Retinal degeneration associated with RDH12 mutations results from decreased 11-cis retinal synthesis due to disruption of the visual cycle

Human Molecular Genetics     

Continuous epidural infusion of racemic methadone results in effective postoperative analgesia and low plasma concentrations

PURPOSE: To compare two protocols of epidural administration of racemic methadone for postoperative analgesia (continuous infusion and intermittent bolus), focussing on plasma concentration, analgesic efficacy and side effects. METHODS: Ninety patients undergoing abdominal or lower-limb surgery were randomly assigned to two groups in a prospective double-blind design. The continuous infusion patients (n=60) received initial doses of 3 to 6 mg followed by 6 to 12 mg by continuous infusion over 24 hr. The bolus administration patients (n=30) received repeated boluses of 3 to 6 mg of racemic methadone every eight hours. Pain intensity was assessed on a visual analog scale. Amount of supplementary analgesia was recorded, as was the incidence of side effects. Plasma methadone concentrations were determined by high performance liquid chromatography. Treatment was continued for 72 hr. RESULTS: Pain relief was good and comparable in both groups throughout the three days of treatment. No accumulation of plasma racemic methadone was observed in either group, although the concentrations were significantly higher in the bolus group. Miosis was significantly more frequent in the bolus group. CONCLUSION: Plasma methadone concentrations were significantly lower with continuous infusion. Plasma methadone accumulation, which is considered the main disadvantage for its purported influence on the incidence of side effects, did not occur at the doses used over the three days of treatment that we report.     

Prevalence of Parkinson's disease in Cantalejo, Spain: a door-to-door survey.

We assessed the prevalence of Parkinson's disease in Cantalejo, Spain. In 1994, we screened 1,579 persons (age > or = 40 years) using a high-sensitivity method. Cases fulfilling established clinical criteria were followed for a minimum of 3 years. Prevalences were compared with those from other door-to-door surveys. We detected 27 individuals with parkinsonism, 20 of whom had Parkinson's disease. The prevalence of Parkinson's disease increased with age and, when age-adjusted to European standards, was 9.01 per 1,000 (age 40 years and over; 10.78 in men and 5.23 in women). Of the 11 men, three were in Hoehn & Yahr grades III-IV, but six of the nine women were more severely affected. Overall, we found 18 newly diagnosed cases of parkinsonism, 13 of which were Parkinson's disease, and the majority of which were in men aged 80 years or older with a mean duration of illness of 5 years. Our prevalence figures are the highest reported, apparently because of the inclusion of several very elderly men. Parkinson's disease in Cantalejo is less severe in men than in women, particularly in those newly diagnosed. Despite the low numbers, the high prevalence and sex-related pattern are unexplained but they probably relate to the high sensitivity of the screening method.     

Suppressor response in lepromatous leprosy patients: role of Leu 2a cells.

The contribution of non-specific suppressor mechanisms to the overall immunoregulatory defect observed in lepromatous leprosy was evaluated. Con A-induced suppression was assayed using the standard two-stage test in 27 lepromatous leprosy patients, 19 of them during the quiescent stage (LL) and eight during erythema nodosum lepromatosum (ENL). Lymphocytes from normal individuals react in this assay, yielding higher suppression as the numbers of Con A-induced suppressor cells (Leu 2a+ cells) increase. In contrast, two patterns of response were observed in both LL and ENL patients: those giving lower suppression as the number of suppressor cells increased (LL-A and ENL-A) and those responding with the normal pattern (LL-B and ENL-B). The abnormal dose-response profile was not related to the disease stage, as both ENL and LL patients were included in groups with normal or atypical response. Reaction of the potential suppressor cells with anti-Leu 2a antibody abolished suppression in LL-B and normals, whereas Con A-induced suppression was unchanged or higher in ENL-A, ENL-B and LL-A, indicating that in these patients Leu 2a+ cells interfered with the generation of Con A-induced suppression. The contribution of spontaneous suppression was examined and it was shown that suppressor activity in the absence of Con A stimulus was higher in ENL (both ENL-A and ENL-B) and LL-A. Thus, it appears that the occurrence of high spontaneous suppressor activity, probably related to in vivo activation, is associated with a relative inability to generate de novo suppression after Con A stimulation in these patients.     

Postnatal changes in membrane properties of mice trigeminal ganglion neurons

Intracellular recordings from neurons in the mouse trigeminal ganglion (TG) in vitro were used to characterize changes in membrane properties that take place from early postnatal stages (P0-P7) to adulthood (>P21). All neonatal TG neurons had uniformly slow conduction velocities, whereas adult neurons could be separated according to their conduction velocity into Adelta and C neurons. Based on the presence or absence of a marked inflection or hump in the repolarization phase of the action potential (AP), neonatal neurons were divided into S- (slow) and F-type (fast) neurons. Their passive and subthreshold properties (resting membrane potential, input resistance, membrane capacitance, and inward rectification) were nearly identical, but they showed marked differences in AP amplitude, AP overshoot, AP duration, rate of AP depolarization, rate of AP repolarization, and afterhyperpolarization (AHP) duration. Adult TG neurons also segregated into S- and F-type groups. Differences in their mean AP amplitude, AP overshoot, AP duration, rate of AP depolarization, rate of AP repolarization, and AHP duration were also prominent. In addition, axons of 90% of F-type neurons and 60% of S-type neurons became faster conducting in their central and peripheral branch, suggestive of axonal myelination. The proportion of S- and F-type neurons did not vary during postnatal development, suggesting that these phenotypes were established early in development. Membrane properties of both types of TG neurons evolved differently during postnatal development. The nature of many of these changes was linked to the process of myelination. Thus myelination was accompanied by a decrease in AP duration, input resistance (R(in)), and increase in membrane capacitance (C). These properties remained constant in unmyelinated neurons (both F- and S-type). In adult TG, all F-type neurons with inward rectification were also fast-conducting Adelta, suggesting that those F-type neurons showing inward rectification at birth will evolve to F-type Adelta neurons with age. The percentage of F-type neurons showing inward rectification also increased with age. Both F- and S-type neurons displayed changes in the sensitivity of the AP to reductions in extracellular Ca(2+) or substitution with Co(2+) during the process of maturation.     

Evolution of foot-and-mouth disease virus

Foot-and-mouth disease virus evolution is strongly influenced by high mutation rates and a quasispecies dynamics. Mutant swarms are subjected to positive selection, negative selection and random drift of genomes. Adaptation is the result of selective amplification of subpopulations of genomes. The extent of adaptation to a given environment is quantified by a relative fitness value. Fitness values depend on the virus and its physical and biological environment. Generally, infections involving large population passages result in fitness gain and population bottlenecks lead to fitness loss. Very different types of mutations tend to accumulate in the foot-and-mouth disease virus (FMDV) genome depending on the virus population size during replication. Quasispecies dynamics predict higher probability of success of antiviral strategies based on multivalent vaccines and combination therapy, and this has been supported by clinical and veterinary practice. Quasispecies suggest also new antiviral strategies based on virus entry into error catastrophe, and such procedures are under investigation. Studies with FMDV have contributed to the understanding of quasispecies dynamics and some of its biological implications.