Biomedical subjects
Publications and source records attributed to J Leung.
A 22 year old woman, who at the age of 6 years had prophylactic cranial irradiation for acute lymphoblastic leukaemia, presented with both astrocytoma of the brain and breast carcinoma. The link between the two solid tumours and previous cranial irradiation is discussed.
BACKGROUND: Cholangiocarcinoma of the biliary tract is a rare tumour which has been treated with surgery, radiotherapy, chemotherapy, bypass procedures and stenting. Surgery remains the only curative treatment for these tumours, but a large proportion are unresectable. Intraluminal brachytherapy has been reported as an effective treatment for localized cholangiocarcinoma of the biliary tract. The purpose of our study was to analyse the survival of patients with biliary tract carcinoma treated with iridium-192 brachytherapy. METHODS: A retrospective review of patients treated at Peter MacCallum was undertaken. From 1989 to 1994, 16 patients underwent brachytherapy via transhepatic approach for cholangiocarcinoma. There were 12 male and four female patients. The median age was 65 (range 40-83). All patients had cholangiocarcinoma. Prior treatment included complete resection in three, partial resection in one, bypass procedures in eight, endoscopic stents in five and external biliary drainage in 15 of the 16 patients. One patient had received external beam irradiation. RESULTS: The median survival was 23 months and 61% survived 1 year. The most common acute complication was cholangitis seen in four patients and the most common late complications were duodenal ulcer seen in two patients and cholangitis seen in two patients. CONCLUSIONS: We conclude that iridium-192 brachytherapy is a safe effective treatment for biliary tract carcinoma but a comparison between surgery and stenting would be of value. However, the cost of brachytherapy is not cheap and its value in this regard should be carefully analysed.
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Abscisic acid (ABA) modulates the activities of three major classes of ion channels--inward- and outward-rectifying K+ channels (IK,in and IK,out, respectively) and anion channels--at the guard-cell plasma membrane to achieve a net efflux of osmotica and stomatal closure. Disruption of ABA sensitivity in wilty abi1-1 mutants of Arabidopsis and evidence that this gene encodes a protein phosphatase suggest that protein (de)-phosphorylation contributes to guard-cell transport control by ABA. To pinpoint the role of ABI1, the abi1-1 dominant mutant allele was stably transformed into Nicotiana benthamiana and its influence on IK,in, IK,out, and the anion channels was monitored in guard cells under voltage clamp. Compared with guard cells from wild-type and vector-transformed control plants, expression of the abi1-1 gene was associated with 2- to 6-fold reductions in IK,out and an insensitivity of both IK,in and IK,out to 20 microM ABA. In contrast, no differences between control and abi1-1 transgenic plants were observed in the anion current or its response to ABA. Parallel measurements of intracellular pH (pHi) using the fluorescent dye 2',7'-bis(2-carboxyethyl)-5-(and -6)-carboxyfluorescein (BCECF) in every case showed a 0.15- to 0.2-pH-unit alkalinization in ABA, demonstrating that the transgene was without effect on the pHi signal that mediates in ABA-evoked K+ channel control. In guard cells from the abi1-1 transformants, normal sensitivity of both K+ channels to and stomatal closure in ABA was recovered in the presence of 100 microM H7 and 0.5 microM staurosporine, both broad-range protein kinase antagonists. These results demonstrate an aberrant K+ channel behavior--including channel insensitivity to ABA-dependent alkalinization of pHi--as a major consequence of abi1-1 action and implicate AB11 as part of a phosphatase/kinase pathway that modulates the sensitivity of guard-cell K+ channels to ABA-evoked signal cascades.
Long term survival [> 3 years] has been documented in patients treated with radiotherapy for bronchial stump recurrence following surgery for non-small cell lung cancer [NSCLC]. In this retrospective review of 45 patients with locoregional recurrence of NSCLC we measured survival following radiotherapy according to site of recurrence [bronchial stump or elsewhere] and treatment intent. Estimated median survival for all 45 patients from presentation was 10 months. Ten patients whose disease was confined to the bronchial stump had an estimated median survival of 15 months compared with 9 months for patients with recurrence elsewhere [P = 0.4]. Seventeen patients treated with radical intent [dose > 50 Gy] had an estimated median survival of 16 months, with an estimated 41% alive at two years. The overall survival of patients treated with radical intent is not dissimilar to that of a group of our patients treated similarly with primary radiotherapy for inoperable NSCLC. We conclude that a policy of high dose radiotherapy may be justified in selected patients with recurrent NSCLC.
BACKGROUND: Dexmedetomidine, a highly selective alpha 2-adrenergic agonist, increases perioperative hemodynamic stability in healthy patients but decreases blood pressure and heart rate. The goal of this study was to evaluate, in a preliminary manner, the hemodynamic effects of perioperatively administered dexmedetomidine in surgical patients at high risk for coronary artery disease. METHODS: Twenty-four vascular surgery patients received a continuous infusion of placebo or one of three doses of dexmedetomidine, targeting plasma concentrations of 0.15 ng/ml (low dose), 0.30 ng/ml (medium dose), or 0.45 ng/ml (high dose) from 1 h before induction of anesthesia until 48 h postoperatively. All patients received standardized anesthesia and hemodynamic management. Blood pressure, heart rate, and Holter ECG were monitored; additional monitoring included continuous 12-lead ECG preoperatively, anesthetic concentrations and myocardial wall motion (echocardiography) intraoperatively, and cardiac enzymes postoperatively. RESULTS: Preoperatively, there was a decrease in heart rate (low dose 11%, medium dose 5%, high dose 20%) and systolic blood pressure (low dose 3%, medium dose 12%, high dose 20%) in patients receiving dexmedetomidine. Intraoperatively, dexmedetomidine groups required more vasoactive medications to maintain hemodynamics within predetermined limits. Postoperatively, demedetomidine groups had less tachycardia (minutes/monitored hours) than the placebo group (placebo 23 min/h; low dose 9 min/h, P = 0.006; medium dose 0.5 min/h, P = 0.004; high dose 2.3 min/h, P = 0.004). Bradycardia was rare in all groups. There were no myocardial infarctions or discernible trends in the laboratory results. CONCLUSIONS: Infusion of dexmedetomidine up to a targeted plasma concentration of 0.45 ng/ml appears to benefit perioperative hemodynamic management of surgical patients undergoing vascular surgery but required greater intraoperative pharmacologic intervention to support blood pressure and heart rate.
Plant disease resistance genes function is highly specific pathogen recognition pathways. PRS2 is a resistance gene of Arabidopsis thaliana that confers resistance against Pseudomonas syringae bacteria that express avirulence gene avrRpt2. RPS2 was isolated by the use of a positional cloning strategy. The derived amino acid sequence of RPS2 contains leucine-rich repeat, membrane-spanning, leucine zipper, and P loop domains. The function of the RPS2 gene product in defense signal transduction is postulated to involve nucleotide triphosphate binding and protein-protein interactions and may also involve the reception of an elicitor produced by the avirulent pathogen.
The Arabidopsis ABI1 locus is essential for a wide spectrum of abscisic acid (ABA) responses throughout plant development. Here, ABI1 was shown to regulate stomatal aperture in leaves and mitotic activity in root meristems. The ABI1 gene was cloned and predicted to encode a signaling protein. Although its carboxyl-terminal domain is related to serine-threonine phosphatase 2C, the ABI1 protein has a unique amino-terminal extension containing an EF hand calcium-binding site. These results suggest that the ABI1 protein is a Ca(2+)-modulated phosphatase and functions to integrate ABA and Ca2+ signals with phosphorylation-dependent response pathways.
Based on low-stringency genomic Southern analysis, the recently described human breast basic conserved 1 (BBC1) gene has been proposed to be conserved throughout Eukaryota [Adams et al., Hum. Mol. Genet. 1 (1992) 91-96]. We have isolated and characterized a cDNA clone (AtBBC1) which corresponds to a BBC1 homologue from the model plant species, Arabidopsis thaliana. Furthermore, upon Northern analysis, the AtBBC1 probe detects related transcripts in various dicotyledenous and monocotyledonous plant species, indicating that actively transcribed BBC1-related genes are widespread in the plant kingdom. BBC1 has been shown to be expressed in all mammalian tissues examined [Adams et al., Hum. Mol. Genet. 1 (1992) 91-96]; similarly, here the AtBBC1 transcript has been detected in a variety of A. thaliana organs. In addition, the abundance of the AtBBC1 mRNA is developmentally regulated during the course of fruit maturation, and is positively correlated with active cell division.
Abscisic acid (ABA) participates in the control of diverse physiological processes. The characterization of deficient mutants has clarified the ABA biosynthetic pathway in higher plants. Deficient mutants also lead to a revaluation of the extent of ABA action during seed development and in the response of vegetative tissues to environmental stress. Although ABA receptor(s) have not yet been identified, considerable progress has been recently made in the characterization of more downstream elements of the ABA regulatory network. ABA controls stomatal aperture by rapidly regulating identified ion transporters in guard cells, and the details of the underlying signalling pathways start to emerge. ABA actions in other cell types involve modifications of gene expression. The promoter analysis of ABA-responsive genes has revealed a diversity of cis-acting elements and a few associated trans-acting factors have been isolated. Finally, characterization of mutants defective in ABA responsiveness, and molecular cloning of the corresponding loci, has proven to be a powerful approach to dissect the molecular nature of ABA signalling cascades.
A limited number of rare missense mutations in exons 16 and 17 of the amyloid precursor protein (APP) gene have been reported. They are associated with a variety of phenotypes including cerebral haemorrhage, multi-infarct dementia and Alzheimer's disease. We recently reported an alanine to valine mutation in codon 713 in a single case of chronic familial schizophrenia with cognitive deficits. Using denaturing gradient gel electrophoresis (DGGE) we have screened a cohort of 250 chronic schizophrenics for further mutations of exons 7, 16 and 17. None were found. Nevertheless recent evidence suggests that the 713 mutation is indeed pathogenic for the clinical phenotype observed; the mechanisms involved are outlined.
There is increasing evidence that leukocyte-endothelial adhesion molecules are important in inflammatory airway disease because of their involvement in the primary steps of entrapment and migration of leukocytes to the site of inflammation. Recently, circulating forms of these adhesion molecules have been described, although their origin, fate, and function are still unknown. We have used an antigen capture ELISA to measure the concentrations of circulating intercellular adhesion molecule-1 (cICAM-1), E-selectin (cE-selectin), and vascular cell adhesion molecule-1 (cVCAM-1) in the peripheral blood of 13 atopic and 16 non-atopic normal subjects, 29 patients with stable asthma, and inpatients with acute asthma on Day 1 (n = 38), Day 3 (n = 29), and Day 28 (n = 13) of an asthmatic episode. Circulating ICAM-1 and E-selectin levels were significantly raised in acute asthma on all three study days when compared with those observed in stable asthma, atopic normal, or nonatopic normal volunteers with no significant differences among the latter three groups. Circulating VCAM-1 was not significantly increased in any of the groups studied. There were no correlations among the concentrations of these three circulating adhesion molecules. The elevated concentrations of cICAM-1 and cE-selectin in acute asthma may reflect the extensive inflammatory response occurring in the airways during acute exacerbations of the disease with airway obstruction. It is possible that the cytokine and mediator profiles in acute asthma lead to the preferential synthesis and expression of these two circulating adhesion molecules in comparison with cVCAM-1.
OBJECTIVE: Patients in the intensive care unit are at increased risk of developing acute calculous and acalculous cholecystitis. Diagnosis based on clinical and sonographic findings is difficult in the presence of severe intercurrent disease. We did a study to evaluate the efficacy of percutaneous cholecystostomy as a diagnostic and therapeutic maneuver in 82 patients in the intensive care unit who had persistent unexplained sepsis. SUBJECTS AND METHODS: Eighty-two patients with unexplained sepsis underwent percutaneous cholecystostomy after a complete clinical, laboratory, and radiologic search showed no source of sepsis outside the gallbladder. All patients were febrile, 65 had an increased WBC count, and 37 were receiving vasopressors. Sonographic abnormalities included a distended gallbladder (71 patients), sludge (63 patients), gallstones (26 patients), wall thickening (34 patients), pericholecystic fluid (25 patients), and Murphy's sign (19 patients). RESULTS: Sonographic findings were not helpful in predicting response to percutaneous cholecystostomy. A dramatic improvement in clinical condition was observed in 48 patients (59%) within 48 hr. Signs of improvement included defervescence (41 patients), discontinuance of vasopressors (26 patients), and reduction in WBC count (33 patients). No clinical response was observed in 34 patients (41%). No complications related to catheter insertion occurred. CONCLUSION: Because acute cholecystitis is difficult to diagnose in patients in the intensive care unit, percutaneous cholecystostomy serves as a diagnostic and therapeutic maneuver in patients with unexplained sepsis when the gallbladder is the suspected source of sepsis. A response rate to percutaneous cholecystostomy of 59% was seen in this study. The gallbladder was cleared as a potential source of sepsis in the remaining patients.
F9 embryonic carcinoma cells are a multipotent cell line which can be induced to differentiate into cells resembling the visceral endoderm, an extraembryonic absorptive epithelium characterized by apical microvilli. We have examined the role of villin, fimbrin, and myosin I, the major actin-binding proteins in the intestinal and visceral yolk sac microvilli, in the development of epithelial polarity and the assembly of the microvillus cytoskeleton in differentiating F9 cells. By immunoblot analysis villin was first detected at 4 days of differentiation. Confocal microscopy localized villin at Day 4 to the apical surface and by Day 6 to the basolateral surfaces as well. In comparison, fimbrin and myosin I were both present in undifferentiated F9 cells and became associated with the apical surface after villin during differentiation to visceral endoderm. The accumulation of villin, fimbrin, and myosin I at the apical surface in differentiating F9 cells correlated with the appearance of microvilli containing organized actin filament bundles. Two mouse villin cDNAs were isolated and characterized to examine villin expression during F9 differentiation. Mouse villin was encoded by two transcripts (3.8 and 3.4 kb) which differ in their 3'-noncoding region. Both villin mRNAs were first detected by Day 4 of differentiation and their appearance coincided with expression of the visceral endoderm marker alpha-fetoprotein. The pattern of expression and order of accumulation of villin, fimbrin, and myosin I in differentiating F9 cells are common to developing gut and yolk sac epithelium. This suggests that microvillus assembly is directed by a sequence of temporally and spatially regulated localizations of these actin-binding proteins.
Variant tRNA genes have been widely observed in multicellular eukaryotes. Recent biochemical studies have shown that some of them are expressed in a tissue- or a stage-specific manner. These findings would thus imply that certain modified tRNAs may be crucial for the development of the organism. Using Drosophila melanogaster as a model, we have taken a combined genetic and molecular approach to examine critically the possible biological functions of tRNA(4, 7Ser) genes. We showed that at least 50% of the total templates can be deleted from the genome without inducing abnormal phenotypes such as Minute, or a decrease in viability. In addition, two of the tRNASer variant genes that are unique in sequence are also completely dispensable. This strongly implies that even though they may be expressed in vivo, they play no essential role in the development of the fruitfly. By comparison with some of the corresponding tRNA genes in another sibling species, Drosophila erecta, our results suggest strongly that the variants are products non-reciprocal exchanges among the tRNA(4, 7Ser), genes. Such intergenic recombination events may have a major influence in the concerted evolution of the two gene families.
The dual MAS1'-2' promoter regulating two divergently transcribed mannopine synthase genes has been widely employed in plant expression vectors. As part of an effort towards its rational design as a genetic engineering tool, we have undertaken a functional analysis of the promoter by deletion mutagenesis and by the use of hybrid promoter constructs. Our results indicate that the central region of the intergenic promoter is composed of at least four domains. Three of these contain complementary sequences, which can potentially hybridize to form alternative palindromic structures. These three domains can function cooperatively, and in an orientation-independent manner, in imparting a sevenfold higher expression level at the 2' end relative to the corresponding 1'. The remaining domain is characterized by tracts of repeated A/T-rich elements, and appears to confer the weak activity at the MAS1' promoter end. However, even though this A/T-rich DNA segment is functional, our deletion analysis provided strong evidence that it is completely dispensable for wild-type promoter activity. In addition, the relative distances between these enhancer domains and the 1'-2' TATA-proximal regions can have a pronounced influence on the level of expression in both directions. In young tobacco seedlings, the two promoter ends are expressed in similar, if not identical, tissues in the aerial parts of the plants, but major differences can be observed in roots. Transient expression assays using hybrid promoter constructs showed that cis-elements that can respond to auxin induction signals are redundant in nature, in that they are dispersed throughout the promoter and showed no obvious consensus sequence.
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The paper describes thickening of the wall of the common bile duct in acute pyogenic cholangitis demonstrated by ultrasound. The abnormality appears as a hypoechoic stripe lying internal to the echogenic line of the normal common bile duct. The clinical features of acute cholangitis may be atypical and this new sign should be of value in these difficult cases.