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Biomedical subjects

John Bennett

Publications and source records attributed to John Bennett.

At least 19 recordsLinked to original sources
PubMed2007

The rice genome encodes two vacuolar invertases with fructan exohydrolase activity but lacks the related fructan biosynthesis genes of the Pooideae.

* Fructans are believed to contribute to cold and drought tolerance in several plant families (Poaceae, Asparagaceae and Asteraceae), but it is not clear why the ability to accumulate these polymers is found in some genera (e.g. Triticum) but not in others (e.g. Oryza). * As fructan biosynthesis enzymes (FBEs) evolved from vacuolar invertases (VINs), we searched the rice genome sequence for genes related to both FBE and VIN genes of wheat and other members of the Pooideae. We compared them at the levels of exon-intron structure, protein sequence, and the enzymatic properties of recombinant proteins after expression in the yeast Pichia pastoris. * We found that rice possesses two VIN genes (OsVIN1 and OsVIN2) and no FBE genes. FBE genes appear to have arisen in the Pooideae by a series of gene duplications from an ancestor of wheat TaVIN3. Recombinant TaVIN2, OsVIN1 and OsVIN2 behaved as invertases with no FBE activity, but possessed high fructan exohydrolase activity, especially OsVIN1. * The engineering of fructan accumulation into rice for greater stress tolerance could founder on endogenous exohydrolases, but the fact that OsVIN1 transcripts are absent from peduncles of well watered and drought-stressed plants removes one potential obstacle to this endeavour.

Amino Acid Sequence↗
PubMed2006

Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion.

BACKGROUND: Severe, often refractory anemia is characteristic of the myelodysplastic syndrome associated with chromosome 5q31 deletion. We investigated whether lenalidomide (CC5013) could reduce the transfusion requirement and suppress the abnormal 5q31- clone in patients with this disorder. METHODS: One hundred forty-eight patients received 10 mg of lenalidomide for 21 days every 4 weeks or daily. Hematologic, bone marrow, and cytogenetic changes were assessed after 24 weeks of treatment by an intention-to-treat analysis. RESULTS: Among the 148 patients, 112 had a reduced need for transfusions (76%; 95% confidence interval [CI], 68 to 82) and 99 patients (67%; 95% CI, 59 to 74) no longer required transfusions, regardless of the karyotype complexity. The response to lenalidomide was rapid (median time to response, 4.6 weeks; range, 1 to 49) and sustained; the median duration of transfusion independence had not been reached after a median of 104 weeks of follow-up. The maximum hemoglobin concentration reached a median of 13.4 g per deciliter (range, 9.2 to 18.6), with a corresponding median rise of 5.4 g per deciliter (range, 1.1 to 11.4), as compared with the baseline nadir value before transfusion. Among 85 patients who could be evaluated, 62 had cytogenetic improvement, and 38 of the 62 had a complete cytogenetic remission. There was complete resolution of cytologic abnormalities in 38 of 106 patients whose serial bone marrow samples could be evaluated. Moderate-to-severe neutropenia (in 55% of patients) and thrombocytopenia (in 44%) were the most common reasons for interrupting treatment or adjusting the dose of lenalidomide. CONCLUSIONS: Lenalidomide can reduce transfusion requirements and reverse cytologic and cytogenetic abnormalities in patients who have the myelodysplastic syndrome with the 5q31 deletion. (ClinicalTrials.gov number, NCT00065156 [ClinicalTrials.gov].).

Adult↗
PubMed2006

Comparative transcriptome analyses of barley and rice under salt stress.

Although barley and rice belong to the same family Poaceae, they differ in their ability to tolerate salt stress. In an attempt to understand the molecular bases of such differences, we compared changes in transcriptome between barley and rice in response to salt stress using barley cDNA microarrays. At 1 and 24 h after salt stress, many genes were up-regulated in barley, but not in rice. Leaf water potential declined in the first 10 h of stress in both species, but recovered in the period 24-48 h only in barley. In addition, we found that barley partitioned Na+ to the roots and away from the shoots more efficiently than rice. These differences in physiological responses were correlated with the differences in the steady-state abundance of transcripts for the genes related to adaptive functions. Transcripts for plasma membrane protein 3 and inorganic pyrophosphatase were up-regulated in both species, but only transiently in rice. This indicates that adaptive mechanisms for regulating ion homeostasis are partly conserved in the two species, but it seems that rice cannot sustain cellular ion homeostasis for a long time like barley. These results imply that genetic modification of regulatory controls of early salt-responsive genes might lead to development of the salt tolerance trait in rice.

Gene Expression Regulation, Plant↗
PubMed2006

Phase II trial of subcutaneous recombinant human interleukin 11 with subcutaneous recombinant human granulocyte-macrophage colony stimulating factor in patients with acute myeloid leukemia (AML) receiving high-dose cytarabine during induction: ECOG 3997.

Randomized trials of substituting high-dose cytarabine (HiDAC) for standard dose cytarabine (SDAC) during induction therapy for newly diagnosed AML have not demonstrated an improvement in the complete remission (CR) rate. Phase II trials of the scheduled administration of HiDAC after SDAC suggest an improved outcome. The hematological complications of intensification are considerable. GM-CSF after chemotherapy improved the survival of older patients in a randomized trial. Recombinant human interleukin 11, a thrombopoietic cytokine, reduced the incidence of chemotherapy-induced thrombocytopenia in patients with solid tumors. Therefore, 34 patients were treated, with newly diagnosed AML less than 56 years of age, with daunorubicin 45 mg/m2 on days 1-3, cytarabine 100mg/m2 days 1-7 and cytarabine 2g/m2 for 12 h on days 8-10 (7+3+3). rhIL-11 (50 microg/kg/day,) and GM-CSF (250 microg/kg/day) were administered subcutaneously from day 11 until recovery. The complete remission rate was 59% (90% C.I. 43-73%). The median time to recovery of neutrophils to >500 and platelets to > or =20,000 microl(-1) was 27 days (95% C.I. 27-30 days) and 25 days (95% C.I. 24-29 days), respectively. The trial does not confirm the high CR rate observed in phase II trials, despite optimal supportive care.

Acute Disease↗
PubMed2006

Prospective trial of laparoscopic nissen fundoplication versus proton pump inhibitor therapy for gastroesophageal reflux disease: Seven-year follow-up.

Laparoscopic Nissen fundoplication and proton pump inhibitor (PPI) therapy are both established treatments for gastroesophageal reflux disease (GERD). We have performed a prospective randomized study comparing these two treatments and now have long-term follow-up data. Between July 1997 and August 2001, 183 patients in Norwich took part in a randomized controlled trial comparing laparoscopic Nissen fundoplication and PPI therapy for the treatment of GERD. In October 2005, patients were followed up and asked to complete a reflux symptom questionnaire. Ninety-one patients were randomized to have surgery and 92 to have optimized PPI therapy. After 12 months, those who had been randomized to PPI were offered the opportunity to have surgery. Fifty-four patients went on to have antireflux surgery; the remaining 38 did not. In all three groups, there was a significant improvement in symptom score after the initial 12 months (P < 0.01; Mann-Whitney U test). However, those who later had surgery despite having had optimal PPI treatment beforehand experienced further symptomatic improvement (P < 0.01) at long-term follow-up (median 6.9 years, range, 4.3-8.3). Both optimal PPI therapy and laparoscopic Nissen fundoplication are effective treatments for GERD. However, surgery offers additional benefit for those who have only partial symptomatic relief whilst on PPIs.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed2006

Is there a role for serum endothelin in predicting the severity of acute pancreatitis?

BACKGROUND: Acute pancreatitis remains a common presentation to acute surgical units and carries significant morbidity and mortality. The progression of the disease to necrotizing pancreatitis and multi-organ dysfunction syndrome (MODS) is associated with a very poor clinical outcome, and persistently high mortality. Increases in serum endothelin (ET) have been seen in animal models of acute pancreatitis and this study aims to investigate whether there is a change in serum ET-1 in patients with acute pancreatitis and whether any such change is linked to disease severity. METHODS: All patients admitted with acute pancreatitis were prospectively recruited from the emergency admissions at the Norfolk and Norwich University Hospital. Serum ET levels were determined on admission, at 24 hours and 5 days post admission. Healthy adult controls were recruited from dermatology outpatients. RESULTS: A total of 21 patients joined the trial after giving informed consent. There were 3 men and 18 women with a median age of 65 years (range 26-87 years). Serum ET levels were significantly higher in acute pancreatitis patients than in normal controls (P<0.05). An association was seen between persistently raised serum ET levels and progression to MODS. CONCLUSIONS: The study does demonstrate a correlation between the circulating levels of ET and acute pancreatitis in humans, although it does not elicit its involvement in the pathogenesis of the disease. The observation that a persistently high level of circulating ET-1 is associated with progression to MODS may indicate a role for ET in the monitoring of acute pancreatitis patients for recovery or progression to MODS.

Acute Disease↗
PubMed2005

The rice nucellin gene ortholog OsAsp1 encodes an active aspartic protease without a plant-specific insert and is strongly expressed in early embryo.

The barley nucellin gene was reported to be nucellus specific in its expression and was hypothesized to play a role in the programmed cell death of the nucellus as an aspartic protease. Here we provide direct evidence that the rice ortholog encodes an active aspartic protease, but we prefer the name aspartic protease1 (OsAsp1) to nucellin after a detailed analysis of its expression pattern in rice and barley. Northern blots, RT-PCR and RNA in situ hybridization showed that OsAsp1 is expressed most abundantly in zygotic embryos 1-2 d after fertilization. It is also expressed in pollen, nucellus, ovary wall, shoot and root meristem, coleoptiles of immature seeds, and somatic embryos. A parallel study in barley showed that the barley nucellin gene was expressed not only in the nucellus but also strongly in embryos. Recombinant protein proOsAsp1 expressed in the bacterium Escherichia coli refolded and autolysed at acidic pH 3.5 in vitro, and the mature peptide displayed protease activity. Nucellin has three close homologs in rice on chromosomes 11 and 12 and in Arabidopsis on chromosomes 1 and 4. They lack the plant-specific insert that distinguishes the typical plant aspartic protease from aspartic proteases of other organisms. They constitute a new class of aspartic protease that is present in both monocots and dicots but whose function remains to be explored further.

Amino Acid Sequence↗
PubMed2005

Structure, evolution, and expression of the two invertase gene families of rice.

Invertases catalyze the irreversible hydrolysis of sucrose to glucose and fructose. Plants contain two unrelated families of these enzymes: acid forms that derive from periplasmic invertases of eubacteria and are found in cell wall and vacuole, and neutral/alkaline forms evolved from the cytosolic invertases of cyanobacteria. Genomes of rice (Oryza sativa) and thale cress (Arabidopsis thaliana) contain multiple genes encoding these two families. Here for rice we identify the member genes of a cell-wall group (designated OsCIN1-9), a vacuolar group (OsVIN1-2), and two ancient neutral/alkaline groups: alpha (OsNIN1-4) and beta (OsNIN5-8). In Arabidopsis these groups contain six, two, four and five members, respectively. It is believed that the vacuolar group evolved from the cell-wall group. We provide evidence that the N-terminal signal peptide that directs cell-wall invertases co-translationally into the endoplasmic reticulum for secretion was replaced in the vacuolar group by a sequence similar to the complex N-terminal motif that targets alkaline phosphatase post-translationally to the vacuolar membrane of yeast. Since the last common ancestor of Arabidopsis and rice, the two invertase families evolved equally rapidly via gene duplication and gene loss, but the acid invertase family underwent approximately 10 events of intron loss compared with a single event of intron gain in the neutral/alkaline invertase family. Transcripts were detected for all rice invertase genes except OsCIN9. The acid invertase genes showed greater spatial and temporal diversity of expression than the neutral/alkaline genes.

Amino Acid Sequence↗
PubMed2005

Pregnancy after uterine artery embolization for leiomyomata: the Ontario multicenter trial.

OBJECTIVE: To report on pregnancies and deliveries occurring in a large cohort of women who underwent uterine artery embolization instead of surgery for symptomatic leiomyomata. METHODS: A total of 555 women underwent uterine embolization in a multicenter clinical trial. The primary embolic agent was 355-500 microm polyvinyl alcohol particles with treatment end-point as bilateral stasis in the uterine arteries. Women desiring pregnancy were informed of the uncertain effect of embolization on fertility and pregnancy. Average age at embolization was 43 years (range 18-59 years). Thirty-one percent were younger than age 40 years. Women were followed up prospectively by telephone, and obstetric records of the women who conceived were reviewed. RESULTS: Twenty-one women of average age 34 years (range 27-42 years) conceived, (3 of these twice), and 13 women were nulliparous. Twenty-three of the 24 pregnancies were conceived spontaneously (1 woman had in vitro fertilization). There were 4 spontaneous abortions (16.7%, 95% confidence interval 5.4-41.9%) and 2 elective pregnancy terminations. Fourteen of the 18 live births were full term and 4 were preterm. There were 9 vaginal deliveries and 9 cesarean deliveries, 4 of which were elective. Abnormal placentation occurred in 3 cases, all nulliparas (12.5% 95% confidence interval 3.1-36.3%). Two cases developed placenta previa (1 had a clinical partial accreta) and the third developed a placenta membranacea with accreta resulting in cesarean hysterectomy. Three postpartum hemorrhages all secondary to placental abnormalities occurred. Four newborns were small for gestational age (< or = 5th percentile); 2 of these pregnancies were complicated by gestational hypertension. CONCLUSION: Women are able to achieve pregnancies after uterine artery embolization, and most resulted in term deliveries and appropriately grown newborns. Close monitoring of placental status, however, is recommended.

Adolescent↗
PubMed2004

Osmotic stress in barley regulates expression of a different set of genes than salt stress does.

Under high salt conditions, plant growth is severely inhibited due to both osmotic and ionic stresses. In an effort to dissect genes and pathways that respond to changes in osmotic potential under salt stress, the expression patterns were compared of 460 non-redundant salt-responsive genes in barley during the initial phase under osmotic versus salt stress using cDNA microarrays with northern blot and real-time RT-PCR analyses. Out of 52 genes that were differentially expressed under osmotic stress, 11, such as the up-regulated genes for pyrroline-5-carboxylate synthetase, betaine aldehyde dehydrogenase 2, plasma membrane protein 3, and the down-regulated genes for water channel 2, heat shock protein 70, and phospholipase C, were regulated in a virtually identical manner under salt stress. These genes were involved in a wide range of metabolic and signalling pathways suggesting that, during the initial phase under salt stress, several of the cellular responses are mediated by changes in osmotic potential.

Enzymes↗
PubMed2004

The relationship of coexisting extranidal aneurysms to intracranial hemorrhage in patients harboring brain arteriovenous malformations.

OBJECTIVE: We hypothesized that coexisting extranidal arterial aneurysms (EAs) would be associated with an increased risk of incident intracranial hemorrhage (ICH) from brain arteriovenous malformation (BAVM) rupture. METHODS: To determine the presence of EAs and compare the sources and locations of ICH, we retrospectively reviewed the computed tomographic, magnetic resonance imaging, and angiographic studies of patients who presented between 1990 and 1999. EAs were defined as saccular luminal dilations of the parent feeding vessels that were proximally flow-related (i.e., at the circle of Willis), distally flow-related (i.e., distal to the circle of Willis), and unrelated (i.e., in circulation distant from the BAVM). RESULTS: Of 314 BAVM patients, 138 (44%) presented with ICH. In the ICH group, 22 patients (16%) had aneurysmal ICH, 100 (72%) had BAVM ICH, and 16 (12%) had ICH from an indeterminate source. There were 61 patients with 1 or more EAs (29 patients with 42 flow-related proximal aneurysms, 39 patients with 48 flow-related distal aneurysms, and 10 patients with 20 unrelated aneurysms). Multivariate regression analysis revealed that ICH patients were more likely than non-ICH patients to have a coexisting EA (35 versus 13%; odds ratio = 3.9; 95% confidence interval, 2.1-7.5; P < 0.001), but this effect was not present when only BAVM-related ICH was considered (odds ratio = 0.3; 95% confidence interval, 0.1-1.0; P = 0.052). Other independent predictors of ICH included small AVM size (<3 cm), exclusively deep venous drainage, and the presence of an intranidal aneurysm. CONCLUSION: Clinical presentation with ICH was associated with EA aneurysms, but the association was due to aneurysmal rather than BAVM rupture, suggesting that EAs and the BAVM ICH risks may be considered as separate entities in future studies.

Adolescent↗
PubMed2003

The Ontario Uterine Fibroid Embolization Trial. Part 2. Uterine fibroid reduction and symptom relief after uterine artery embolization for fibroids.

OBJECTIVE: To evaluate fibroid uterine volume reduction, symptom relief, and patient satisfaction with uterine artery embolization (UAE) for symptomatic fibroids. DESIGN: Multicenter, prospective, single-arm clinical treatment trial. SETTING: Eight Ontario university and community hospitals. Five hundred thirty-eight patients undergoing bilateral UAE. INTERVENTION(S): Bilateral UAE performed with polyvinyl alcohol particles sized 355-500 microm. MAIN OUTCOME MEASURE(S): Three-month follow-up evaluations including fibroid uterine volume reductions, patient reported symptom improvement (7-point scale), symptom life-impact (10-point scale) reduction, and treatment satisfaction (6-point scale). RESULT(S): Median uterine and dominant fibroid volume reductions were 35% and 42%, respectively. Significant improvements were reported for menorrhagia (83%), dysmenorrhea (77%), and urinary frequency/urgency (86%). Mean menstrual duration was significantly reduced after UAE (7.6 to 5.4 days). Improvements in menorrhagia were unrelated to pre-UAE uterine size or post-UAE uterine volume reduction. Amenorrhea occurring after the procedure was highly age dependent, ranging from 3% (1%-7%) in women under age 40 to 41% (26%-58%) in women age 50 or older. Median fibroid life-impact scores were significantly reduced after UAE (8.0 to 3.0). The majority (91%) expressed satisfaction with UAE treatment. CONCLUSION(S): UAE reduced fibroid uterine volume and provided significant relief of menorrhagia that was unrelated to initial fibroid uterine size or volume reduction. Patient satisfaction with short-term UAE treatment outcomes was high.

Adult↗
PubMed2003

Hysterectomy for complications after uterine artery embolization for leiomyoma: results of a Canadian multicenter clinical trial.

STUDY OBJECTIVE: To determine the complication-related hysterectomy rate after uterine artery embolization (UAE) for symptomatic uterine leiomyomas. DESIGN: Prospective, multicenter, nonrandomized, single-arm clinical trial (Canadian Task Force classification II-2). SETTING: Eight Ontario University-affiliated teaching and community hospitals. PATIENTS: Five hundred fifty-five women. INTERVENTION: Polyvinyl alcohol particles were delivered through a catheter into uterine arteries under fluoroscopic guidance. MEASUREMENTS AND MAIN RESULTS: Prospective follow-up investigations consisted of telephone interviews, ultrasound examinations, and reviews of pathology and surgery reports. Median follow-up was 8.1 months, and all but five patients had complete 3-month follow-up. At 3 months, eight women (1.5%, 95% CI 0.6-2.8) underwent complication-related hysterectomy. Half of the surgeries were performed at institutions other than where UAE had been performed. Indications for hysterectomies were infections (2), postembolization pain (4), vaginal bleeding (1), and prolapsed leiomyoma (1). CONCLUSIONS: The 3-month complication rate resulting in hysterectomy after UAE in a large cohort of women was low. Hysterectomy after UAE is an important measure of safety and a key outcome measure of this new therapy.

Adult↗
PubMed2003

Technical results and effects of operator experience on uterine artery embolization for fibroids: the Ontario Uterine Fibroid Embolization Trial.

PURPOSE: To document the technical results and spectrum of practice of uterine artery embolization (UAE) for fibroids in the health care setting in Canada. The effects of interventional radiologist's (IR's) experience with UAE on procedure and fluoroscopy time were also investigated. MATERIALS AND METHODS: The study involved a multicenter prospective single-arm clinical treatment trial and included the practices of 11 IRs at eight university-affiliated teaching and community hospitals. Vascular access with percutaneous femoral artery approach was followed by transcatheter delivery of polyvinyl alcohol (PVA) particles into uterine arteries with fluoroscopic guidance. Technical success, complications, procedural time, fluoroscopy time, and effects of operator experience were outcomes analyzed. RESULTS: Between November 1998 and November 2000, 570 embolization procedures were performed in 555 patients. UAE was bilaterally successful in 97% (95% CI: 95%-98%). Variant anatomy was the most common reason for failure to embolize bilaterally. The procedural complication rate was 5.3% (95% CI: 3.6%-7.4%). Of the 30 events, three involved major complications (one seizure and two allergic reactions) that resulted in additional care or extended hospital stay. Procedure time and fluoroscopy time averaged 61 minutes (95% CI; 58-63 minutes) and 18.9 minutes (95% CI; 18-19.8) and varied significantly among IRs (P <.001; P <.001). The average 27% reduction in procedure time (20 minutes; P <.001) and 24% reduction in fluoroscopy time (5.1 minutes; P <.001) with increasing UAE experience were significant. CONCLUSIONS: A high level of technical success with few complications was obtained with a variety of operators in diverse practice settings. Increased experience in UAE significantly reduced procedure and fluoroscopy time.

Adolescent↗
PubMed2003

Tolerance, hospital stay, and recovery after uterine artery embolization for fibroids: the Ontario Uterine Fibroid Embolization Trial.

PURPOSE: Uterine artery embolization (UAE) is gaining popularity as an alternative to hysterectomy for the treatment of fibroids. Although minimally invasive treatments such as UAE offer the potential of fewer complications, shorter hospital stay, and quicker recovery than surgery, there have been few published data on tolerance and recovery in patients undergoing UAE. MATERIALS AND METHODS: This was a multicenter prospective single-arm clinical treatment trial involving the practices of 11 interventional radiologists in eight Ontario university-affiliated and community hospitals. Between November 1998 and November 2000, 555 women underwent UAE for symptomatic uterine fibroids. Follow-up included ultrasound examinations and telephone interviews. UAE was performed under conscious sedation. Polyvinyl alcohol particles (355-500 micro m) were the primary embolic agent, and the procedural endpoint involved stasis in the uterine arteries. Pain protocols included antiinflammatory medications and narcotics and a planned overnight hospital admission. Tolerance and recovery were measured by patient-reported pain intensity (10-point numeric rating and five-point descriptor scale), hospital length of stay (LOS), and time until return to work. RESULTS: Intraprocedural pain was reported by 30% of patients and postprocedural pain was reported by 92% of patients (mean pain rating +/- SD, 7.0 +/- 2.47). The mean hospital LOS was 1.3 nights. Postprocedural pain was the most common indication for an LOS greater than 1 night (18%) or 2 nights (5%). Return visits to the hospital (10%) and readmissions (3%) were primarily for pain. The overall postprocedural complication rate was 8.0% (95% CI: 5.9%-10.6%). Of the 44 complications, 32 (73%) were pain-related. The mean recovery time after UAE was 13.1 days (median, 10.0 d). CONCLUSION: The majority of patients had a 1-night LOS after UAE and recovered within 2 weeks. Postprocedural pain varied considerably and was the major indication for extended hospital stay and recovery.

Adolescent↗