HLA-DRB1 genes and disease severity in rheumatoid arthritis. The MIRA Trial Group. Minocycline in Rheumatoid Arthritis

OBJECTIVE: To examine the effect of alleles encoding the "shared"/"rheumatoid" epitope on rheumatoid arthritis (RA) disease severity in patients who participated in the minocycline in RA (MIRA) trial. METHODS: Of 205 patients with a week-48 visit, blood was available for typing of HLA-DRB1 and HLA-DQB1 in 174 (85%) and successfully completed in 169 (82%). Baseline erosions were used to assess disease severity and new erosions at the last visit served as a proxy for progression. RESULTS: At baseline, there was no association between the presence of erosive disease or rheumatoid factor status and the dose of rheumatoid epitope (homozygous, heterozygous, none) or the specific alleles identified. At the final visit, a gradient was observed for the 3 allelic subgroups (and their gene doses) in the occurrence of new erosions among the Caucasian placebo-treated, but not the minocycline-treated, patients. A treatment group/HLA-DR4 epitope interaction was demonstrated in multivariate analyses. Approximately two-thirds of African-American patients did not have the rheumatoid epitope. CONCLUSION: HLA-DRB1 oligotyping may be useful in predicting the progression of disease in some Caucasian patients. Our study corroborates the infrequency of the epitope among African-American patients with RA.     

Physician judgments of chronic pain patients

Recent evidence has indicated that physician judgments of patients can be influenced by contextual factors. This study examined three contextual factors relevant to hypothetical patients with low back pain, using vignettes that were varied in a 2 x 2 x 2 factorial design: level of reported pain (high vs low), level of supporting medical evidence (high vs low), and the valence of the physician-patient interaction (positive vs negative). Perceived levels of pain, disability, emotional distress, and somatic preoccupation were rated by internists after reading a vignette. Ratings of pain and disability were lower for patients without supporting medical evidence; ratings of distress, somatic preoccupation, and disability were greater for patients who exhibited negative rather than positive affect; internist ratings of pain were lower than patient ratings among patients reporting high levels of pain, while ratings were inflated for patients with low levels of pain. The results suggest that characteristics of both the patient and the situation may influence medical judgments.     

Catecholamine response during 12 days of high-altitude exposure (4, 300 m) in women

Atrial natriuretic peptide (ANP) has been considered a potential candidate participating in the inhibitory control of pituitary-adrenal secretory activity. Here, we investigated the influence of ANP, infused at two different doses and over infusion intervals of two different durations, on the release of ACTH and cortisol after stimulation with CRH and with combined administration of CRH and vasopressin (VP). In young healthy men, three experiments were conducted. In Exp I, ACTH/cortisol secretory responses to CRH (50 microg) were examined during and after a 45-min period of ANP infusion at a rate of 4.4 microg/min (starting 15 min before CRH injection). In Exp II, ACTH/cortisol secretory responses to CRH (50 microg) were examined during and after a 90-min infusion period of ANP administered at rates of 4.4 and 8.8 microg/min. In Exp III, ANP was infused at a rate of 4.4 microg/min over 90 min, but instead of CRH, a combined administration of CRH (50 microg) and VP (0.5 IU infused within 5 min) was employed to stimulate ACTH/cortisol release. ANP diminished pituitary-adrenal secretory responses within the first hour after stimulation with exogenous secretagogues. Thereafter, the effect of ANP turned in the opposite direction, with distinctly enhanced concentrations of ACTH and cortisol during the third hour after stimulation. The inhibitory effect of ANP during the first hour of the pituitary-adrenal response was more pronounced on concentrations of cortisol than ACTH and was also more pronounced after combined administration of CRH/VP than after stimulation with CRH alone. Increasing the dose of ANP enhanced the late stimulatory effect on ACTH/cortisol release, thereby terminating the early period of inhibited ACTH/cortisol release more abruptly. The late stimulatory effect was enhanced with prolonged infusion of ANP. In addition, it was associated with reduced hematocrit, increased urine volumes collected, increased heart rate, and enhanced plasma VP concentrations. Together, these changes suggest that the late stimulatory effect of ANP on ACTH/cortisol release reflects an effect secondary to its hypovolemic actions. This stimulatory effect originating from peripheral systemic actions of ANP after exogenous administration appears to override a more direct inhibitory action of the peptide on pituitary-adrenal secretory activity. Therefore, we would expect that with localized release into portal hypophyseal blood the inhibitory component of the action of ANP on pituitary-adrenal secretory activity prevails.     

Hypoxic ventilatory responsiveness in Tibetan compared with Han residents of 3,658 m

Lifelong high-altitude residents of North and South America acquire blunted hypoxic ventilatory responses and exhibit decreased ventilation compared with acclimatized newcomers. The ventilatory characteristics of Himalayan high-altitude residents are of interest in the light of their reportedly lower hemoglobin levels and legendary exercise performance. Until recently, Sherpas have been the only Himalayan population available for study. To determine whether Tibetans exhibited levels of ventilation and hypoxic ventilatory drives that were as great as acclimatized newcomers, we compared 27 lifelong Tibetan residents of Lhasa, Tibet, China (3,658 m) with 30 acclimatized Han ("Chinese") newcomers matched for age, body size, and extent of exercise training. During room air breathing, minute ventilation was greater in the Tibetan than in the Han young men because of an increased respiratory frequency, but arterial O2 saturation and end-tidal PCO2 did not differ, indicating similar levels of effective alveolar ventilation. The Tibetan subjects had higher hypoxic ventilatory response shape parameter A values and hypercapnic ventilatory responsiveness than the Han subjects. Among the Han subjects, duration of high-altitude residence correlated with the degree of blunting of the hypoxic ventilatory drive. Paradoxically, hyperoxia (inspired O2 fraction 0.70) increased minute ventilation and decreased end-tidal PCO2 in the Tibetan but not in the Han men. We concluded that lifelong Tibetan residents of high altitude neither hypoventilated nor exhibited blunted hypoxic ventilatory responses compared with acclimatized Han newcomers, suggesting that the effects of lifelong high-altitude residence on ventilation and ventilatory response to hypoxia differ in Tibetan compared with other high-altitude populations.     

Effects of serotonin and the serotonin blocker metergoline on meal patterns and macronutrient selection

Serotonin [5-hydroxytryptamine(5-HT)] in the paraventricular nucleus (PVN) of rats has a suppressive effect on feeding behavior and causes a selective decrease in carbohydrate ingestion, specifically at the onset of the natural (dark) feeding period. Studies conducted here provide further evidence for this phenomena, showing a similar dose-related decrease in carbohydrate ingestion at dark onset after PVN injection of 5-HT or of the agonists, d-norfenfluramine or fluoxetine, which act through endogenous 5-HT. To further characterize the effects of this indoleamine on the macrostructure of feeding, a computer-automated data acquisition system was used to analyze macronutrient feeding patterns in freely feeding animals maintained on the pure diets of protein, carbohydrate, and fat. Results indicate that PVN administration of 5-HT at dark onset decreases intake of the carbohydrate nutrient by decreasing meal size, feeding time, and feeding rate for this nutrient and increasing the satiating effect of carbohydrate. These effects, which occur specifically during the first meal after injection, are opposite those seen after peripheral administration of the 5-HT receptor antagonist, metergoline. This drug stimulates feeding through a selective increase in carbohydrate intake, characterized by an increase in meal size, percent composition, and feeding time for this nutrient and a decrease in the satiety ratio for carbohydrate. These results implicate the serotonergic system in the termination of carbohydrate-rich meals that are prevalent during the early hours of the natural feeding cycle.     

Optical activity and conformation of cobra neurotoxin

Cobra neurotoxin from Formosan cobra (Naja naja atra) venom is a compact globular protein having an intrinsic viscosity of 4.5 mL/g. The protein is stable in 7.5 M urea but can be denatured in 4.1 M guanidine hydrochloride or at elevated temperature (above 70 degrees C). Its conformation remains virtually the same in solvents of lower polarity than water such as 1,2-ethanediol or a mixed solvent of 1-propanol-1,2-ethanediol-water (5:1:1 by volume). The circular dichroism spectrum is "atypical" in water in that the peptide chromophores show a small negative circular dichroic (CD) band at 215 nm, a large positive one at 199 nm, and another large negative one below 190 nm. The CD pattern resembles to some extent that of a beta form but differs in both positions and magnitudes from the latter. It agrees qualitatively with the theoretical calculations of the reverse beta bends, suggesting that cobra toxin contains a considerable amount of beta turns and possibly a mixture of beta form and beta turns.     

Developmental and behavioral effects of prenatal primidone exposure in the rat

Pregnant Sprague-Dawley rats were administered primidone (PRM) by oral gavage on gestation days 8-17 in doses of 0.40, and 80 mg/kg. Although these doses of PRM did not produce significant differences in litter size, birth weight, mortality, date of attainment of developmental landmarks or measures of preweaning reflex and motor development, there were a number of significant differences that developed as the animals approached and entered adulthood. When tested as adults, the 80 mg/kg male rats showed a deficit in the performance of an eight-arm radial maze task. These same animals showed a significant reduction in open field activity when tested as adults. In addition, both male and female PRM-treated animals showed reduced body weights at different periods corresponding to onset of sexual maturation during development. These findings are consistent with the larger body of literature reporting on the neurobehavioral teratology of phenobarbital, including its ability to produce lesions in the hippocampus and endocrine dysfunction resulting in reproductive deficits. These results suggest that PRM produces its adverse effects as a result of its metabolism to phenobarbital, which in turn affects the limbic system.