Can UK healthcare workers remotely support medical education in the developing world?: Focus group evaluation.

OBJECTIVES: To evaluate the feasibility of providing regular, live, text-based teaching to medical students and junior doctors in Somaliland using a dedicated case-based medical education website (www.MedicineAfrica.com). DESIGN: Review of MedicineAfrica database for details of teaching sessions held in Somaliland from December 2008-October 2010 and evaluation of user experiences through focus groups. SETTING: King's College Hospital, London, UK and Ahmoud University, Borama, Somaliland. PARTICIPANTS: Final year medical students, newly graduated interns and second year interns at Ahmoud University, Borama, Somaliland. MAIN OUTCOME MEASURES: Qualitative and quantitative user rating of online case-based tutorials in the context of pre-existing educational opportunities available to them. RESULTS: Regular online teaching sessions are received enthusiastically by students and junior doctors and are reported to improve their clinical practice. CONCLUSIONS: Despite technological limitations in Somaliland, a live text-based teaching service can be delivered effectively and streamlined with local curricula. This represents an alternative to traditional static teaching methodologies currently used in international medical education.

DNA methylation changes in atypical adenomatous hyperplasia, adenocarcinoma in situ, and lung adenocarcinoma.

BACKGROUND: Aberrant DNA methylation is common in lung adenocarcinoma, but its timing in the phases of tumor development is largely unknown. Delineating when abnormal DNA methylation arises may provide insight into the natural history of lung adenocarcinoma and the role that DNA methylation alterations play in tumor formation. METHODOLOGY/PRINCIPAL FINDINGS: We used MethyLight, a sensitive real-time PCR-based quantitative method, to analyze DNA methylation levels at 15 CpG islands that are frequently methylated in lung adenocarcinoma and that we had flagged as potential markers for non-invasive detection. We also used two repeat probes as indicators of global DNA hypomethylation. We examined DNA methylation in 249 tissue samples from 93 subjects, spanning the putative spectrum of peripheral lung adenocarcinoma development: histologically normal adjacent non-tumor lung, atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS, formerly known as bronchioloalveolar carcinoma), and invasive lung adenocarcinoma. Comparison of DNA methylation levels between the lesion types suggests that DNA hypermethylation of distinct loci occurs at different time points during the development of lung adenocarcinoma. DNA methylation at CDKN2A ex2 and PTPRN2 is already significantly elevated in AAH, while CpG islands at 2C35, EYA4, HOXA1, HOXA11, NEUROD1, NEUROD2 and TMEFF2 are significantly hypermethylated in AIS. In contrast, hypermethylation at CDH13, CDX2, OPCML, RASSF1, SFRP1 and TWIST1 and global DNA hypomethylation appear to be present predominantly in invasive cancer. CONCLUSIONS/SIGNIFICANCE: The gradual increase in DNA methylation seen for numerous loci in progressively more transformed lesions supports the model in which AAH and AIS are sequential stages in the development of lung adenocarcinoma. The demarcation of DNA methylation changes characteristic for AAH, AIS and adenocarcinoma begins to lay out a possible roadmap for aberrant DNA methylation events in tumor development. In addition, it identifies which DNA methylation changes might be used as molecular markers for the detection of preinvasive lesions.

Genome variation in Cryptococcus gattii, an emerging pathogen of immunocompetent hosts.

Cryptococcus gattii recently emerged as the causative agent of cryptococcosis in healthy individuals in western North America, despite previous characterization of the fungus as a pathogen in tropical or subtropical regions. As a foundation to study the genetics of virulence in this pathogen, we sequenced the genomes of a strain (WM276) representing the predominant global molecular type (VGI) and a clinical strain (R265) of the major genotype (VGIIa) causing disease in North America. We compared these C. gattii genomes with each other and with the genomes of representative strains of the two varieties of Cryptococcus neoformans that generally cause disease in immunocompromised people. Our comparisons included chromosome alignments, analysis of gene content and gene family evolution, and comparative genome hybridization (CGH). These studies revealed that the genomes of the two representative C. gattii strains (genotypes VGI and VGIIa) are colinear for the majority of chromosomes, with some minor rearrangements. However, multiortholog phylogenetic analysis and an evaluation of gene/sequence conservation support the existence of speciation within the C. gattii complex. More extensive chromosome rearrangements were observed upon comparison of the C. gattii and the C. neoformans genomes. Finally, CGH revealed considerable variation in clinical and environmental isolates as well as changes in chromosome copy numbers in C. gattii isolates displaying fluconazole heteroresistance.

Cryptococcus gattii infections on Vancouver Island, British Columbia, Canada: emergence of a tropical fungus in a temperate environment.

BACKGROUND: Cryptococcus gattii causes disease among immunocompetent individuals in the tropics and subtropics. We document the appearance of C. gattii infections on Vancouver Island (VI), a temperate region, and discuss reasons for this emergence. METHODS: Data on Cryptococcus hospitalizations for the calendar years 1995 through 2004 were reviewed. Viable historic isolates stored at the provincial public health laboratory between 1987 and 2000 were serotyped. Human cases were mapped by place of residence. RESULTS: Cryptococcosis among HIV negative individuals diagnosed on VI increased sharply after 1999. C. gattii was not detected in stored isolates prior to 1999. C. gattii cases lived in a specific biogeoclimatic zone on VI. Higher rates of illness were associated with exposure to the central region of VI. CONCLUSIONS: The emergence of C. gattii in a temperate region is unprecedented. Clinicians should consider C. gattii in the differential diagnosis of individuals who travelled to certain areas in British Columbia.

Estimation of the costs of acute gastrointestinal illness in British Columbia, Canada.

The costs associated with gastrointestinal infection (GI) in the province of British Columbia, Canada, were estimated using data from a population-based survey in three health service delivery areas, namely Vancouver, East Kootenay and Northern Interior. The number of cases of disease, consequent expenditure of resources and associated economic costs were modeled as probability distributions in a stochastic model. Using 2004 prices, the estimated mean annual cost per capita of gastrointestinal infection was CAN$128.61 (207.96 euros), with a mean annual cost per case of CAN$1,342.57 (2,170.99 euros). The mean estimate of the overall economic burden to British Columbia was CAN$514.2 million (831.5 million euros) (95% CFI CAN$161.0 million to CAN$5.8 billion; 260.3 million euros to 9.38 billion euros). The major element of this cost was the loss of productivity associated with time away from paid employment by both the sick and their caregivers. Sensitivity analysis suggested that the uncertainty associated with the base model assumptions did not significantly affect the estimates. The results are comparable to those obtained in an earlier study using a similar analytical framework and data from the city of Hamilton, Ontario, Canada.

GPR119, a novel G protein-coupled receptor target for the treatment of type 2 diabetes and obesity.

GPR119 is a G protein-coupled receptor expressed predominantly in the pancreas (beta-cells) and gastrointestinal tract (enteroendocrine cells) in humans. De-orphanization of GPR119 has revealed two classes of possible endogenous ligands, viz., phospholipids and fatty acid amides. Of these, oleoylethanolamide (OEA) is one of the most active ligands tested so far. This fatty acid ethanolamide is of particular interest because of its known effects of reducing food intake and body weight gain when administered to rodents. Agonists at the GPR119 receptor cause an increase in intracellular cAMP levels via G(alphas) coupling to adenylate cyclase. In vitro studies have indicated a role for GPR119 in the modulation of insulin release by pancreatic beta-cells and of GLP-1 secretion by gut enteroendocrine cells. The effects of GPR119 agonists in animal models of diabetes and obesity are reviewed, and the potential value of such compounds in future therapies for these conditions is discussed.

Drinking water consumption patterns in British Columbia: an investigation of associations with demographic factors and acute gastrointestinal illness.

A cross-sectional telephone survey was performed in the province of British Columbia, Canada, to investigate drinking water consumption patterns and their associations with various demographic characteristics and acute gastrointestinal illness (AGI). Water consumption included plain water and water used in the preparation of cold beverages. The median amount of water consumed daily was four-250 mL servings (1.0 L), although responses were highly variable (0 to 9.0 L). Alternative water use was common: bottled water was the primary source of drinking water (i.e. >or=75% of the total daily water intake) for 23% of respondents and 47% of households used in-home water treatment methods. Approximately 10% of respondents reported an episode of AGI (vomiting or diarrhea) in the previous 4-week period. Such illness was associated with age (continuous variable in years, OR=-0.98), sex (male vs. female, OR=0.8) and the amount of water consumed (continuous variable in 250-mL servings, OR=1.06); however, a causal relationship with water consumption cannot be established based on this study alone. Overall, the associations of drinking water patterns with age, sex, education, and household income serve as important reminders to researchers and public health professionals of the non-uniform nature of drinking water consumption, and indicate potential differences in exposure to waterborne hazards in this population.

Glucokinase activator PSN-GK1 displays enhanced antihyperglycaemic and insulinotropic actions.

AIMS/HYPOTHESIS: We evaluated the insulinotropic and antihyperglycaemic actions of glucokinase activators (GKAs), especially through acute and subchronic studies in rodent diabetes models with (2R)-2-(4-cyclopropanesulphonylphenyl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydropyran-4-yl)propionamide (PSN-GK1), a novel and potent GKA. MATERIALS AND METHODS: The action of PSN-GK1 on or in the following were investigated: (1) on human liver glucokinase, insulin secretion from MIN6 cells and 2-deoxy-D: -[(3)H]glucose (2-DG) uptake into rat hepatocytes; and (2) in Zucker diabetic fatty rats and in non-diabetic C57Bl/6, diabetic db/db and ob/ob mice. RESULTS: At 5 mmol/l glucose, PSN-GK1 activated glucokinase (4.3-fold, median effective concentration [EC(50)] 130 nmol/l), increased MIN6 insulin secretion (26-fold, EC(50) 267 nmol/l) and 2-DG hepatocytic uptake (threefold, EC(50) 1 micromol/l); at higher glucose concentrations, EC(50)s and fold-effectiveness were both lower. In C57Bl/6 mice, PSN-GK1 reduced blood glucose at 1 and 10 mg/kg (by mouth), but insulin was increased significantly at only the higher dose. In hyperinsulinaemic 10-mmol/l glucose clamps, PSN-GK1 increased 2-DG incorporation into liver glycogen sixfold, directly demonstrating liver effects. PSN-GK1 improved glycaemic profiles in db/db mice and Zucker diabetic fatty rats, diabetic animal models in which GKA efficacy has not previously been described, without causing hypoglycaemia. In ob/ob mice, it dose-dependently reduced excursions in OGTTs. Moreover, after subchronic administration, no tachyphylaxis was evident and glycaemia was improved without alterations to lipid levels, liver weight, glycogen content or body weight. CONCLUSIONS/INTERPRETATION: PSN-GK1 was potently antihyperglycaemic through its effects on insulin release and hepatic glucose metabolism. It is one of the most potent GKAs described in the literature and is active in diabetic animal models where GKAs have not been reported to show efficacy to date. Ongoing human trials are investigating the potential of this novel therapeutic approach.

Emergence of Cryptococcus gattii in a novel environment provides clues to its incubation period.

Cryptococcus gattii emerged in 1999 in a distinct ecologic environment on Vancouver Island, Canada. Estimates of incubation period were derived from an analysis of travelers with discreet exposures to this region. Individual case incubation periods ranged from 2 to 11 months, with a median of 6 to 7 months.

Outbreak of cyclosporiasis in British Columbia associated with imported Thai basil.

Sporadic outbreaks of cyclosporiasis, a common cause of protracted diarrhoea in underdeveloped countries, are often undetected and undiagnosed in industrial countries. In May 2001, an outbreak of Cyclospora cayetanensis gastroenteritis was identified in British Columbia, Canada, with 17 reported cases. We conducted a case-control study involving 12 out of the 17 reported and confirmed case patients. Eleven (92%) of the patients had consumed Thai basil, an essential ingredient in Vietnamese cuisine, compared to 3 out of 16 (19%) of the control patients (P = 0.003). Trace-back investigations implicated Thai basil imported via the United States as the vehicle for this outbreak. This is the first documented sporadic outbreak of cyclosporiasis linked to Thai basil in Canada, and the first outbreak of cyclosporiasis identified in an ethnic immigrant population. This outbreak provides the opportunity to increase our understanding of this emerging pathogen and improve on our prevention and control for future outbreaks.

A rare genotype of Cryptococcus gattii caused the cryptococcosis outbreak on Vancouver Island (British Columbia, Canada).

Cryptococcus gattii causes life-threatening infection of the pulmonary and central nervous systems in hosts with normal immunity and traditionally has been considered to be restricted geographically to tropical and subtropical climates. The recent outbreak of C. gattii in the temperate climate of Vancouver Island, BC, Canada, led to a collaborative investigation. The objectives of the current study were to ascertain the environmental source of the outbreak infections, survey the molecular types of the outbreak and environmental cryptococcal isolates, and determine the extent of genetic diversity among the isolates. PCR-fingerprinting and amplified fragment length polymorphism (AFLP) were used to examine the genotypes, and mating assays were performed to determine the mating type of the isolates. All outbreak and environmental isolates belonged to C. gattii. Concordant results were obtained by using PCR-fingerprinting and AFLP analysis. The vast majority of clinical and veterinary infections were caused by isolates of the molecular type VGII/AFLP6, but two were caused by molecular type VGI/AFLP4. All environmental isolates belonged to molecular type VGII/AFLP6. Two or three subtypes were observed within VGII/AFLP6 among outbreak and environmental isolates. All mating-competent isolates were of the alpha-mating type. The emergence of this usually tropical pathogen on Vancouver Island highlights the changing distribution of this genotype and emphasizes the importance of an ongoing collaborative effort to monitor the global epidemiology of this yeast.

An outbreak due to peanuts in their shell caused by Salmonella enterica serotypes Stanley and Newport--sharing molecular information to solve international outbreaks.

Salmonellosis is a global problem caused by the international movement of foods and high incidence in exporting countries. In September 2001, in an outbreak investigation Australia isolated Salmonella Stanley from imported peanuts, which resulted in a wider investigation in Canada, England & Wales and Scotland. Patients infected with Salmonella serotypes known to be isolated from peanuts and reported to surveillance systems were interviewed to determine exposure histories. Tagged image file format (TIFF) images of pulsed-field gel electrophoresis (PFGE) patterns of Salmonella isolates were shared electronically amongst laboratories. Laboratories tested packets of 'Brand X' peanuts from various lots and product lines. In total, 97 cases of S. Stanley and 12 cases of S. Newport infection were found. Seventy-three per cent (71/97) of S. Stanley cases were in persons of Asian ethnicity. Twenty-eight per cent of cases recalled eating Brand X peanuts and a further 13% had peanuts in their house in the previous month or had eaten Asian-style peanuts. Laboratories isolated S. Stanley, S. Newport, S. Kottbus, S. Lexington and S. Unnamed from Brand X peanuts. Isolates of S. Stanley from peanuts and human patients were indistinguishable by PFGE. This international outbreak resulted from a product originating from one country affecting several others. Rapid sharing of electronic DNA images was a crucial factor in delineating the outbreak; multinational investigations would benefit from a harmonized approach.

Risk factors for Salmonella typhimurium DT104 and non-DT104 infection: a Canadian multi-provincial case-control study.

To identify risk factors for sporadic Salmonella Typhimurium definitive phage-type 104 (DT104) and non-DT104 diarrhoeal illness in Canada, we conducted a matched case-control study between 1999 and 2000. Cases were matched 1:1 on age and province of residence. Multivariate analysis suggested that recent antibiotic use [odds ratio (OR) 5.2, 95% confidence interval (CI) 1.8-15.3], living on a livestock farm (OR 4.9, 95% CI 1.9-18.9), and recent travel outside Canada (OR 4.1, 95% CI 1.2-13.8) are independent risk factors for DT104 illness. Similar analyses suggested that recent travel outside North America is a sizable risk factor for non-DT104 illness (OR 66.8, 95% CI 6.7-665.3). No food exposure was a risk factor in either analysis. Educating health-care providers and the public about appropriate antibiotic use and antimicrobial resistance is important. Appropriate administration of antibiotics to livestock, particularly cattle, and hygienic measures such as handwashing after contact with farm animals may reduce risk. Travel represents an important and probably underestimated risk factor for sporadic illness with S. Typhimurium. Improved national surveillance and detailed investigation of travel-related illness are required.

Escherichia coli O157:H7 outbreak linked to salami, British Columbia, Canada, 1999.

An outbreak of E. coli O157:H7 infections was identified in November 1999 with a fivefold increase in the occurrence of laboratory-confirmed cases of E. coli O157:H7 infection. A matched case-control study was conducted. Samples of food from cases and from retailers were analysed for the presence of E. coli O157:H7. A total of 143 cases were identified over a 12-week period with the same pulsed-field gel electrophoresis (PFGE) pattern. The case-control study found that Company A salami was significantly associated with illness (Mantel-Haenszel matched odds ratio 10.0%, 95% CI 1.4-434, P=0.01). Company A salami tested positive for E. coli O157:H7 and isolates had the same PFGE pattern as case isolates. An immediate voluntary national recall of Company A dry fermented meat products took place. Findings from the investigation of this outbreak suggest that the hold-and-test option may not be adequate to prevent shiga-toxigenic Escherichia coli (STEC) infection in salami consumers.