Phenylthiourea specifically reduces zebrafish eye size.

Phenylthiourea (PTU) is commonly used for inhibiting melanization of zebrafish embryos. In this study, the standard treatment with 0.2 mM PTU was demonstrated to specifically reduce eye size in larval fish starting at three days post-fertilization. This effect is likely the result of a reduction in retinal and lens size of PTU-treated eyes and is not related to melanization inhibition. This is because the eye size of tyr, a genetic mutant of tyrosinase whose activity is inhibited in PTU treatment, was not reduced. As PTU contains a thiocarbamide group which is presented in many goitrogens, suppressing thyroid hormone production is a possible mechanism by which PTU treatment may reduce eye size. Despite the fact that thyroxine level was found to be reduced in PTU-treated larvae, thyroid hormone supplements did not rescue the eye size reduction. Instead, treating embryos with six goitrogens, including inhibitors of thyroid peroxidase (TPO) and sodium-iodide symporter (NIS), suggested an alternative possibility. Specifically, three TPO inhibitors, including those that do not possess thiocarbamide, specifically reduced eye size; whereas none of the NIS inhibitors could elicit this effect. These observations indicate that TPO inhibition rather than a general suppression of thyroid hormone synthesis is likely the underlying cause of PTU-induced eye size reduction. Furthermore, the tissue-specific effect of PTU treatment might be mediated by an eye-specific TPO expression. Compared with treatment with other tyrosinase inhibitors or bleaching to remove melanization, PTU treatment remains the most effective approach. Thus, one should use caution when interpreting results that are obtained from PTU-treated embryos.

Interferon-gamma release assays are a better tuberculosis screening test for hemodialysis patients: A study and review of the literature.

Diagnosing latent tuberculosis (TB) infection (LTBI) in dialysis patients is complicated by poor response to tuberculin skin testing (TST), but the role of interferon-gamma release assays (IGRAs) in the dialysis population remains uncertain. Seventy-nine patients were recruited to compare conventional diagnosis (CD) with the results of two IGRA tests in a dialysis unit. Combining TST, chest x-ray and screening questionnaire results (ie, CD) identified 24 patients as possible LTBI. IGRA testing identified 22 (QuantiFERON Gold IT, Cellestis, USA) and 23 (T-spot.TB, Oxford Immunotec, United Kingdom) LTBI patients. IGRA and CD correlated moderately (κ=0.59). IGRA results correlated with history of TB, TB contact and birth in an endemic country. TST was not helpful in identifying LTBI patients in this population. The tendency for IGRAs to correlate with risk factors for TB, active TB infection and history of TB argues for their superiority over TST in dialysis patients. There was no superiority of one IGRA test over another.

Le diagnostic d'infection tuberculeuse latente (ITBL) chez les patients sous dialyse est compliqué par le peu de réponse au test cutané à la tuberculine (TCT), mais le rôle du test de libération d'interféron gamma (TLIG) au sein de la population sous dialyse demeure incertain. Les auteurs ont recruté 79 patients pour comparer le diagnostic classique (DC) aux résultats de deux TLIG au sein d'une unité de dialyse. L'association du TCT, de la radiographie pulmonaire et des résultats d'un questionnaire de dépistage (c.-à-d. le DC) a permis de dépister 24 patients comme pouvant être atteints d'une ITBL. Le TLIG a permis de dépister 22 (QuantiFERON Gold IT, Cellestis, États-Unis) et 23 (T-spot.TB, Oxford Immunotec, Royaume-Uni) patients atteints d'une ITBL. Le TLIG et le DC avaient une corrélation modérée (κ=0,59). Les résultats du TLIG étaient corrélés avec les antécédents de tuberculose (TB), les contacts atteints de TB et la naissance dans un pays endémique. Le TCT ne contribuait pas à dépister les patients atteints d'une ITBL au sein de cette population. La tendance des TLIG à être corrélés avec les facteurs de risque de TB, une infection active par la TB et les antécédents de TB laisse supposer leur supériorité par rapport au TCT chez les patients sous dialyse. Aucun type de TLIG n'était supérieur aux autres.

Risk factors for developing tuberculosis: a 12-year follow-up of contacts of tuberculosis cases.

BACKGROUND: Many risk factors for the development of tuberculosis (TB) have been reported but have not been simultaneously assessed. OBJECTIVE: To determine the risk of developing TB associated with each risk factor, after adjusting for all others. METHODS: We performed a population-based, retrospective cohort study of the contacts of TB cases recorded in British Columbia, Canada. Known risk factors for the development of TB were assessed over a 12-year period; Cox regression was used to estimate the hazard ratios (HRs) of TB, adjusting for the other factors. RESULTS: Among 33 146 TB contacts, 228 developed TB during the study period (TB rate 668 per 100,000 population, 95%CI 604-783). The main risk factors for TB development were malnutrition (HR 37.5), no treatment of latent TB infection (HR 25) or <6 months of treatment (HR 5.38), age 0-10 years (HR 7.87), being a household contact (HR 8.47) and having a tuberculin skin test induration of >or=5 mm (HR >or=4.99). Bacille Calmette-Guérin vaccination significantly reduced the risk of TB development (HR 0.32, 95%CI 0.20-0.50). CONCLUSIONS: Among contacts of TB cases, we have identified the few factors that carry a very high risk for developing TB. These factors identify populations at highest risk and permit more effective TB control.

Genetic variation in carboxylesterase genes and susceptibility to isoniazid-induced hepatotoxicity.

Treatment of latent tuberculosis infection (LTBI) generally includes isoniazid (INH), a drug that can cause serious hepatotoxicity. Carboxylesterases (CES) are important in the metabolism of a variety of substrates, including xenobiotics. We hypothesized that genetic variation in CES genes expressed in the liver could affect INH-induced hepatotoxicity. Three CES genes are known to be expressed in human liver: CES1, CES2 and CES4. Our aim was to systematically characterize genetic variation in these novel candidate genes and test whether it is associated with this adverse drug reaction. As part of a pilot study, 170 subjects with LTBI who received only INH were recruited, including 23 cases with hepatotoxicity and 147 controls. All exons and the promoters of CES1, CES2 and CES4 were bidirectionally sequenced. A large polymorphic deletion was found to encompass exons 2 to 6 of CES4. No significant association was found. Eleven single-nucleotide polymorphisms (SNPs) in CES1 were in high linkage disequilibrium with each other. One of these SNPs, C(-2)G, alters the translation initiation sequence of CES1 and represents a candidate functional polymorphism. Replication of this possible association in a larger sample set and functional studies will be necessary to determine if this CES1 variant has a role in INH-induced hepatotoxicity.

Tuberculin skin test size and risk of tuberculosis development: a large population-based study in contacts.

SETTING: Contacts of tuberculosis (TB) cases identified from eight Provincial databases in British Columbia, Canada, between 1990 and 2000. OBJECTIVE: To assess the risk of developing TB based on tuberculin skin test (TST) sizes in contacts of TB cases who did not receive treatment for latent TB infection. DESIGN: Retrospective, population-based cohort study with a 12-year follow-up. RESULTS: Among 26,542 contacts, 180 individuals developed TB (TB rate 678/100,000). Household contacts with a TST size 0-4 mm had a TB rate of 1014/100,000, those with 5-9 mm a TB rate of 2162/100,000 and those with 10-14 mm a rate of 4478/100,000. Children aged 0-10 years with 0-4 mm had a TB rate of 806/100,000, those with 5-9 mm a TB rate of 5556/100,000 and those with 10-14 mm a rate of 42,424/100,000. Immunosuppressed contacts with TST sizes 0-4 mm had a TB rate of 630/100,000, those with 5-9 mm a TB rate of 1923/100,000, and those with 10-14 mm a rate of 1770/100,000. CONCLUSIONS: TB rates were high for all TST sizes in household contacts, 0-10 year old contacts and immunosuppressed contacts. These contacts may benefit from treatment for latent TB infection, regardless of the size of their TST.

Interoceptive "satiety" signals produced by leptin and CCK.

The present studies assessed the extent to which the adiposity signal leptin and the brain-gut hormone cholecystokinin (CCK), administered alone or in combination, give rise to interoceptive sensory cues like those that are produced by a low (1h) level of food deprivation. Rats were trained with cues arising from 1 to 24-h food deprivation as discriminative stimuli. For one group, 24-h food deprivation predicted the delivery of sucrose pellets, whereas 1-h food deprivation did not. Another group received the reversed deprivation level-sucrose contingency. After asymptotic performance was achieved, the effects of leptin and CCK on food intake and on discrimination performance were tested under 24-h food deprivation. In Experiment 1a, leptin administered into the third cerebroventricle (i3vt) at 3.5 or 7.0 microg doses had little effect, compared to saline on food intake or discriminative responding. In Experiment 1b, leptin (7.0 microg, i3vt) combined with CCK-8 (2 microg/kg, i.p.) reduced food intake significantly, but the findings indicated that CCK-8 alone produces interoceptive discriminative cues more like those produced by 1- than 24-h food deprivation. Experiment 2a tested rats with i.p. leptin (0.3 and 0.5mg/kg). Although neither dose suppressed intake, the 0.3mg/kg dose produced interoceptive cues like 1-h food deprivation. Experiment 2b tested two doses of CCK-8 (2 and 4 mg/kg, i.p.) and found significant intake suppression and generalization of discrimination with both doses of CCK-8. These findings suggest a role for both leptin and CCK in the production of sensory consequences that correspond to "satiety".

Memory inhibition and energy regulation.

At a simple behavioral level, food intake and body weight regulation depend on one's ability to balance the tendency to seek out and consume food with the ability to suppress or inhibit those responses. Accordingly, any factor that augments the tendency to engage in food seeking and eating or that interferes with the suppression of these behaviors could produce (a) caloric intake in excess of caloric need; (b) increases in body weight leading to obesity. This paper starts with the idea that excess body weight and obesity stem from a failure or degradation of mechanisms that normally function to inhibit eating behavior. Unlike previous approaches, we focus not on failures of traditional physiological (e.g., neural, hormonal) regulatory control mechanisms, but on disruptions of inhibitory learning and memory processes that may help to regulate energy intake. This view of energy dysregulation as a type of "learning disorder" leads us to the hippocampus, a brain structure that has long been regarded as an important substrate for learning and memory and which we think may be critically involved with a specific type of memory inhibition function that could contribute to the suppression of food intake. With this focus, the search for environmental origins of the current obesity epidemic in Western populations is directed toward factors that alter hippocampal functioning. We conclude by offering a preliminary account of how consumption of foods high in saturated fats might lead to impaired hippocampal function, reduced ability to inhibit caloric intake and, ultimately, to increased body weight.

The interoceptive cue properties of ghrelin generalize to cues produced by food deprivation.

A number of recent studies implicate the gut-brain peptide ghrelin as a putative "hunger signal". Most of these studies, however, rely on either consummatory behavior (in humans or nonhuman animals) or self-report (in humans) to draw conclusions regarding the orexigenic properties of this peptide. The present study employs the deprivation intensity discrimination paradigm to assess the interoceptive sensory properties of ghrelin in rats. In this paradigm, one group of rats was placed in a training context and presented with sucrose pellets when 24 h food deprived, but not when 1 h food deprived (24+ group). A second group was trained using the opposite sucrose-deprivation level contingency (1+ group). Learning in this paradigm was demonstrated by animals approaching the food delivery location more frequently under their rewarded compared to their non-rewarded deprivation condition (prior to actual pellet delivery). After asymptotic performance of this discrimination was achieved, these animals (1 h food deprived) were administered ghrelin or saline, either i.p. (3 or 6 nmol) or i3vt (0.1 or 1 nmol), placed in the training context, and appetitive responses were measured. Testing was conducted in extinction, eliminating confounding effects of food consumption. Results of these tests showed that 6 nmol i.p. ghrelin and 0.1 and 1 nmol i3vt ghrelin all generalized to a state of 24 h food deprivation, indicating that exogenous ghrelin has sensory properties in common with the stimuli produced by 24 h food deprivation. These results support the notion that endogenous ghrelin contributes to an interoceptive hunger cue, and that this may be a mechanism by which ghrelin influences food intake and appetitive behavior.

Multidrug-resistant tuberculosis in Alberta and British Columbia, 1989 to 1998.

OBJECTIVE: To describe the extent of the problem of multidrug-resistant tuberculosis (MDR-TB) in Alberta and British Columbia from 1989 to 1998. DESIGN: A retrospective, population-based descriptive study of all notified MDR-TB cases in the context of all notified TB cases, all notified culture-positive TB cases and all notified drug-resistant TB cases. SETTING: Provinces of Alberta and British Columbia, and their TB registries. PATIENTS: All people with TB reported to the TB registries of Alberta and British Columbia between January 1, 1989 and June 30, 1998. MAIN OUTCOME MEASURES: Drug susceptibility testing was performed in all cases of culture-positive TB. Demographic, clinical and laboratory data on all cases of MDR-TB were recorded. RESULTS: Of 4606 notified cases of TB, 3553 (77.1%) were culture positive. Of these, 365 (10.3%) were drug resistant; of the drug-resistant cases, 24 (6.6%) were MDR. Most MDR-TB patients were foreign-born; of the four Canadian-born patients, two were infected while travelling abroad. Although foreign-born patients were significantly more likely to harbour drug-resistant strains, 14.3% versus 4.8%, respectively (P<0.001), among those who were harbouring a drug-resistant strain, the proportion of Canadian-born versus foreign-born patients with an MDR strain was the same (6.7% versus 6. 6%, respectively). From 1994 to 1998 versus 1989 to 1993, the proportion of all drug-resistant strains that were MDR was greater (9.0% versus 4.3%, respectively), but the difference was not statistically significant. Isolates from 16 of the 24 MDR-TB cases had been archived. Each of these was fingerprinted and found to be unique. Most MDR-TB cases (88%) were respiratory. Of those tested for human immunodeficiency virus (n=17), only one was seropositive. MDR-TB was 'acquired' in 67% and 'primary' in 33% of cases. Eight (33%) of the MDR-TB cases received curative courses of treatment, six (25%) are still being treated, and the remainder have either died (five, 21%), transferred out (four, 17%) or become 'chronic' (one, 4%). No secondary case of MDR-TB has been identified in Alberta and British Columbia. CONCLUSIONS: Most MDR-TB in Alberta and British Columbia is imported. The proportion of all drug-resistant cases that are MDR appears to be increasing, but not because of disease acquired from recent contact with MDR-TB in Canada.

Pulmonary disease due to Mycobacterium malmoense in British Columbia.

Mycobacterium malmoense was first described in northern Europe and the United Kingdom in 1977. Since then, reports have appeared with increasing frequency. Cases have, however, rarely been reported from the United States, and, until now, none have been reported in Canada. This may reflect either true low prevalence of the disease or under-diagnosis by laboratories due to slow growth of the organism. This report describes a case of pulmonary disease caused by M malmoense in a 44-year-old man from British Columbia who was successfully treated with an 18-month course of conventional antituberculous drugs combined with a macrolide. This is the first report of this disease in British Columbia and, to our knowledge, in Canada.

Differences in encoding for free recall vs. recognition.

Three experiments examined effects of test expectancy on memory for relatively unrelated words. In Experiment I, where preliminary recall or recognition practice was given, both recall and recognition were superior when the subjects expected and had practiced for recall. Free study led to better recall and recognition than paced presentation, but did not interact with test expectancy. Experiment II demonstrated that recall was better for subjects expecting a recall vs. a recognition test in the absence of preliminary practice. In Experiment III all subjects practiced both recall and recognition prior to presentation of the critical list. Study time also was varied. With longer study, recall was better when a recall test was expected, with no test expectancy effect on recognition. There were no appreciable expectancy effects with the short study period. Self-reports and other data suggested that the critical encoding differences produced by test expectancy manipulation were quantitative in nature.