Intrinsic activity determinations at the dopamine D2 guanine nucleotide-binding protein-coupled receptor: utilization of receptor state binding affinities.

Guanine nucleotide-binding protein-coupled receptors have been shown to exist in both a high affinity agonist (HiAg) and a low affinity agonist (LowAg) state. The formation of the HiAg state is promoted by agonists, and the formation of this state of the receptor appears to be a critical factor in the generation of the effector-activating complex G alpha.GTP.Mg2+ and in the production of a stimulus. The magnitude of the difference in the affinity a compound has for the HiAg versus the LowAg state of the receptor has been related to the intrinsic activity of the compound. In this paper the HiAg and LowAg affinities (Ki) of full and partial dopamine agonists of varying levels of intrinsic activity were determined using membranes from Chinese hamster ovary cells stably transfected with the D2i receptor. The HiAg state was defined using the recently described dopamine agonist ligand [3H]U-86170, and the LowAg state was defined using [3H] raclopride plus 600 microM GTP. The LowAg/HiAg ratios for apomorphine (43), HW-165 (12.5), (-)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine [(-)-3-PPP] (4.5), terguride (1.6), SDZ-208-911 (1.2), and SDZ-208-912 (0.3) were found to correlate well with their electrophysiologically derived intrinsic activities (r = 0.92). Using this relationship, the intrinsic activity for compounds such as (+)-3-PPP (112%), quinpirole (104%), U-68553B (102%), and U-86170 (95%) was predicted to be high (greater than 90%); (-)-apomorphine (73%) was of high/moderate intrinsic activity, HW-165 (52%), (+)-apomorphine (51%), and (-)-3-PPP (34%) were in the intermediate range, and terguride (16.5%), SDZ-208-911 (11.7%), and SDZ-208-912 (-12%) were at the lower end of the intrinsic activity spectrum. The receptor state binding-determined intrinsic activity values for quinpirole (100%), U-86170F (94.8%), HW-165 (52.1%), (-)-3-PPP (34.3%), SDZ-208-911 (11.7%), and SDZ-208-912 (-12%) were found to correlate well (r = 0.908) with their maximum response (intrinsic activity), as determined using ATP-mediated increases in arachidonic acid release from CHO-D2i cells. In addition, the maximal effect of several of these compounds on rat striatal homovanillic acid (HVA) levels was determined. The drug-induced changes in tissue HVA levels were found to be consistent with the affinity-derived intrinsic activities of the drugs.(ABSTRACT TRUNCATED AT 400 WORDS)     

Gastric air contrast: useful adjunct to hepatic artery scintigraphy

The utility of scintigraphic views obtained after administration of sodium bicarbonate-citric acid-simethicone crystals (E-Z-GAS) for the determination of gastric extrahepatic perfusion was evaluated in 20 technetium-99m macroaggregated albumin hepatic arterial perfusion studies performed in 19 patients. These crystals produce carbon dioxide gas, distend the stomach, and allow better delineation of gastric activity (extrahepatic perfusion to the stomach). Conversely, a lack of change in activity in the left upper quadrant after the effervescent crystals have been ingested suggests no gastric activity (and no extrahepatic perfusion to the stomach). These "air-contrast" views added useful information in 16 of 20 studies. In three cases prior hepatic arterial perfusion studies without air contrast were misinterpreted as lacking extrahepatic perfusion, which was only recognized on subsequent studies through the use of the air-contrast views. In another case extrahepatic perfusion was erroneously diagnosed on a hepatic arterial perfusion study without air contrast, with a follow-up air-contrast hepatic arterial perfusion study showing this to have been a false-positive diagnosis. Air-contrast views of the stomach can be extremely helpful in verifying or excluding the diagnosis of gastric extrahepatic perfusion on technetium-99m macroaggregated albumin hepatic arterial perfusion studies.     

Lipids in the pulmonary circulation after fatal trauma. A postmortem study

Lipids in the pulmonary circulation were determined biochemically and histologically in seven patients (group A) who died following multiple blunt trauma and in five patients (group B) who died of some other traumatic or nontraumatic cause. Autopsy was performed on average 4.5 hours after death. Blood samples were collected from the right ventricle (RV) and the left atrium (LA). The vasculature of the left lung was perfused in a retrograde direction. The inferior lobe of the right non-perfused lung was examined histologically. Intravascular pulmonary fat was observed in 4/6 cases in group A and in 1/5 cases in group B. No intravascular fat was observed in the tissue samples of brain, liver or kidney. The concentration of free fatty acids (FFA) in blood from RV was higher than in blood from LA both in group A (P is less than 0.01) and in group B (P is less than 0.05). The considerable difference in concentrations of FFA between RV and LA and the low concentration of FFA in the lung perfusate may be due to some kind of "fixation" of FFA in the lung tissue, possibly connected with the aetiological factors of the fat embolism syndrome (FES).     

Pre- and postsynaptic dopaminergic activities of U-86170F

Summary The biochemical, endocrine, receptor binding, and behavioral effects of the putative dopamine autoreceptor agonist, U-86170F, were evaluated in various in vivo and in vitro models. U-86170F and apomorphine were shown to cause a significant reversal of the effects of -butyrolactone (GBL) on dopamine accumulation in mouse striata. In contrast to apomorphine, U-86170F had a ceiling effect on the extent of the reversal of GBL effects (55%), whereas apomorphine had an 82% reversal. The effect on striatal homovanillic acid (HVA) levels was also monitored, and both compounds exerted a similar and significant reduction in striatal HVA. A comparison was made between the effects of intraperitoneal (i.p.) and oral administration of U-86170F in the -methyl-p-tyrosine (-MPT)/prolactin model in rats. When administered by the i.p. route, U-86170F suppressed the effects of -MPT on prolactin level increase, having an ED₅₀ of about 0.03 mg/kg, and when administered by the oral route, its ED₅₀ was approximately 0.1 mg/kg. U-86170F has been shown to be a potent dopamine autoreceptor agonist in the GBL, prolactin, and HVA models, with an effective i.p. dose of approximately 0.03 mg/kg. When evaluated for postsynaptic dopaminergic activity in the reserpinized mouse model, and compared to apomorphine, U-86170F was found to increase locomotor activity, but its maximum effect was only 65% of that attained with apomorphine. Higher doses were needed for postsynaptic effects.In receptor binding studies using cloned D2 receptor preparations, U-86170F was found to exhibit agonist binding properties similar to dopamine as demonstrated by their inhibition of 3H-raclopride binding. Both compounds exhibited biphasic inhibition curves, with U-86170F having K_i values of 7.5 nM and 250 nM, and for dopamine the K_i values were 34.7 nM and 1031 nM. Binding studies conducted in the presence of GTP yielded only one site with Kis of 289 nM and 670 nM, for both U-86170F and dopamine, respectively.The results presented in this report demonstrated that U-86170F is a potent dopamine autoreceptor agonist, with limited activity at the postsynaptic receptor. Send offprint requests to R.A. Lahti at the above address     

Brain activation patterns in schizophrenic and comparison volunteers during a matched-performance auditory recognition task

OBJECTIVE: The biological characteristics of schizophrenia are often studied by using functional imaging techniques. However, since volunteers with schizophrenia routinely fail to perform as accurately or as quickly as healthy volunteers, it is difficult to ascertain whether a particular deficit in blood flow to a brain region is due to behavior or to the underlying illness. In this report, investigators used an auditory recognition task to assess brain blood flow patterns and behavioral correlates of schizophrenic patient volunteers trained on the task. METHOD: Twelve healthy volunteers and 18 volunteers with schizophrenia were trained to make tone frequency recognitions. Accuracy and stimuli were matched between groups. Participants were required to press a button to indicate whether a briefly presented tone was the high-frequency (1500 Hz) reference tone or one of a lower frequency level (level chosen to elicit an 80% accuracy score). Subjects underwent bolus [(15)O]H(2)O blood flow positron emission tomography during inactive rest, a sensory motor control condition, and the decision task. Blood flow patterns were assessed between conditions and between groups. RESULTS: As a group, the patients with schizophrenia (who performed as quickly and accurately as the comparison subjects) exhibited significantly less change in regional cerebral blood flow (rCBF) to the anterior cingulate and supplementary motor cortices when switching from the sensory motor control to the decision condition. There were also marked between-group differences in correlations between rCBF and response time. Whereas the comparison subjects exhibited progressively greater blood flow to the frontal cortex in association with longer response times, the schizophrenic patients exhibited progressively lower blood flow in conjunction with extended response times. CONCLUSIONS: The failure to appropriately enhance cingulate activity when engaged in a demanding task and the progressive, time-dependent decline in frontal blood flow suggest that patients with schizophrenia are unable to make optimal use of frontocingulate systems when maximally engaged in high-error tasks.     

Smoking among participants in the childhood cancer survivors cohort: the Partnership for Health Study.

PURPOSE: This article describes baseline data collection and the intervention design of Partnership for Health, a smoking cessation intervention for smokers in the Childhood Cancer Survivors Study. The purpose of this article is to evaluate demographic, psychosocial, and cancer-related factors that are associated with smoking behavior and mediators of smoking cessation. PATIENTS AND METHODS: This study includes 796 smokers from the Childhood Cancer Survivors Study database who were diagnosed with cancer before the age of 21, had survived at least 5 years, and were at least 18 years of age at the time of the baseline survey. Correlates of smoking behaviors included smoking rate, number of recent quit attempts, and nicotine dependence; two key mediators of smoking cessation, readiness to quit smoking and self-efficacy, were also assessed. RESULTS: Participants smoked, on average, 14 cigarettes/day; 53.2% were nicotine dependent, and 58% had made at least one quit attempt in the past year. Smoking behaviors were primarily associated with demographic variables; mediators of cessation were primarily associated with age at cancer diagnosis and perceived vulnerability to smoking-related illnesses. Severity of psychologic symptoms was associated with increased smoking rate, high nicotine dependence, and low self-efficacy. Support for quitting was related to smoking rate, number of quit attempts, readiness to quit smoking, and self-efficacy. CONCLUSION: These findings indicate that many cancer survivors who smoke are receptive to smoking cessation interventions. Factors related to mediators of smoking cessation might be particularly good targets for intervention.     

Dental fear affects adolescent perception of interaction with dental staff

The main purpose of this study was to explore whether subjective perception of interaction with dental staff is associated with dental fear in a population‐based sample of 18‐yr‐old adolescents (n = 773). The interaction was measured using the Patient Dental Staff Interaction Questionnaire (PDSIQ), validated with exploratory and confirmatory factor analyses, which yielded the factors of ‘kind atmosphere and mutual communication’, ‘roughness’, ‘insecurity’, ‘trust and safety’, and ‘shame and guilt’. Dental fear was measured using the Modified Dental Anxiety Scale (MDAS). Gender and sense of coherence (SOC) were included as potential confounding variables. Adolescents with high dental fear more often perceived their interaction with dental staff negatively and more often felt insecure than others. This difference persisted after adjustment for gender and SOC. In conclusion, adolescents with high dental fear may perceive their interaction with dental staff more positively if the staff succeed in creating a positive, trusting, approving, and supportive atmosphere with kindness, calmness, and patience. The communication and interaction skills of dental staff may play a particularly important role when encountering highly fearful dental patients.     

Oral health behavior at age of 11–12 years predicting educational plans at age of 15–16 years

Objective. The aim was to determine if oral health-related behavior at the age of 11–12 years predicts adolescents' educational plans at the age of 15–16 years when adjusting for gender and parents' occupational level. Materials and methods. The study population consisted of all fifth and sixth graders starting in the 2001–2002 school year in Pori, Finland (n = 1691); of these, 1467 returned properly filled questionnaires on behavior (toothbrushing and consumptions of xylitol products, candies, soft drinks and sports drinks) in 2001 and on educational plans in 2005. Parents' occupational levels were reported in 2001 by one of the parents of 1352 of these children. Associations between adolescents' educational plans and their behavior, gender and parents' occupation were evaluated using logistic regression model. Results. Children's oral health-related behavior at age 11–12, gender and parent's occupational level predicted their educational plans at age 15–16. Association between educational plans and behavior, especially cumulative health behavior, remained statistically significant when controlling for gender and parent's occupation: OR = 1.4 for difference of one good habit, and OR = 5.3 for difference of five good habits. Conclusions. Since difference in oral health-related behavior can be seen already in primary school, even when controlling for parents' occupational level, polarization of adolescents may begin already in primary school stage or even earlier.     

Inequality in oral health‐related quality of life before and after a major subsidization reform

In Finland, a dental subsidization reform, implemented in 2001–2002, abolished age restrictions on subsidized dental care. We investigated income‐related inequality in oral health‐related quality of life (OHRQoL) and its determinants among adult Finns before and after the reform. Three cross‐sectional postal surveys, focusing on perceived oral health and the use of dental services among people born before 1971, were conducted in 2001 (n = 2,046), 2004 (n = 1,728), and 2007 (n = 1,560). Five measures, based on the Oral Health Impact Profile‐14, were used as indicators of OHRQoL. Income‐related inequality and associated factors were analysed using the concentration index and its decomposition. Prevalence, extent, and severity of oral health impacts were slightly lower in 2007 than in 2001. The oral health impacts were concentrated, at all study time points, among individuals with lower income. Most of the inequality was related to self‐perceived general health, tooth loss, and income. Contributions of time since the last dental visit and satisfaction with the last treatment period to the inequality decreased from 2001 to 2007. However, the contributions of these factors were already small (10–20%) in 2001. In general, OHRQoL improved slightly; however, no clear or dramatic change in inequality in OHRQoL was seen after the reform.     

A juvenile sheep model for the long-term evaluation of stentless bioprostheses implanted as aortic root replacements

BACKGROUND AND AIM OF THE STUDY: Orthotopic valve replacement in large animals is an important component of the preclinical assessment of bioprosthetic valves. To provide the most useful preclinical information, the development of models that parallel clinical practice patterns is essential. Therefore, we sought to develop a technically feasible and reproducible model for chronic evaluation of stentless bioprosthetic aortic valves implanted as aortic root replacements in juvenile sheep. METHODS: Juvenile domestic sheep (mean age 21+/-2.28 weeks; range: 17-26 weeks) underwent aortic root replacement using standard cardiopulmonary bypass (CPB) and surgical techniques. Animals were implanted with 19 mm (n = 21), 21 mm (n = 18) or 23 mm (n = 4) bioprostheses from two different manufacturers, and followed for 150 days. Animals surviving at least 150 days were considered long-term survivors; those which died prior to postoperative day (POD) 31 were considered operative deaths. RESULTS: Forty-three animals underwent aortic root replacement. The mean CPB time was 91+/-20 min (range: 62-149 min); mean cross-clamp time was 63+/-13 min (range: 39-95 min). Thirty-five animals (81%) survived the first 30 days of the study period. Five deaths occurred at POD 0 due to anastomotic complications. One death occurred each on POD 3, 6, and 26 as a result of prosthesis size mismatching, thromboembolic complications, and endocarditis, respectively. There were five late deaths. Twenty animals survived the minimum 150-day study period, and 12 were sacrificed at 183+/-17 days. Six animals remain alive at 151+/-0.98 days, and one animal died each on POD 184 and 190. The remaining 10 animals are not yet 150 days from their operation. Currently, all are well at 102+/-34 days (range: 33-140) days. CONCLUSION: These data suggest that long-term evaluation of stentless aortic bioprostheses implanted as aortic root replacements can be accomplished using juvenile sheep.