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.

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.

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.

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.

Human plasma and amino acids as moderators of uptake and metabolic consequences of antifolates in WIL-2 and human leukemia cells.

Plasma and medium composition significantly affect cellular association of the lipid-soluble antifolate 2,4-diamino-5-(3',4'-dichlorophenyl)-6-methylpyrimidine (DDMP). This was demonstrated by measuring association of labeled drug with cells and by assaying the antimetabolic effect of DDMP on incorporation of deoxyuridine into DNA. Uptake of both aqueous and lipid-soluble antifolates was substantially reduced in the human lymphoblastoid cell line WIL-2 when Eagle's minimum essential medium (EMEM) was substituted for a basal salts solution containing glucose [DDMP approximatley 50%, methotrexate (MTX) approximately 30%]. Uptake of DDMP, however, was inhibited by the amino acid fraction of EMEM or glutamine alone, whereas MTX uptake was unaffected by amino acids. Further studies with human leukemia cells showed that DDMP was only about 25% as effective an inhibitor of deoxyuridine incorporation in autologous human plasma when compared to its inhibitory effect in RPMI-1640 medium MTX inhibition of deoxyuridine incorporation in these cells was essentially unaffected by substitution of autologous human plasma for RPMI-1640 medium. Replacing EMEM with pooled human plasma resulted in a 60-70% decrease in DDMP uptake but had only a marginal effect upon MTX uptake. Thus the choice of medium is important in studies of lipid-soluble antifolates such as DDMP that have a high affinity for cellular and medium lipoprotein components.

Long-term remission durability and functional status of patients treated for diffuse histiocytic lymphoma with the CHOP regimen.

Thirty-eight (51%) of 75 patients treated with CHOP for diffuse histiocytic lymphoma achieved complete remission. Twenty-three of the complete responders are currently alive in complete remission 24-78 months (median, 38 months) after discontinuing therapy. Eleven patients died from recurrent lymphoma and four patients died in complete remission from other causes. Evaluation of the 23 patients alive in complete remission found them mostly well and without serious sequelae to therapy. Comparison with 20 patients who were in the same age range, were disease free after surgery, and had no other therapy for colon cancer revealed only an increased frequency of sexual dysfunction in the chemotherapy-treated lymphoma patients. Sixty-one percent of patients who achieved complete remission with the CHOP regimen are long-term disease-free survivors and are generally well except for an apparently high frequency of sexual dysfunction.

Marrow transplantation for stable-phase chronic granulocytic leukemia.

Ten patients with chronic granulocytic leukemia in the stable phase underwent marrow transplantation from HLA-identical siblings (nine cases) or an identical twin (one case) following preparation with cytarabine, cyclophosphamide, and total body irradiation. Marrow cytogenetics on all patients prior to transplantation revealed the Philadelphia chromosome without other evidence of aneuploidy. The immediate posttransplant course was in most cases relatively uncomplicated with only two serious infections and one death. All patients recovered with cytogentically normal marrow and leukemia has recurred only in the syngeneic transplant recipient. At present, nine patients are surviving from 358 to 961 days (median 597 days) after bone marrow transplantation. Bone marrow transplantation is capable of eliminating the abnormal clone of myeloid cells in patients with stable-phase chronic granulocytic leukemia and can be performed relatively safely in this "healthy" group of patients.

The use of partially matched, unrelated donors in clinical bone marrow transplantation.

It is estimated that 60-70% of patients who might benefit from a bone marrow transplant will not have a suitably matched, related donor. We have, therefore, designed a clinical experiment to test the safety and feasibility of using marrow from partially matched, unrelated donors. This paper details our transplant experience in the first eight patients with leukemia. The first four patients had advanced leukemia at the time of transplantation. Each showed hematopoietic recovery, but all died from septic complications largely related to extended neutropenia encompassing both the pre-marrow-grafting and the post-marrow-grafting period. The next four patients were in remission at the time of transplantation. Each showed prompt and sustained hematopoiesis with variable graft-versus-host disease (GVHD). No acute or chronic GVHD was seen in two patients, grade II (skin only) was seen in one patient, and grade IV (skin, liver, and gut) was seen in one patient. One patient has died from sepsis five-and-one-half months following transplantation, and three are alive and well six-and-one-half to nine-and-one-half months postengraftment. This preliminary experience, together with several case reports in the literature, leads us to conclude that bone marrow transplantation with partially matched, unrelated marrow is a safe and feasible approach. If these results are confirmed by longer follow-up in a larger group of patients, the development of marrow donor pools would appear to be justified.

Two-year adjustment of bone marrow transplant survivors.

Very little systematic analysis exists on the psychological and emotional factors involved in bone marrow transplantation, either during or after treatment. However, recent published findings, contrary to earlier anecdotal and case study evidence, indicate that bone marrow transplant survivors appear to be functioning adequately on a variety of 'quality of life' variables. The purpose of the present study was to compare bone marrow transplant survivors to a matched sample of patients undergoing maintenance chemotherapy in four areas of function; physical health, including symptoms and physician visits; personal functioning, emphasizing ability to care for self; psychological functioning; and role functioning, including employment and sexual difficulties. Our data reveal that the bone marrow transplant patients were experiencing greater difficulties than the maintenance chemotherapy patients in several areas. For example, the bone marrow transplant patients had experienced greater disruption of vocational functioning and reported more sexual difficulties. However, in spite of more objective difficulties, bone marrow transplant patients, compared to maintenance chemotherapy patients, viewed themselves as equally healthy and reported similarly low levels of psychological distress. The findings are discussed in the context of necessary future research on bone marrow transplant survivors.

Toward interlocked molecules beyond catenanes and rotaxanes.

A linear bis secondary dialkylammonium ion-containing scaffold-based upon an anthracenyl core-has been synthesized. It has been demonstrated that it is possible to dock either one or two dibenzo[24]crown-8 (DB24C8) macrocycles onto this scaffold to afford either a [2]- or [3]pseudorotaxane, respectively. In solution, the association constants for the formation of each of these species has been quantified by employing (1)H NMR spectroscopy, and both species survive in the "gas phase" as evidenced by FAB mass spectrometry. Additionally, the X-ray crystal superstructure of the [3]pseudorotaxane has been determined.

Ammonium ion binding with pyridine-containing crown ethers.

Dipyrido[24]crown-8 (DP24C8) has been synthesized and shown to form [2]pseudorotaxanes spontaneously with dibenzylammonium ions. These complexes, which have been demonstrated by (1)H NMR spectroscopy to form faster in solution than when the macrocyclic polyether is dibenzo[24]crown-8 (DB24C8), are also stronger than their DB24C8 counterparts. One of the [2]pseudorotaxanes has been used to construct a [2]rotaxane (see above) comprising a dumbbell-shaped component based on a dibenzylammonium ion which is encircled by a DP24C8 macrocycle and terminated by (triphenylphosphonium)methyl stoppers.

Epidemic and endemic seroprevalence of antibodies to Cryptosporidium and Giardia in residents of three communities with different drinking water supplies.

This study was carried out to compare cryptosporidiosis and giardiasis seroprevalence rates in residents of three communities. Community (Com 1) uses drinking water from deep wells, community 2 (Com 2) uses surface water from a protected watershed, and community 3 (Com 3) uses surface water frequently containing Cryptosporidium oocysts and Giardia cysts. Unfiltered drinking water from each community was collected at the tap and tested for Cryptosporidium oocysts and Giardia cysts during the 12 months in which sera were collected for testing. No oocysts or cysts were detected in the water from the Com 1 deep wells; oocysts and cysts were detected intermittently in the drinking water from the other two communities. A waterborne outbreak of cryptosporidiosis occurred in a municipality adjacent to Com 3 six months into this 12-month study. Sera from residents of each of the communities were collected proportionately by month and by population size. Coded sera were tested for IgG to Cryptosporidium using a previously developed Western blotting method. The presence or absence of bands at 15-17 kD and/or 27 kD was recorded for the 1,944 sera tested. Definite bands at 15-17 kD and/or 27 kD were detected in 981 (50.5%) of the sera. A total of 33.2% of sera from Com 1 (community using deep wells) were positive using the same criteria compared with 53.5% (Com 2) and 52.5% (Com 3) of sera from the two communities using surface drinking water. Both bands (15-17 kD plus 27 kD) were detected in 582 sera (29.9%) from the three communities: 14.1% of sera from Com 1 compared with 32.7% from Com 2 and 31.5% from Com 3. These findings are consistent with a lower risk of exposure to Cryptosporidium from drinking water obtained from deep well sources. However, analysis of results by calendar quarter showed a significant (P < 0.001) increase in the number of Com 3 positive sera (compared with Com 1) following the waterborne outbreak. Without this outbreak-related observation, a significant overall difference in seropositivity would not have been seen. We also observed that in sera from the community affected by the outbreak, the presence on immunoblots of both Cryptosporidium bands appeared to be the best indicator of recent infection. Seroprevalence rates using an ELISA to detect IgG to Giardia were estimated using the same sera. Overall 30.3% (590 of 1,944) of sera were positive by the ELISA. A total of 19.1% of sera from Com 1, 34.7% from Com 2 and 16.0% from Com 3 were seropositive. Rates for both Com 3 and Com 1 did not change significantly over time. In Com 2, rates decreased significantly (P < 0.001) during the last half of the study period (third and fourth calendar quarters). The reasons for the decrease in seroprevalence in Com 2 sera are presently not known. These studies show intriguing associations between seroprevalence, outbreak-related laboratory serologic data, and patterns of parasite contamination of drinking water. Further studies are required to validate the serologic approach to risk assessment of waterborne parasitic infections at a community level.

Molecular epidemiology of cryptosporidiosis outbreaks and transmission in British Columbia, Canada.

Isolates from 25 (13 sporadic and 12 outbreak) cryptosporidiosis cases, 24 of which were from British Columbia, Canada, were characterized using nested polymerase chain reaction amplification of the polymorphic internal transcribed spacer 1 locus. Two predominant Cryptosporidium parvum genotypes were found. Twelve (8 sporadic and 4 outbreak) isolates amplified with the cry7/cry21 primer pair and 12 (5 sporadic and 7 outbreak) isolates amplified with the cry7/cryITS1 primer pair. Multi-locus gene analysis using sequence polymorphisms on 3 other loci, i.e., the thrombospondin-related adhesion protein gene, the dihydrofolate reductase gene, and the 18S rRNA gene on 8 (4 outbreak and 4 sporadic) isolates showed non-random association among the human and animal alleles of the 4 different C. parvum gene loci. Associations between these 2 parasite genotypes and different routes of cryptosporidiosis transmission such as zoonotic, anthroponotic, and waterborne transmission were studied using municipal population and agricultural information, as well as detection of C. parvum oocysts in municipal drinking water specimens of the residential communities of sporadic and outbreak cases.

The effect of single or repeated applications of "therapeutic" ultrasound on plasma extravasation during silver nitrate induced inflammation of the rat hindpaw ankle joint in vivo.

The effect of "therapeutic" ultrasound upon plasma extravasation during the inflammatory process induced in the rat hindpaw ankle by intra-articular injection of silver nitrate was investigated in two series of experiments. Both series utilised three ultrasonic frequencies, 0.75, 1.5, and 3.0 MHz, and two pulse ratios, mark:space 1:4 and 1:1. Series 1 examined the effect of two durations of ultrasound, 1 or 2 min, administered once only, and series 2 examined the effect of single or repeated insonations of 1 min duration. It was found that ultrasound treatment increased plasma extravasation compared to controls during the first 24 hr, but later reduced it significantly compared to controls. This secondary effect of reduction in plasma extravasation was delayed in animals given three insonations, this number of insonations being found to prolong the plasma extravasation phase.

Mediators of the plasma extravasation response to silver nitrate in the rat skin, subplantar region and ankle joint.

Plasma extravasation responses to silver nitrate (AgNO3), histamine, 5-hydroxytryptamine (5-HT), bradykinin and prostaglandin E1 (PGE1) in the abdominal skin, hindpaw ankle joint and subplantar region of rats have been investigated using the Evans blue dye leakage technique. All substances tested produced plasma extravasation and combination of low doses (5 x 10(-10) mol) of either histamine or bradykinin with PGE1 (5 x 10(-10) mol) exhibited potentiation of responses of all regions. Responses to AgNO3 (1 x 10(-6) mol) were significantly reduced by the H1 receptor antagonist, mepyramine, only in the abdominal skin, but the H2 receptor antagonist metiamide reduced the responses at subplantar and ankle joint regions. Indomethacin significantly reduced the AgNO3 responses at the ankle joint only, but aprotinin reduced it at the other two regions. In rats pretreated with a combination of all antagonists the residual plasma extravasation response to AgNO3 was very small, indicating that the response could be almost totally accounted for by the combined actions of mast cell amines, kinins and prostanoids. The finding that prostanoids played a major role in the plasma extravasation response of the rat ankle joint to AgNO3 indicated that this model would be useful for the screening of non-steroidal anti-inflammatory drugs.

Selection of an appropriate initial test cutoff concentration for workplace drug urinalysis--Cannabis example.

Apparent analyte concentration (equivalent of 11-nor-delta 9-tetrahydrocannabinol-9-carboxylic acid [9-THC-COOH]) obtained by radioimmunoassay (RIA) for cannabinoids using reagents manufactured at four different periods (from the same manufacturer) and specific 9-THC-COOH concentration as determined by GC/MS are examined for the significance of their correlation. The resulting regression equations are then used to estimate the apparent RIA analyte concentrations of reagents manufactured at different time periods that are equivalent to a specific 9-THC-COOH concentration. Correlation coefficients of the regression analysis improve from approximately 0.4 to 0.7 in parallel with the increasing reagent specificity. The apparent RIA analyte concentrations that correspond to 15 ng/mL 9-THC-COOH decrease from about 110 to 50 ng/mL again in parallel with the increasing reagent specificity. These findings empirically demonstrate that reagent specificity is the determining factor of the resulting apparent RIA analyte concentration when testing samples that contain 9-THC-COOH and other metabolites (derived from marijuana exposure). Thus, if the 9-THC-COOH concentration as determined by GC/MS is of primary concern, the initial test cutoff concentration should be adjusted in accordance with the specificity of the reagent used.

An outbreak of mumps among young adults in Vancouver, British Columbia, associated with 'rave' parties.

UNLABELLED: In early 1997 an unexpectedly high number of cases of mumps was reported in Vancouver, British Columbia. METHODS: A case control study was conducted to address four objectives: 1) Describe the outbreak and the population at risk, 2) examine the impact of mumps on this population, 3) identify personal risk factors for infection, and 4) test the hypothesis that social gatherings, 'rave' parties in particular, were a risk factor in this outbreak. RESULTS: Mumps infection was associated with: attending a rave party [OR = 17; 95% CI: 2.7-710], residing in Vancouver [OR = 3.7; 95% CI: 1.4-10], and contact with a person with mumps [OR = 13; 95% CI: 2-552], during the 'exposure' period. Vaccine effectiveness, ascertained by self-reported immunization status, was 80% [95% CI: 29%-96%]. CONCLUSIONS: Attendance at rave parties was associated with mumps infection during this outbreak. Many persons aged 17-40 may remain susceptible to mumps; in BC these persons are eligible for one dose of MMR and should be encouraged to be vaccinated.

SKIN TEMPERATURE, COLOUR, and WARMTH FELT, IN HYDROCOLLATOR PACK APPLICATIONS TO THE LUMBAR REGION.

The application of hydrocollator packs carries an inherent danger of overheating, which must be avoided. While a variety of temperatures and coverings for the packs has been reported, it has been stated that a bright red skin colour may be indicative of skin damage. It has also been stated that a therapeutically desirable rise in skin temperature would be one to over 40°C during the treatment. In this study hydro-pack applications to the lumbar region of the back were assessed for onset of sensation after application, and at intervals thereafter for skin temperature, skin colour, and subjective sensation of warmth. The lack of co-relation found between these variables suggests that in clinical work an observation of the skin and also a subjective report, should be obtained at frequent intervals for at least the first nine minutes after application. The need for a rise in skin temperature above 40°C is questioned.

A study of the effects of different ultrasonic frequencies on experimental oedema.

This paper describes an investigation, undertaken at the University of Queensland, into the effect of different ultrasonic frequencies in "therapeutic" dosages on experimental oedema in rats, by means of due leakage estimation. Results indicate that ultra-sound is effective in limiting oedema, but further investigation is required to ascertain the means by which this is brought about.

Acoustic output from therapeutic ultrasound units.

Reports of metered inaccuracy in 'therapeutic' ultrasound unit output have been made since 1962, but have tacitly been accepted, perhaps due to the universal lack of appropriate testing facilities. Factors of treatment selection subject to instrumental error include duration of application, operating frequency, intensity, pulsed output. Metered errors in space-averaged intensity are common and are the most difficult to detect without specialised equipment which is rarely available. Couplants, essential for ultrasound transmission, can be a source of acoustic power loss if incorrectly used. Beam profiles demonstrate the rapid spatial variations in the near (Fresnel) zone, necessitating soundhead movement during treatment. Ultrasound physics must be understood, but professional integrity should demand better output testing facilities and equipment for clinical treatment.