SR-141716A-induced stimulation of locomotor activity. A structure-activity relationship study

The central cannabinoid receptor (CB(1)) antagonist, SR-141716A, has been used extensively to ascertain that cannabinoids interact with the CB(1) receptor. SR-141716A has been shown to produce effects opposite of cannabinoids when administered alone. It has been theorized that SR-141716A may act as an inverse agonist at the CB(1) receptor or by disinhibiting an endogenous cannabinoid tone. In an effort to ascertain the exact interaction between SR-141716A and the CB(1) receptor, we have conducted a structure-activity relationship study to compare CB(1) receptor affinity of SR-141716A analogs with their ability to produce an increase in locomotor activity. SR-141716A produced a significant increase in locomotor activity in mice within the first hour of administration. Twenty SR-141716A analogs from five different chemical series were also tested. Our data implicate particular regions of the SR-141716A molecule that may be involved in stimulation and depression of locomotor activity. When the K(I) of the analogs was plotted against the percent stimulation that each analog produced, it is evident that there is no correlation between the ability of the analogs to stimulate locomotor activity and their affinity for the CB(1) receptor. [35S]GTPgammaS binding data indicate that SR-141716A and five of the analogs are inverse agonists. However, none of the analogs demonstrating inverse agonism produce stimulation of locomotor activity. It is therefore concluded that the SR-141716A-induced stimulation in locomotor activity is not the result of inverse agonist activity at the CB(1) receptor or by disinhibition of an endogenous tone.     

Molecular epidemiology of multidrug-resistant tuberculosis,New York City, 1995-1997

From January 1, 1995, to December 31, 1997, we reviewed records of all New York City patients who had multidrug-resistant tuberculosis (MDRTB); we performed insertion sequence (IS) 6110-based DNA genotyping on the isolates. Secondary genotyping was performed for low IS6110 copy band strains. Patients with identical DNA pattern strains were considered clustered. From 1995 through 1997, MDRTB was diagnosed in 241 patients; 217 (90%) had no prior treatment history, and 166 (68.9%) were born in the United States or Puerto Rico. Compared with non-MDRTB patients, MDRTB patients were more likely to be born in the United States, have HIV infection, and work in health care. Genotyping results were available for 234 patients; 153 (65.4%) were clustered, 126 (82.3%) of them in eight clusters of >or=4 patients. Epidemiologic links were identified for 30 (12.8%) patients; most had been exposed to patients diagnosed before the study period. These strains were likely transmitted in the early 1990 s when MDRTB outbreaks and tuberculosis transmission were widespread in New York.     

Dietary modifications and gene polymorphisms alter serum paraoxonase activity in healthy women

Paraoxonase-1 (PON1), a HDL-associated enzyme, may protect against the development of atherosclerosis. Serum PON1 activity and PON1-mediated capacity of HDL to prevent lipoprotein oxidation are modulated by two common polymorphisms at positions 192 (Gln-->Arg) and 55 (Leu-->Met) of the PON1 gene. We studied the effect of dietary modifications on PON1 activity and the role of PON1 gene polymorphisms in the response. A controlled, crossover dietary intervention of two 5-wk periods was conducted in 37 healthy, nonsmoking women. The two study diets were either low or high in vegetables, and thus in natural antioxidants, with some differences in fatty acid contents. The mean plasma total (-8%, P < 0.001), LDL (-7%, P < 0.01) and HDL (-7%, P < 0.001%) cholesterol, and apolipoprotein A-I (-8%, P < 0.001) concentrations were lower after the high vegetable diet period than after the low vegetable diet period. Also, the serum PON1 activity was lower (P < 0.05) after the high vegetable compared with the low vegetable diet period. The reduction of PON1 activity correlated with the reduction in HDL cholesterol (r = 0.35, P < 0.05). High baseline PON1 activity was related to the presence of the PON1(192Arg) allele (P < 0.001) and PON1(55Leu/Leu) genotype (P < 0.001). The reduction of PON1 activity due to the high vegetable diet was greatest among the women with the PON1(192Arg) allele (P < 0.05) and PON1(55Leu/Leu) genotype (P < 0.05). In conclusion, a diet high in vegetables, berries and fruit reduces PON1 activity, and the response is modulated by the genetic variance of PON1.     

7,12-dimethylbenz[a]anthracene interferes with the development of cultured mouse mandibular molars.

Clinical studies suggest that maternal smoking during pregnancy can reduce the crown size of the child's teeth. Delayed dental age compared with chronological age has also been reported in children whose parents smoke. Among the main components of tobacco smoke are nonhalogenated polycyclic aromatic hydrocarbons (PAHs), many of which are highly toxic. Humans are exposed to PAH compounds mainly via tobacco smoke and diet. The aim of our study was to investigate the effect of PAHs on tooth formation and the function of tooth-forming cells. We exposed mouse (NMRI) E18 mandibular first and second molar explants to 7,12-dimethylbenz[a]anthracene (DMBA), a toxic PAH compound, in organ culture for 7 or 12 days. DMBA concentrations used were 0.1, 0.5, 1, and 2 microM. The mesiodistal width of each first molar (12-day culture) was measured in stereomicroscopic images, and the teeth were analysed histologically. DMBA exposure significantly reduced the mesiodistal width of the first molars. DMBA impaired or delayed amelogenesis and dentinogenesis in both molars at the lowest concentration of 0.1 microM. DMBA affected enamel formation more severely than dentin formation and occasionally prevented amelogenesis completely. Elongation and polarization of ameloblasts were impaired, and blood vessel architecture of the dental papilla (future pulp) was altered. Cusps were thin and sharp. In line with the finding that maternal smoking during pregnancy has an adverse effect on child's tooth development, this study shows the toxic influence of PAHs on tooth development in vitro.     

Challenging the imperative of health? Smoking and justifications of risk-taking

It has been argued that with the decline in the prevalence of smoking, a number of the remaining smokers have become more resilient to health-promotion efforts. In this article, the justifications of smoking in web discussions are analysed, concentrating on perceptions of risk. While previous research concerning lay knowledge has brought out ambivalent meanings of the concept, smoking as a well-known health risk provides an excellent example for studying counter-reactions to current health discourses. Analysis shows the similarities between justifications of smoking and current health ideologies: argumentation stressed personal responsibility and self-management. However, following rules and health recommendations was juxtaposed with ideals of the autonomous, competent individual. While argumentation reflected the basic principles of the imperative of health, a challenging feature emerged through the accounts that disregarded risk. It is suggested that disregard of risks represents a real challenge for the imperative of health by ignoring the notions of autonomy and competence.     

Fever and neutropenia in children with cancer: diagnostic parameters at presentation

We evaluated 91 episodes of fever in 46 profoundly neutropenic children with cancer, in a search for any symptom, sign or laboratory test that would serve to identify patients with septicemia and differentiate them from those in no immediate need of prompt antimicrobial therapy. Seventeen episodes (19%) were bacteremias, 59 (64%) were suspected septic infections, 9 (10%) were focal bacterial infections and 6 (7%) proved not to be bacterial infections. We were unable to detect any parameter, either on admission or after two days of antimicrobial therapy (except for blood culture findings), that would be helpful in differentiating bacteremia from an episode not of bacterial origin. We focused on serum levels of C reactive protein and found them unreliable on an individual level. Prompt institution of antimicrobial therapy at the occurrence of fever results in low mortality, but does not allow assignment of cases to different categories.     

Recombinant human growth hormone treatment after liver transplantation in childhood: the 5-year outcome

BACKGROUND: Because the results of short-term recombinant human growth hormone (rhGH) treatment in children with growth impairment after liver transplantation (LTx) have been promising, we have studied the long-term effects of rhGH on growth and graft function after LTx. METHODS: Indications for rhGH treatment were height standard deviation score (hSDS) below -2.0 or growth velocity SDS below 0 and LTx at least 18 months before inclusion. Eight growth-retarded children were treated with rhGH for more than 5 years. RESULTS: During the first year, median growth rate improved from 3.3 to 7.0 cm/year. In the second and third year, growth velocity remained high at 6.6 cm/year and 6.2 cm/year, respectively (P=0.008). In the fourth year, median growth velocity started to decline but still remained above baseline during the fifth year of treatment (4.2 cm/year). The median hSDS improved from -3.6 to -2.7. During the rhGH treatment, no acute rejection episodes were detected, and graft function remained stable in all except one patient. She was diagnosed with chronic rejection in the third year of rhGH treatment. The patient had elevated liver enzymes and abnormal liver function tests already before rhGH treatment. CONCLUSIONS: The efficacy of rhGH treatment is sustained after the first year in liver-transplant children with non-GH-deficient growth retardation. Because of a potential risk of side effects, close monitoring of these patients is required.     

Effect of sampling frames on response rates in the WHO MONICA risk factor surveys

Sample surveys are used to investigate occurrence and determinants of diseases in populations. Their reliability is influenced by quality of sampling frame and response rate. We investigated relationship between sampling frame type and response rates and assessed their impact on non-response bias, using data from the WHO MONICA Project, where 37 centres in 20 countries conducted sample surveys, employing the best locally available sampling frame. Sampling frames fell into three categories: Population registers (PR), electoral registers (ER), and health care registers (HR). Response rate (rrs) was factored into components reflecting quality of sampling frame (contact rate cr) and characterizing willingness of sample members to participate (enrolment rate er). The mean quality score for the sampling frames was 92 for PR, 87 for HR and 85 for ER; they contributed on average 23, 20, and 26 to the respective non-response rates. For all frame types and both sexes the lowest quality score occurred in the age group 35–44, suggesting a reduced ability to track migration of a highly mobile population group. The patterns in the age/sex distribution of er indicate at least for males in PR and females in HR a potential for non-response bias. Estimation of non-response bias through an abbreviated questionnaire failed because of low item response. We found that contact rate characterizes sampling frame quality. For all frame types it had a major influence on response rate. It is likely that low er and low cr cause different kind of bias, requiring different measures to minimize their effects.for the WHO MONICA Project** Sites and key personnel of the WHO MONICA Project are found at http://www.ktl.fi/publications/monica/rr_sframe/appendix.htm