise the most important functional regions, starting with genes, but also importantly the regulatory motifs and conditions controlling their expression. In a recent paper published in Cell, M.A. Beer and S. Tavazoie report the results obtained by combining statistical classifications (clustering) of transcriptome data (DNA chips), software for the discovery of cis-regulatory patterns, together with a probabilistic learning method to infer regulatory rules tentatively accounting for the observed transcriptional profiles.

Forecasting↗
PubMed2004

Defects in nuclear structure and function promote dilated cardiomyopathy in lamin A/C-deficient mice.

Laminopathies are a group of disorders caused by mutations in the LMNA gene that encodes the nuclear lamina proteins, lamin A and lamin C; their pathophysiological basis is unknown. We report that lamin A/C-deficient (Lmna(-/-)) mice develop rapidly progressive dilated cardiomyopathy (DCM) characterized by left ventricular (LV) dilation and reduced systolic contraction. Isolated Lmna(-/-) myocytes show reduced shortening with normal baseline and peak amplitude of Ca(2+) transients. Lmna(-/-) LV myocyte nuclei have marked alterations of shape and size with central displacement and fragmentation of heterochromatin; these changes are present but less severe in left atrial nuclei. Electron microscopy of Lmna(-/-) cardiomyocytes shows disorganization and detachment of desmin filaments from the nuclear surface with progressive disruption of the cytoskeletal desmin network. Alterations in nuclear architecture are associated with defective nuclear function evidenced by decreased SREBP1 import, reduced PPARgamma expression, and a lack of hypertrophic gene activation. These findings suggest a model in which the primary pathophysiological mechanism in Lmna(-/-) mice is defective force transmission resulting from disruption of lamin interactions with the muscle-specific desmin network and loss of cytoskeletal tension. Despite severe DCM, defects in nuclear function prevent Lmna(-/-) cardiomyocytes from developing compensatory hypertrophy and accelerate disease progression.

Animals↗
PubMed2004

Effects of preexercise carbohydrate ingestion on mountain bike performance.

PURPOSE: This study examined the performance and metabolic effects of consuming 1.0 (LC) and 3.0 (HC) grams of carbohydrate (CHO) per kilogram body mass (BM), 3 h before a 93-min simulated mountain bike race. METHODS: After two familiarization trials, eight male subjects undertook two CHO trials in a double-blind counterbalanced fashion on a cycle ergometer. The HC meal was supplemented with maltodextrin while maintaining the same glycemic index and apparent volume of food as the LC meal. Stochastic cycling was undertaken for 93 min (4 x 22.50-min laps) with performance measured as the total work performed in 6 x 30-s periods each lap during the test. RESULTS: Performance in lap 1 was better with LC (P < 0.03) whereas performance in lap 4 was better with HC (P < 0.02). Overall performance was 3% greater in HC compared with LC (NS, P = 0.13). Serum glucose was significantly lower (P < 0.04) in HC immediately before the mountain bike test (180 min postprandial) and at 10 min into the test (P < 0.01). Gastrointestinal comfort decreased similarly for both trials over time (P < 0.05). CONCLUSION: These data suggest that ingestion of 3.0 g x kg(-1) BM of CHO 3 h before a 93-min mountain bike simulated race does not produce a statistically significant improvement in overall performance compared with 1.0 g x kg(-1) BM. However, in real terms, a 3% performance improvement may benefit athletes in a race situation. Differences in performance during the first and last laps indicate a variation in pacing strategies that may have resulted from differing blood glucose levels between trials.

Adult↗
PubMed2004

Evaluation of a mobile diabetes care telemedicine clinic serving Aboriginal communities in Northern British Columbia, Canada.

INTRODUCTION: In British Columbia, Aboriginal diabetes prevalence, hospitalization and mortality rates are all more than twice as high as in the rest of the population. We describe and evaluate a program to improve access to diabetes care for Aboriginal people in northern communities. STUDY DESIGN: Cost-effectiveness evaluation. METHODS: A diabetes nurse educator and an ophthalmic technician travel to Aboriginal reserves, offering people with diabetes services recommended in current clinical practice guidelines: retinopathy screening by digital retinal fundus photography, glaucoma screening by tonometry, point-of-care urine and blood testing to detect microalbuminuria and dyslipidemia and to measure glycated hemoglobin, foot examinations and foot care advice, blood pressure and height and weight measurement and diabetes care advice. Via electronic communication, an ophthalmologist and an endocrinologist in Vancouver review the findings and supervise the mobile clinic staff. RESULTS: During the first year, 25 clinics were held at 22 sites, examining 339 clients with diabetes. Exit surveys showed high levels of client satisfaction. Mean cost per client (Cdn dollars 1,231) was less than for the alternative, transporting clients to care in the nearest cities (Cdn dollars 1,437). CONCLUSIONS: The mobile clinic is cost-effective and improves access to the recommended standard of diabetes care.

Adult↗
PubMed2004

Primary duodenal low-grade mucosa-associated lymphoid tissue lymphoma presenting with outlet obstruction.

Low-grade lymphoma arising in mucosa-associated lymphoid tissue (MALT) of the duodenum represents a very rare neoplasm. We report an unusual presentation of primary duodenal MALT lymphoma in a 78-year-old man. The patient initially presented with a suspected pulmonary embolus and was anticoagulated, which precipitated a major gastrointestinal hemorrhage. A large atypical ulcer with narrowing of the duodenum beyond the bulb was seen on endoscopy. Biopsies revealed atypical lymphoid cells. Abdominal CT scan revealed a mass in either the duodenum or head of the pancreas. An endoscopic retrograde cholangiopancreatography (ERCP) was performed, which revealed a normal pancreatic duct with a large calculus in the common bile duct, which was extracted after sphincterotomy. Elective surgery was planned for suspected lymphoma of the duodenum. The patient developed severe nausea, vomiting, and fullness after meals. The patient underwent pancreaticoduodectomy for a neoplastic mass causing duodenal obstruction. Pathological examination of the resected specimen revealed a low-grade B-cell lymphoma (MALToma) arising in the duodenum and invading the pancreas. Flow cytometry confirmed the phenotype typical of MALT lymphoma. Celiac, peripancreatic, pelvic, and cervical nodes were also involved with tumor. Bone marrow was also positive for metastasis. The patient was postoperatively treated with chemotherapy for stage IV disease.

Aged↗
PubMed2003

Functional classification of proteins for the prediction of cellular function from a protein-protein interaction network.

We here describe PRODISTIN, a new computational method allowing the functional clustering of proteins on the basis of protein-protein interaction data. This method, assessed biologically and statistically, enabled us to classify 11% of the Saccharomyces cerevisiae proteome into several groups, the majority of which contained proteins involved in the same biological process(es), and to predict a cellular function for many otherwise uncharacterized proteins.

Cluster Analysis↗
PubMed2003

Pharmacodynamics of the type II calcimimetic compound cinacalcet HCl.

Calcimimetic compounds, which activate the parathyroid cell Ca(2+) receptor (CaR) and inhibit parathyroid hormone (PTH) secretion, are under experimental study as a treatment for hyperparathyroidism. This report describes the salient pharmacodynamic properties, using several test systems, of a new calcimimetic compound, cinacalcet HCl. Cinacalcet HCl increased the concentration of cytoplasmic Ca(2+) ([Ca(2+)](i)) in human embryonic kidney 293 cells expressing the human parathyroid CaR. Cinacalcet HCl (EC(50) = 51 nM) in the presence of 0.5 mM extracellular Ca(2+) elicited increases in [Ca(2+)](i) in a dose- and calcium-dependent manner. Similarly, in the presence of 0.5 mM extracellular Ca(2+), cinacalcet HCl (IC(50) = 28 nM) produced a concentration-dependent decrease in PTH secretion from cultured bovine parathyroid cells. Using rat medullary thyroid carcinoma 6-23 cells expressing the CaR, cinacalcet HCl (EC(50) = 34 nM) produced a concentration-dependent increase in calcitonin secretion. In vivo studies in rats demonstrated cinacalcet HCl is orally bioavailable and displays approximately linear pharmacokinetics over the dose range of 1 to 36 mg/kg. Furthermore, this compound suppressed serum PTH and blood-ionized Ca(2+) levels and increased serum calcitonin levels in a dose-dependent manner. Cinacalcet was about 30-fold more potent at lowering serum levels of PTH than it was at increasing serum calcitonin levels. The S-enantiomer of cinacalcet (S-AMG 073) was at least 75-fold less active in these assay systems. The present findings provide compelling evidence that cinacalcet HCl is a potent and stereoselective activator of the parathyroid CaR and, as such, might be beneficial in the treatment of hyperparathyroidism.

Animals↗
PubMed2003

Critical role of the transcriptional repressor neuron-restrictive silencer factor in the specific control of connexin36 in insulin-producing cell lines.

Connexin36 (Cx36) is specifically expressed in neurons and in pancreatic beta-cells. Cx36 functions as a critical regulator of insulin secretion and content in beta-cells. In order to identify the molecular mechanisms that control the beta-cell expression of Cx36, we initiated the characterization of the human 5' regulatory region of the CX36 gene. A 2043-bp fragment of the human CX36 promoter was identified from a human BAC library and fused to a luciferase reporter gene. This promoter region was sufficient to confer specific expression to the reporter gene in insulin-secreting cell lines. Within this 5' regulatory region, a putative neuron-restrictive silencer element conserved between rodent and human species was recognized and binds the neuron-restrictive silencing factor (NRSF/REST). This factor is not expressed in insulin-secreting cells and neurons; it functions as a potent repressor through the recruitment of histone deacetylase to the promoter of neuronal genes. The NRSF-mediated repression of Cx36 in HeLa cells was abolished by trichostatin A, confirming the functional importance of histone deacetylase activity. Ectopic expression, by viral gene transfer, of NRSF/REST in different insulin-secreting beta-cell lines induced a marked reduction in Cx36 mRNA and protein content. Moreover, mutations in the Cx36 neuron-restrictive silencer element relieved the low transcriptional activity of the human CX36 promoter observed in HeLa cells and in INS-1 cells expressing NRSF/REST. The data showed that cx36 gene expression in insulin-producing beta-cell lines is strictly controlled by the transcriptional repressor NRSF/REST indicating that Cx36 participates to the neuronal phenotype of the pancreatic beta-cells.

Adenoviridae↗
PubMed2003

Connexin-36 contributes to control function of insulin-producing cells.

Connexin-36 (Cx36) is a gap junction protein expressed by the insulin-producing beta-cells. We investigated the contribution of this protein in normal beta-cell function by using a viral gene transfer approach to alter Cx36 content in the insulin-producing line of INS-1E cells and rat pancreatic islets. Transcripts for Cx43, Cx45, and Cx36 were detected by reverse transcriptase-PCR in freshly isolated pancreatic islets, whereas only a transcript for Cx36 was detected in INS-1E cells. After infection with a sense viral vector, which induced de novo Cx36 expression in the Cx-defective HeLa cells we used to control the transgene expression, Western blot, immunofluorescence, and freeze-fracture analysis showed a large increase of Cx36 within INS-1E cell membranes. In contrast, after infection with an antisense vector, Cx36 content was decreased by 80%. Glucose-induced insulin release and insulin content were decreased, whether infected INS-1E cells expressed Cx36 levels that were largely higher or lower than those observed in wild-type control cells. In both cases, basal insulin secretion was unaffected. Comparable observations on basal secretion and insulin content were made in freshly isolated rat pancreatic islets. The data indicate that large changes in Cx36 alter insulin content and, at least in INS-1E cells, also affect glucose-induced insulin release.

Adenoviridae↗
PubMed2003

The poplar root transcriptome: analysis of 7000 expressed sequence tags.

To date, most poplar expressed sequence tags (ESTs) are from above-ground tissues such as wood, leaf and buds. Here, we present a large-scale production of ESTs from roots of the hybrid cottonwood, Populus trichocarpaxdeltoides. cDNA libraries were generated from the root system of 2-month-old rooted cuttings, and roots of 2.5-month-old cuttings water-stressed for 19 days. Partial sequences obtained from 7013 clones were assembled into 1347 clusters and 3527 singletons. This set of ESTs represents 4874 unique transcripts expressed in roots. Putative functions could be assigned to 3021 (62%) of the transcripts. A significant portion of the ESTs encode proteins of common metabolic pathways; energy and metabolism represented 5% and 8% of total transcripts, respectively. Of specific interest to root functions are the 6% of ESTs involved in signalling pathways and hormone metabolism, and 4% encoding transporters and channels. The current poplar root ESTs and the aspen root ESTs present in public databases represent 6700 unique transcripts. The Unigene set was selected from the ESTs and used to generate nylon microarrays. Changes in aquaporins and transporter transcripts were then studied during adventitious root development.

Aquaporins↗
PubMed2003

The scaffold protein IB1/JIP-1 is a critical mediator of cytokine-induced apoptosis in pancreatic beta cells.

In insulin-secreting cells, cytokines activate the c-Jun N-terminal kinase (JNK), which contributes to a cell signaling towards apoptosis. The JNK activation requires the presence of the murine scaffold protein JNK-interacting protein 1 (JIP-1) or human Islet-brain 1(IB1), which organizes MLK3, MKK7 and JNK for proper signaling specificity. Here, we used adenovirus-mediated gene transfer to modulate IB1/JIP-1 cellular content in order to investigate the contribution of IB1/JIP-1 to beta-cell survival. Exposure of the insulin-producing cell line INS-1 or isolated rat pancreatic islets to cytokines (interferon-gamma, tumor necrosis factor-alpha and interleukin-1beta) induced a marked reduction of IB1/JIP-1 content and a concomitant increase in JNK activity and apoptosis rate. This JNK-induced pro-apoptotic program was prevented in INS-1 cells by overproducing IB1/JIP-1 and this effect was associated with inhibition of caspase-3 cleavage. Conversely, reducing IB1/JIP-1 content in INS-1 cells and isolated pancreatic islets induced a robust increase in basal and cytokine-stimulated apoptosis. In heterozygous mice carrying a selective disruption of the IB1/JIP-1 gene, the reduction in IB1/JIP-1 content in happloinsufficient isolated pancreatic islets was associated with an increased JNK activity and basal apoptosis. These data demonstrate that modulation of the IB1-JIP-1 content in beta cells is a crucial regulator of JNK signaling pathway and of cytokine-induced apoptosis.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Evaluation of annotation strategies using an entire genome sequence.

MOTIVATION: Genome-wide functional annotation either by manual or automatic means has raised considerable concerns regarding the accuracy of assignments and the reproducibility of methodologies. In addition, a performance evaluation of automated systems that attempt to tackle sequence analyses rapidly and reproducibly is generally missing. In order to quantify the accuracy and reproducibility of function assignments on a genome-wide scale, we have re-annotated the entire genome sequence of Chlamydia trachomatis (serovar D), in a collaborative manner. RESULTS: We have encoded all annotations in a structured format to allow further comparison and data exchange and have used a scale that records the different levels of potential annotation errors according to their propensity to propagate in the database due to transitive function assignments. We conclude that genome annotation may entail a considerable amount of errors, ranging from simple typographical errors to complex sequence analysis problems. The most surprising result of this comparative study is that automatic systems might perform as well as the teams of experts annotating genome sequences.

Amino Acid Sequence↗
PubMed2003

Spinal glia and proinflammatory cytokines mediate mirror-image neuropathic pain in rats.

Mirror-image allodynia is a mysterious phenomenon that occurs in association with many clinical pain syndromes. Allodynia refers to pain in response to light touch/pressure stimuli, which normally are perceived as innocuous. Mirror-image allodynia arises from the healthy body region contralateral to the actual site of trauma/inflammation. Virtually nothing is known about the mechanisms underlying such pain. A recently developed animal model of inflammatory neuropathy reliably produces mirror-image allodynia, thus allowing this pain phenomenon to be analyzed. In this sciatic inflammatory neuropathy (SIN) model, decreased response threshold to tactile stimuli (mechanical allodynia) develops in rats after microinjection of immune activators around one healthy sciatic nerve at mid-thigh level. Low level immune activation produces unilateral allodynia ipsilateral to the site of sciatic inflammation; more intense immune activation produces bilateral (ipsilateral + mirror image) allodynia. The present studies demonstrate that both ipsilateral and mirror-image SIN-induced allodynias are (1) reversed by intrathecal (peri-spinal) delivery of fluorocitrate, a glial metabolic inhibitor; (2) prevented and reversed by intrathecal CNI-1493, an inhibitor of p38 mitogen-activated kinases implicated in proinflammatory cytokine production and signaling; and (3) prevented or reversed by intrathecal proinflammatory cytokine antagonists specific for interleukin-1, tumor necrosis factor, or interleukin-6. Reversal of ipsilateral and mirror-image allodynias was rapid and complete even when SIN was maintained constantly for 2 weeks before proinflammatory cytokine antagonist administration. These results provide the first evidence that ipsilateral and mirror-image inflammatory neuropathy pain are created both acutely and chronically through glial and proinflammatory cytokine actions.

Aconitate Hydratase↗
PubMed2003

The effect of clinical experience on cue trading for the /r-w/ contrast.

Although the ability of clinicians to perceptually process speech sound productions is a key ingredient in the evaluation and remediation of articulatory disorders, very little attention has been given to this important skill. This study explored the potential of a perceptual task, known as cue trading, to assess perceptual skill among students with varying clinical experience. A cue-trading paradigm for the /r-w/ contrast was used in which a temporal-spectral cue on F2 was balanced against a spectral cue on F3. Results indicated a trading relationship for all students. However, students without clinical experience demonstrated reduced sensitivity to the acoustic cues for /w/ and identification functions that were less clearly separated compared to students with clinical experience. Furthermore, the magnitude of the difference between functions (the trading relationship) was significantly smaller for students without practicum experience: They showed weaker phonetic percepts for /r/ and /w/ than did the students with practicum experience. Preliminary results suggest that a task based on cue trading could be useful in assessing perceptual sensitivity to the acoustic cues representative of misarticulated /r/.

Adult↗