Biomedical subjects

Adrian Lee

Publications and source records attributed to Adrian Lee.

6 recordsLinked to original sources

PubMed2003

Distinct gene expression profiles characterize the histopathological stages of disease in Helicobacter-induced mucosa-associated lymphoid tissue lymphoma.

Long-term colonization of humans with Helicobacter pylori can cause the development of gastric B cell mucosa-associated lymphoid tissue lymphoma, yet little is known about the sequence of molecular steps that accompany disease progression. We used microarray analysis and laser microdissection to identify gene expression profiles characteristic and predictive of the various histopathological stages in a mouse model of the disease. The initial step in lymphoma development is marked by infiltration of reactive lymphocytes into the stomach and the launching of a mucosal immune response. Our analysis uncovered molecular markers of both of these processes, including genes coding for the immunoglobulins and the small proline-rich protein Sprr 2A. The subsequent step is characterized histologically by the antigen-driven proliferation and aggregation of B cells and the gradual appearance of lymphoepithelial lesions. In tissues of this stage, we observed increased expression of genes previously associated with malignancy, including the laminin receptor-1 and the multidrug-resistance channel MDR-1. Finally, we found that the transition to destructive lymphoepithelial lesions and malignant lymphoma is marked by an increase in transcription of a single gene encoding calgranulin AMrp-8.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2003

Animal models of Helicobacter pylori infection and disease.

The acceptance of Helicobacter pylori as a major human pathogen has necessitated the development of animal models to help elucidate the pathogenic mechanisms of this bacterium and aid in the development of improved strategies for the treatment of gastric disease. Appropriate models, utilising a range of animal species, have been developed to examine factors such as the influence of host responses and bacterial factors in disease development and the success of new therapeutic regimens, including vaccination, to cure infection.

Animals↗

PubMed2003

Temporal dermoids: three cases and a modified treatment algorithm.

Congenital orbitofacial dermoids can be segregated into frontotemporal, orbital, and nasoglabellar regions. Although 10% to 45% of nasoglabellar dermoids present with sinus tracts and occasional intracranial extension, it is rare for frontotemporal dermoids to do so. Frontotemporal dermoids typically manifest as superficial, slow-growing masses that are treated by simple excision. In this retrospective review of 24 patients with congenital orbitofacial dermoids, the authors noted three cases of temporal dermoids with sinus tracts and bony involvement. All three patients were female, with an average presenting age of 4.2 years. Two lesions appeared on the left and one on the right. Each lesion involved the sphenotemporal suture, requiring debridement of the outer cranial table to prevent recurrence. In light of their experience, the authors offer an amendment to the current treatment algorithm for congenital orbitofacial dermoids. A congenital frontotemporal dermoid with a sinus tract should have preoperative radiological evaluation with computed tomography or magnetic resonance imaging to define the pathological anatomy. If bony invasion exists, aggressive exposure and resection of at least the outer cranial table is necessary to prevent recurrence. Temporal dermoids may represent a distinct entity that requires a separation classification from frontotemporal dermoids.

Adolescent↗

PubMed2003

Gastric transitional zones, areas where Helicobacter treatment fails: results of a treatment trial using the Sydney strain mouse model.

Current combination therapies cure Helicobacter pylori infection in 75 to 85% of cases. However, many treatment failures are not explained by antibiotic resistance. Our goal was to explore treatment failures under in vivo conditions by using the H. pylori Sydney strain (SS1) mouse model. Mice infected with H. pylori (SS1) were treated with monotherapies or combination therapies used in human trials. Bacterial levels and distribution of organisms within the stomach were assessed 24 h after treatment to determine clearance and location of treatment failures and 29 days after treatment to determine cure rates. Except for treatment with metronidazole, mono- and dual therapies did not cure infection but resulted in decreases in bacterial levels and differences in distribution within the stomach. In cases of treatment failure when clarithromycin was used, omeprazole and dual therapy with omeprazole and amoxicillin resulted in organisms being cleared from the antrum, but organisms remained in the antrum-body transitional zone. The triple therapies of OMC and bismuth subcitrate, metronidazole, and tetracycline were successful in eradicating infection. Except for metronidazole monotherapy and triple therapy with OAC, there was good correlation between the Sydney strain mouse model and humans with respect to the success of antimicrobial therapy. The antrum-body transitional zone was identified as a sanctuary site in treatment failure. This could result from antimicrobial agents not functioning effectively at this site or bacteria in this location expressing products that protect them against antimicrobial agents. This is the first demonstration of a possible sanctuary site as a reason for failure of therapy.

Amoxicillin↗

PubMed2003

Gene expression profiling of Helicobacter pylori reveals a growth-phase-dependent switch in virulence gene expression.

The global pattern of growth-phase-dependent gene expression of Helicobacter pylori during in vitro culture was analyzed by using a high-density DNA microarray. To detect consistent coordinated gene expression in this bacterium, temporal changes in transcription were assessed in two independent time courses. Cluster analysis of the expression profiles highlighted a major switch in gene expression during the late log-to-stationary phase transition that we have termed the Log-Stat switch. Statistical analysis of the genes that were significantly induced or repressed during the Log-Stat switch revealed that many of these genes were related to virulence. Among these, expression of the genes for the neutrophil activating protein (napA) and the major flagellin subunit (flaA) were significantly induced. Additionally, the expression of a number of genes involved in iron homeostasis changed dramatically at this switch; the gene for the iron-storage protein, pfr, was induced, while the genes for two putative iron uptake proteins, fecA and frpB, were significantly repressed. These data suggest that the late log phase may correspond to the most virulent phase of growth in H. pylori and may be intimately related to its pathogenesis. The use of microarrays to analyze the kinetics of the transcriptional response of a bacterial pathogen to a changing environment has enabled the discovery of previously unappreciated relationships between genes by elucidation of coordinated gene expression profiles.

Flagella↗

PubMed2002

In vivo behavior of a Helicobacter pylori SS1 nixA mutant with reduced urease activity.

Helicobacter pylori mutants devoid of urease activity fail to colonize the gastric mucosa of mice; however, the effect of decreased levels of urease on colonization has not been examined. The nixA gene, required for full urease activity, encodes a cytoplasmic membrane nickel transporter that imports nickel ions and leads to incorporation of nickel ions into apourease. A nixA mutant of the Sydney strain of H. pylori (SS1) was constructed by disruption of the nixA gene with a kanamycin resistance cassette. This mutant retained only half the urease activity of the wild-type (wild-type) SS1 strain. C57BL/6j (n = 75) and BALB/c (n = 75) mice were inoculated independently with the wild-type or the nixA strain. The level and distribution of colonization were assessed by bacterial colony counts and histological grading at 4, 12, and 24 weeks postinfection. Colonization levels of the nixA strain in BALB/c mice were significantly lower compared with SS1 (P = 0.005), while colonization in C57BL/6j mice was similar for both the wild-type and mutant strains. Subtle differences in colonization of the different regions of the stomach, determined by microscopic grading, were observed between wild-type SS1 and the nixA strain in BALB/c mice. On the contrary, when C57BL/6j (n = 35) and BALB/c (n = 35) mice were coinfected with the wild-type and nixA strains simultaneously, the nixA mutant failed to colonize and was outcompeted by the wild-type SS1 strain, which established normal levels of colonization. These results demonstrate the importance of the nixA gene for increasing the fitness of H. pylori for gastric colonization. Since nixA is required for full urease activity, the decreased fitness of the nixA mutant is likely due to reduced urease activity; however, pleiotropic effects of the mutation cannot be completely ruled out.

Animals↗