Striatal dopamine D2 receptors in modulation of pain in humans: a review

We review evidence indicating that the striatum and striatal dopamine D2 receptors are involved in the regulation of pain in humans. Painful stimulation produces an increase in regional cerebral blood flow in the human striatum. Pain is a common symptom in patients with nigrostriatal dopaminergic hypofunction. Positron emission tomography findings show that a low dopamine D2 receptor availability in the striatum of healthy subjects (indicating either a low density of dopamine D2 receptors or a high synaptic concentration of dopamine) is associated with a high cold pain threshold and a low capacity to recruit central pain inhibition by conditioning stimulation. Patients with chronic orofacial pain have higher dopamine D2 receptor availability than their age-matched controls. We propose that the striatal dopamine D2 receptor may be an important target for the diagnosis and treatment of chronic pain.     

Developmental toxicity of dioxin to mouse embryonic teeth in vitro: arrest of tooth morphogenesis involves stimulation of apoptotic program in the dental epithelium

Previous studies have shown that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can arrest molar tooth development in rats after in utero and lactational exposure, and that the sensitive stage is temporally restricted. To define the stage in which TCDD is able to arrest tooth development and the cellular background of the effect, mouse embryonic molar tooth explants including various early developmental stages from initiation to late cap stage were exposed to TCDD in organ culture. TCDD did not inhibit morphogenesis of the first molar teeth including the early bud-staged E12 first molars, but the teeth were smaller than in control cultures. Accordingly, the second molars underwent morphogenesis in the presence of TCDD when explanted at E15 when they were at the bud stage. TCDD arrested their development when explanted at E14 when they had not yet reached the early bud stage. Immunohistochemical localization of incorporated bromodeoxyuridine in cultured E14 teeth showed that TCDD did not affect cell proliferation. Localization of apoptosis by terminal deoxynucleotidyl transferase (TdT)-mediated nick end labeling (TUNEL) method revealed that TCDD enhanced apoptosis of dental epithelial cells, especially in the dental lamina of both the first and second molars, and in the inner dental epithelium at the cusp tips of the first molars. Thus, TCDD can arrest tooth development in vitro if the exposure starts at the initiation stage, whereas exposure at later stages leads to smaller tooth size and deformation of cuspal morphology. TCDD interferes with tooth development by stimulating apoptosis in those cells of the dental epithelium, which are predetermined to undergo apoptosis during normal development.     

Relationship between children's first dental visit and their dental anxiety in the Veneto Region of Italy

The aim of this study was to explore the association between negative experiences during children's first dental visit and any subsequent dental anxiety and related factors in three dental clinics in the Veneto Region of Italy. For this purpose, parents of 378 children filled out a questionnaire. Factors related to child dental anxiety (none-some/fairly much-very much) were explored by means of logistic regression analysis. The independent variables were: problems with tht first dental visit (no/yes), parental dental anxiety (none-some/fairly much-very much), number of previous visits (0-3/4 < or =) site visited (public/private) and age of the child (< 10 years/10 < or = years). Parental anxiety was associated with child's anxiety (OR = 2.3, 95% CI = 1.1-4.9). A problematic first visit was a strong predictor of dental anxiety. However, this effect was modified by the number of subsequent visits. Children with 4 or more visits after the first visit were less likely to be anxious after a problematic first visit (OR = 4.6, 95% CI = 1.5-14.1) than children with 3 visits or less after the first visit (OR = 19.8, 95% CI = 7.2-54.5). Thus, the negative effect of a problematic first visit may fade during subsequent dental visits.     

Body fat distribution and cortisol metabolism in healthy men: enhanced 5beta-reductase and lower cortisol/cortisone metabolite ratios in men with fatty liver

In Cushing's syndrome, cortisol causes fat accumulation in specific sites most likely to be associated with insulin resistance, notably in omental adipose and also perhaps in the liver. In idiopathic obesity, cortisol-metabolizing enzymes may play a key role in determining body fat distribution. Increased regeneration of cortisol from cortisone within adipose by 11beta-hydroxysteroid dehydrogenase (HSD) type 1 (11HSD1) has been proposed to cause visceral fat accumulation, whereas decreased hepatic 11HSD1 may protect the liver from glucocorticoid excess. Increased inactivation of cortisol by 5alpha- and 5beta-reductases in the liver may drive compensatory activation of the hypothalamic-pituitary-adrenal axis, hence increasing adrenal androgens and 'android' central obesity. This study aimed to examine relationships between these enzymes and detailed measurements of body fat distribution. Twenty-five healthy men (age, 22-57 yr; body mass index, 20.6-35.6 kg/m(2)) were recruited from occupational health services. Body composition was assessed by anthropometric measurements, bioimpedance, and cross-sectional abdominal magnetic resonance imaging scans. Liver fat content was assessed by magnetic resonance imaging spectroscopy. Insulin sensitivity was measured in a euglycemic hyperinsulinemic clamp. Cortisol metabolites were measured in a 24-h urine sample by gas chromatography-mass spectrometry. In vivo hepatic 11HSD1 activity was measured by generation of plasma cortisol after an oral dose of cortisone. In vitro 11HSD1 activity and mRNA were measured in 18 subjects who consented to provide abdominal sc adipose biopsies. Indices of obesity (body mass index, whole-body percentage fat, waist/hip ratio) were associated with higher urinary excretion of 5alpha- and 5beta-reduced cortisol metabolites (for percentage fat, P < 0.05 and P < 0.01, respectively) and increased adipose 11HSD1 activity (P < 0.05). Liver fat accumulation was associated with a selective increase in urinary excretion of 5beta-reduced cortisol and cortisone metabolites (P < 0.01) and a lower ratio of cortisol/cortisone metabolites in urine (P < 0.001) but no difference in in vivo cortisone-to-cortisol conversion or in vitro adipose 11HSD1. Higher excretion of 5beta-reduced cortisol metabolites was independently associated with insulin resistance and hypertriglyceridemia. Lower conversion of cortisone to cortisol was associated with lower fasting plasma cortisol (P < 0.01). However, visceral adipose fat mass was not associated with indices of cortisol metabolism; indeed, after adjusting for the effects of whole-body and liver fat, increased visceral fat was associated with lower cortisol metabolite excretion. We conclude that alterations in 11HSD1 and hepatic 5alpha-reductase activity are associated with generalized, rather than central, obesity in humans. Activation of 5beta-reductase in men with fat accumulation in the liver may confound the interpretation of cortisol metabolite excretion when liver fat content is unknown, and may contribute to altered bile acid and cholesterol metabolism in nonalcoholic steatohepatitis.     

No variants in the cardiac actin gene in Finnish patients with dilated or hypertrophic cardiomyopathy

Background Dilated and hypertrophic cardiomyopathies are primary myocardial diseases that cause considerable morbidity and mortality. Although these cardiomyopathies are clinically heterogeneous, genetic factors play an important role in their etiology and pathogenesis. The defects in the cardiac actin (ACTC) gene can cause both cardiomyopathies. The aim of our study was to screen for variants in the ACTC gene in patients with dilated or hypertrophic cardiomyopathy from Eastern Finland. Materials and Methods Altogether, 32 patients with dilated and 40 patients with hypertrophic cardiomyopathy were included in the study. Commonly approved diagnostic criteria were applied, and secondary cardiomyopathies were carefully excluded. All 6 exons of the ACTC gene were amplified with polymerase chain reaction and screened for variants with single-strand conformation polymorphism analysis. Results and Conclusion We did not find any new or previously reported variants. Our results indicate that defects in the ACTC gene do not explain dilated cardiomyopathy or hypertrophic cardiomyopathy in subjects from Eastern Finland and confirm earlier results that the ACTC gene does not play an important role in the genetics of dilated or hypertrophic cardiomyopathies. (Am Heart J 2002;143:11-4.)     

Human leukocyte antigen-B8-DR3 is a more important risk factor for severe Puumala hantavirus infection than the tumor necrosis factor-alpha(-308) G/A polymorphism

The tumor necrosis factor (TNF)-alpha(-308) G/A polymorphism (TNF-2) is in linkage disequilibrium with the human leukocyte antigen (HLA)-B8-DR3 haplotype. Both factors have been associated with severe Puumala hantavirus-induced nephropathia epidemica (NE). To examine which part of this extended haplotype might show the strongest association with the outcome of NE, the HLA-B, HLA-DRB1, and TNF-alpha(-308) alleles in 116 hospital-treated patients with NE were analyzed. The findings pointing to clinically severe NE were strongly associated with HLA-B8-DR3 haplotype. There was a trend toward severe disease in persons positive for TNF-2. This was probably due to strong linkage disequilibrium with HLA-B8-DR3, since there were no differences in the clinical severity of NE when TNF-2-positive/B8-DR3-negative persons were compared with TNF-2-negative/B8-DR3-negative persons. It is concluded that the HLA-B8-DR3 haplotype is an important contributor to the course of NE. The data indicate that the TNF-2 allele is not an independent risk factor for severe NE but a passive component in the extended haplotype.     

Interrelationships between muscle structure,muscle strength,and running economy

PURPOSE: The present study was designed to investigate possible differences in running economy (RE) among elite middle-distance runners by examining muscle structure and maximal isometric force (MVC). METHODS: Ten young male runners ran at six different running speeds. During the running bouts, respiratory gases, and blood lactate were measured. Muscle biopsies were obtained from the vastus lateralis muscle for analyzing fiber type distribution, muscle fiber area, myosin heavy chain (MHC) composition, activities of a number of metabolic enzymes (citrate synthase, lactate dehydrogenase, phosphofruktokinase, and 3-hydroxyacyl-CoA-dehydrogenase), and titin isoforms. RESULTS: Energy expenditure (EE) increased linearly up to the speed of 6.0 m.s. The relative distribution of the MHC isoforms was MHC I: 67.0%, MHC IIA: 31.5%, and MHC IIX: 1.5%. The present results demonstrated that higher the area of Type II fibers, higher the MVC (r = 0.59, P< 0.05). The amount of MHC II correlated inversely with EE when running close to the competition speed (r = -0.61, P< 0.05). Enzyme activities did not correlate significantly with either RE or EE. Titin analysis revealed that a faster-mobility titin band was observed in all subjects, whereas a lower-mobility titin band was observed only in the most economical runner. CONCLUSION: Differences in RE among homogeneous group of middle-distance runners were observed at various running speeds. This may partly be explained by differences in muscle fiber distribution, MHC composition, and titin isoforms.     

Efficacy of a slow-release device containing fluoride, xylitol and sorbitol in preventing infant caries

A novel slow-release administration device, the "Fall-Asleep Pacifier" (FAP), was studied as a prophylactic measure against mutans streptococcal oral infection and dental caries in a risk group of 1-year-old children by comparing the test (T, n = 34) and control (C, n = 88) groups in a prospective cohort study. In the T group the children received their fluoride tablets (Fludent, containing NaF corresp. 0.25 mg F0- , xylitol 159 mg and sorbitol 153 mg) in the evenings in FAP. In the C group the children received the same dose of Fludent crushed in food in the evenings. The proportion of children, whose plaque samples from the upper incisors were mutans streptococcus positive at the age of 24 months, was significantly (P < 0.05) greater in group C (25%) than in group T (9%). The children in the T group developed significantly (P < 0.001) less (none) new dentinal carious lesions in their primary dentitions than the children in the C group between 2 and 3 1/2 years of age. Fifty-four percent of the children to whom the FAP was offered complied with regular use of it. The beneficial effect observed in the T group compared with the C group was apparently mostly due to the administration mode via FAP, which could prolong the intra-oral bioavailability of the prophylactic preparation.     

CO2 gas perfusion: improved efficiency and safety with sapphire-probe laser ablation of human artery.

CO2 gas has been proposed as a new perfusion medium for laser angioplasty. To compare CO2 gas with conventional saline perfusion, 146 fresh specimens of normal and atheromatous human artery were irradiated with a neodymium: yttrium-aluminum-garnet laser with a sapphire probe in flowing whole blood in an experimental circulation-occlusion model. The dimensions of the ablation crater and the extent of the surrounding tissue damage were measured microscopically. Significantly better ablation of atheromatous plaque was achieved with CO2 perfusion than with saline perfusion: mean ablation areas were 5.0 mm2 versus 2.8 mm2, respectively (P = .001, Student t test). In contrast, the ablation areas on normal vessel wall were identical (mean, 3.4 mm2) with the two perfusion media. Moreover, CO2 gas functioned as a negative contrast agent and facilitated direct monitoring of the laser recanalization procedure. On an experimental basis, CO2 gas perfusion seems to improve the efficiency and safety of laser ablation in human arteries.