Dual effect of temperature on the human epithelial Na+ channel

The amiloride-sensitive epithelial sodium channel (ENaC) is the rate-limiting step for sodium reabsorption in the distal segments of the nephron, in the colon and in the airways. Its activity is regulated by intracellular and extracellular factors but the mechanisms of this regulation are not yet completely understood. Recently, we have shown that the fast regulation of ENaC by the extracellular [Na⁺], a phenomenon termed self-inhibition, is temperature dependent. In the present study we examined the effects of temperature on the single-channel properties of ENaC. Single-channel recordings from excised patches showed that the channel open probability (P _o, estimated from the number of open channels N·P _o, where N is the total number of channels) increased on average two- to threefold while the single-channel conductance decreased by about half when the temperature of the perfusion solution was lowered from ~30 to ~15 °C. The effects of temperature on the single-channel conductance and P _o explain the changes of the macroscopic current that can be observed upon temperature changes and, in particular, the paradoxical effect of temperature on the current carried by ENaC.     

Wagner vitreoretinal degeneration with genetic linkage refinement on chromosome 5q13-q14

· Background: It has been previously described that Wagner disease is linked to chromosome 5q13-q14. This study was carried out to describe the ophthalmological aspects and report the results of genetic linkage analysis in a large pedigree affected by Wagner disease. · Methods: Fourty members of one same family agreed to be examined. · Results: Twenty patients presented vitreoretinal degeneration in both eyes without any extra-ocular abnormalities. In young patients, visual acuity was usually normal after correction of frequent mild myopia. Presenile cataracts progressed by the third decade and required removal for visual rehabilitation. The primary disorder involved an abnormal vitreous. A few avascular vitreous bands were usually the only optical feature in the mostly empty vitreous cavity. A circumferential vitreous condensation formed in contact with the retina on many spots. Less common retinal findings included retinal detachment, abnormal retinal pigmentation, progressive atrophy of the RPE simulating choroideremia and lattice degeneration. Genetic analysis revealed a highly significant linkage (lod score >5.0) between the disease and 10 markers of the chromosome 5q13-q14 region. Two recombination events allowed us to refine the linked interval to 20 cM between the D5S650 and D5S618 markers. · Conclusion: Ophthalmological aspects of Wagner’s disease appear to progress with age. Regular ophthalmological examination is important for detecting retinal abnormalities. The gene involved in Wagner’s disease lies in a 20 cM interval on chromosome 5q13-q14. Received: 30 June 1998 Revised version received: 5 October 1998 Accepted: 6 October 1998     

When Fever, Paracetamol? Theory and Practice in a Paediatric Outpatient Clinic

Objective: To determine how medical and nursing staff treat feverish children and compare the findings with their theoretical knowledge, evaluating how they might contribute to fever phobia in parents.Setting: Paediatric Emergency Department.Method: In the first step, we analysed prospectively the files of all children having consulted the Paediatric Emergency Department with a history of fever or of body temperature above 38 °C during a 2-week period. The second step consisted of evaluating knowledge and perception of fever of doctors and nurses using a questionnaire.Main outcome measures: Prospective study: final diagnosis (viral, non- invasive bacterial disorders, invasive bacterial disorders), site of measurement and average temperature. Evaluation of theoretical knowledge: definition of fever, site of measurement, evaluation of the child’s clinical state, antipyretic drug choice.Results: A total of 114 children under 5 years of age were enrolled and 24 caregivers (12 doctors, 12 nurses, 90 of the staff) responded to the questionnaire. The results showed good consistency in theoretical knowledge, but an excessive fear about cerebral damage was also shown by doctors. This belief likely contributes to the transmission of fever phobia to parents. In contrast, analysis of children management showed that fever was often under-treated, especially by nurses and even more so by parents. Paracetamol remained the first-line antipyretic drug yet was often administered in insufficient doses. Non-steroidal anti-inflammatory drugs were seldom used, except by parents (16 of all the children). Contrary to literature, the favourite route of administration was the rectal one. Physical methods like sponging were largely used by nurses, despite the uncertainties in their real effectiveness and their known side-effects.Conclusion: Our study showed that the management of feverish children was globally correct in the Paediatric Emergency Department, but several improvement measures have been taken (e.g. tables of normal and abnormal ranges of temperature, recommended temperature measurement techniques, dosage regimen of antipyretic drugs, guidelines to parents), justifying the implementation of a pharmaceutical follow-up.     

In face of the increasing efficacy of lipid-lowering therapy, is there still a place for LDL-apheresis?

Based on a large body of evidence, high LDL-cholesterol concentrations in blood is a key factor of coronary heart disease (CHD). Overall, the observational studies show a curvilinear relationship between blood cholesterol level and coronary heart disease risk. Even more relevant are the randomised trials, firmly establishing that within just a few years a cholesterol-lowering therapy confers a dramatic effect on cardiovascular morbidity and mortality. More recent studies indicate that there is a greater risk reduction in those subjects achieving lower low-density lipoprotein cholesterol (LDL-C) levels--i.e. lower is better. While this favours aggressive therapy, it is nevertheless imperative to precise patients selection for every therapy that entails a major commitment for the patient and medical community. Therefore, well-defined criteria for use of LDL-apheresis have yet to be established in the light of the expanding therapeutic armamentarium. Based on the current knowledge of the impact of statin therapy and anticipating that new options will further optimize the management of dyslipidemia in high-risk patients, we propose a reliable assessment of the effects of LDL-apheresis.     

A mouse model for the renal salt-wasting syndrome pseudohypoaldosteronism

Aldosterone-dependent epithelial sodium transport in the distal nephron is mediated by the absorption of sodium through the highly selective, amiloride-sensitive epithelial sodium channel (ENaC) made of three homologous subunits (α, β, and γ). In human, autosomal recessive mutations of α, β, or γENaC subunits cause pseudohypoaldosteronism type 1 (PHA-1), a renal salt-wasting syndrome characterized by severe hypovolemia, high plasma aldosterone, hyponatremia, life-threatening hyperkaliemia, and metabolic acidosis. In the mouse, inactivation of αENaC results in failure to clear fetal lung liquid at birth and in early neonatal death, preventing the observation of a PHA-1 renal phenotype. Transgenic expression of αENaC driven by a cytomegalovirus promoter in αENaC(−/−) knockout mice [αENaC(−/−)Tg] rescued the perinatal lethal pulmonary phenotype and partially restored Na⁺ transport in renal, colonic, and pulmonary epithelia. At days 5–9, however, αENaC(−/−)Tg mice showed clinical features of severe PHA-1 with metabolic acidosis, urinary salt-wasting, growth retardation, and 50% mortality. Adult αENaC(−/−)Tg survivors exhibited a compensated PHA-1 with normal acid/base and electrolyte values but 6-fold elevation of plasma aldosterone compared with wild-type littermate controls. We conclude that partial restoration of ENaC-mediated Na⁺ absorption in this transgenic mouse results in a mouse model for PHA-1.     

Effects of subthalamic nucleus stimulation and levodopa treatment on gait abnormalities in Parkinson disease

BACKGROUND: Stimulation of the subthalamic nucleus is proposed for the treatment of patients presenting with severe Parkinson disease. The effect on gait is not clearly established. OBJECTIVES: To evaluate objectively the influence of bilateral subthalamic nucleus stimulation on gait in Parkinson disease and to compare it with the effects of levodopa treatment. METHODS: Ten patients underwent bilateral subthalamic nucleus stimulation. The preoperative and postoperative (3 months after surgery) clinical gait disturbances, as well as spatial and temporal gait parameters, were analyzed in off and on-drug conditions. The gait analysis was performed using a video motion analysis system (optoelectronic VICON system; Oxford Metrics, Oxford, England). RESULTS: In the off condition, there was an improvement after surgery for the total motor score and the gait subscore. In the on-drug condition, there was an improvement in levodopa-induced dyskinesias and the motor score, whereas the gait subscore was unchanged. For the gait parameters measured by the video motion analysis system system, there was also an improvement in the off condition and to a lesser extent in the on-drug condition. CONCLUSIONS: Our method allowed exact quantification of the benefit of surgery on gait parameters. Compared with the levodopa treatment, the effect of stimulation on gait kinematic parameters seems to be qualitatively similar but quantitatively different with a lower benefit on gait velocity and stride length. Concerning the pathophysiology of gait troubles in Parkinson disease, the deficit in control of stride length would be the fundamental deficit. The study underlines the possible role of the subthalamic nucleus on the stride length regulation.