Patient perspectives following initiation of elexacaftor-tezacaftor-ivacaftor in people with cystic fibrosis and advanced lung disease.

BACKGOUND: Elexacaftor-tezacaftor-ivacaftor partially restores cystic fibrosis transmembrane conductance regulator function, and has been shown to induce significant clinical improvement in patients with at least one Phe508del allele. Yet little data exist on patient perspectives following elexacaftor-tezacaftor-ivacaftor initiation. METHODS: A mixed methods study was conducted using an online 13-item questionnaire (including 9 closed questions and 4 open questions), submitted from July 10th to August 21th 2020 to French patients aged 12 years and older with advanced CF who were treated with elexacaftor-tezacaftor-ivacaftor. Their responses were summarized as numbers (%), and free-text items were analysed using a grounded theory approach. RESULTS: Of 245 patients who started elexacaftor-tezacaftor-ivacaftor in France, 101 (41%) participated. Median [IQR] age was 35 [28-41] years and duration of elexacaftor-tezacaftor-ivacaftor treatment was 4.3 [3.0-5.6] months. Patients generally reported a rapid impact on respiratory symptoms, sleep quality, general well-being and physical self-esteem, and a reduction in overall treatment burden. The majority of patients contrasted treatment burden, symptom severity, depression and a closed future marked by death or transplantation before elexacaftor-tezacaftor-ivacaftor, to renewed and unexpected physical strength, leading to greater self-confidence, autonomy and long-term planning, after treatment initiation. A small number of patients expressed concerns, mainly regarding changes in body representation and/or the fear of becoming dependent on the treatment. CONCLUSION: After initiation of elexacaftor-tezacaftor-ivacaftor, CF patients with advanced disease reported rapid and positive physical, psychological and social effects, which translated into improved quality of life and the formulation of new life goals.

Isolation by distance and sharp discontinuities in gene frequencies: implications for the phylogeography of an alpine insect species, Carabus solieri.

Analysis of genetic isolation by distance (IBD) is of prime importance for the study of processes responsible for spatial population genetic structure and is thus frequently used in case studies. However, the identification of a significant IBD pattern does not necessarily imply the absence of sharp discontinuities in gene frequencies. Therefore, identifying barriers to gene flow and/or secondary contact between differentiated entities remains a major challenge in population biology. Geographical genetic structure of 41 populations (1080 individuals) of an alpine insect species, Carabus solieri, was studied using 10 microsatellite loci. All populations were significantly differentiated and spatially structured according to IBD over the entire range. However, clustering analyses clearly identified three main clusters of populations, which correspond to geographical entities. Whereas IBD also occurs within each cluster, population structure was different according to which group of populations was considered. The southernmost cluster corresponds to the most fragmented part of the range. Consistently, it was characterized by relatively high levels of differentiation associated with low genetic diversity, and the slope of the regression of genetic differentiation against geographical distances was threefold those of the two other clusters. Comparisons of within-cluster and between-cluster IBD patterns revealed barriers to gene flow. A comparison of the two approaches, IBD and clustering analyses, provided us with valuable information with which to infer the phylogeography of the species, and in particular to propose postglacial colonization routes from two potential refugia located in Italy and in southeastern France. Our study highlights strongly the possible confounding contribution of barriers to gene flow to IBD pattern and emphasizes the utility of the model-based clustering analysis to identify such barriers.

Risk-taking restraints in a bird with reduced egg-hatching success.

Risk taking, as is any other phenotypic and/or behavioural trait, is determined by proximate constraints related to time or resource availability and by evolutionary adaptive restraints related to the differences in the costs of risk taking and its benefits in terms of fitness. Because risk taking is influenced by many confounding variables related to experimental design, environment, parents and offspring, few field studies have been reported which unambiguously separate the effects of restraints from those of constraints. We compared parental risk taking in blue tits (Parus caeruleus) during brood defence towards a nest predator in broods with experimentally reduced and natural egg-hatching success leaving the original number of eggs in the nest. The experimentally reduced broods had more time or resources available and lower risk-taking benefits compared to the control broods. 'Constraint' would predict more risk taking in broods having experimentally reduced egg-hatching success, whereas 'restraint' would predict the opposite effect with more risk taking in broods with natural egg-hatching success. We report, to our knowledge, the first field study experimentally demonstrating a brood defence restraint in response to reduced egg-hatching success. This demonstration was only possible after controlling for more than 20 potential confounding variables showing once more how complicated it is to separate proximate from evolutionary levels of analyses in natural populations.

[Control of nosocomial infections by multiresistant bacteria in geriatric services]. / La maîtrise des infections nosocomiales à germes multirésistants dans les services de gériatrie.

Geriatric wards have a higher prevalence of infection than surgical or acute medical wards, and multiresistant organisms contribute a nonnegligeable proportion of infections in elderly inpatients. The measures used to prevent nosocomial infections in geriatric wards are the same as in other types of wards. They include identifying and ensuring the technical and geographic isolation of colonized and infected patients. Health care providers should be informed of the situation, and antimicrobials used with discernment to avoid the selection of multiresistant organisms. Implementation of these measures is made difficult by architectural factors, the fact that many geriatric patients require assistance in all the activities of daily living, and the long duration of stays in geriatric wards. Additional measures are probably essential to achieve long-term control of nosocomial infections. Insufficient attention has been given to health care providers' perceptions of nosocomial infection and to defining the tasks actually performed by these providers.

Effects of adrenal steroid hormones on mitochondrial maturation during the late fetal period.

In the present work, we described the perinatal changes in mitochondrial maturation that contribute to metabolic development in the rat kidney. We focused on cytochrome-c oxidase activity and gene expression from the last three days of gestation to one day after birth. The role of adrenal steroids in the development of cytochrome-c oxidase expression and of mitochondrial DNA content was also investigated by studying the effects of fetal adrenalectomy. During the perinatal period, the developmental pattern of the cytochrome-c oxidase enzymatic complex exhibited parallel increases in transcript levels, protein content and enzyme activity, suggesting a transcriptional regulation of this enzyme. Adrenalectomy led to a decrease in fetal kidney cytochrome-c oxidase messengers and mtDNA content while administration of dexamethasone restored normal levels. In contrast, mtDNA content was unchanged in liver and heart after adrenalectomy whereas levels of cytochrome-c oxidase transcripts were controlled by adrenal steroids in liver but not in heart. These results indicate that adrenal steroid hormones contribute to the regulation of perinatal maturation of mitochondria in rat kidney and that these hormones are involved in the fetal mitochondrial biogenesis in a tissue-specific manner.

Effect of hyperglycemia on the polyol pathway in rat kidney during the perinatal period.

The activity of the polyol pathway was studied in developing rat kidney. For this purpose, sorbitol content, aldose-reductase activity and sorbitol-dehydrogenase activity were determined in papilla from fetuses and 24-h-old neonates. After birth, no significant difference was observed in sorbitol content, whereas sorbitol-dehydrogenase activity decreased and aldose-reductase activity doubled. Changes in aldose-reductase activity were due to an increased number of enzymatic sites but not with a change in affinity. Low levels of sorbitol were found in fetal and neonatal medulla together with low levels of urine osmolarity. In neonates, sorbitol contents were tenfold lower than in the adult, probably as a result of a lower affinity and a lower number of enzymatic aldose-reductase sites. Attempts to increase the activity of polyol pathway in fetal kidney were made by means of hyperglycemic animals; this approach resulted in an increase of aldose-reductase activity without any change in sorbitol content. Our results indicate that, in fetal and neonatal kidneys, aldose-reductase activity is probably not the limiting factor for sorbitol synthesis; another parameter, such as the availability of NADPH, might explain the low efficiency of the polyol pathway during the perinatal period.

Perinatal maturation of rat kidney mitochondria.

In the rat kidney, NaK-ATPase activity increased between days 19 and 20 of gestation (+50%) and between 1 and 24 h after birth (+20%), requiring an increased energy supply. In order to determine whether mitochondrial changes were involved, renal mitochondrial development was investigated from day 19 of gestation to 1 day after birth. Slot-blot analyses of mitochondrial-DNA/nuclear-DNA ratio and determination of citrate synthase activity showed a doubling in the mitochondrial pool between days 19 and 20 of gestation. In isolated mitochondria, oxygen consumption remained unchanged between days 19 and 20 of gestation, and then it was enhanced between days 20 and 21 of gestation (+70%) and between 1 and 24 h after birth (+50%). We also focused on one of the respiratory-chain complexes, ATP synthase, and measured its activity and content during the perinatal period. We demonstrated increases in both activity and content of ATP synthase between days 20 and 21 of gestation and between 1 and 24 h after birth, thus suggesting that changes in ATP synthase activity are ascribed to an increase in the mitochondrial density of ATP synthase complexes. Moreover, the mitochondrial ATP/ADP ratio only increased between 1 and 24 h (+90%), indicating a critical step in the renal respiratory-chain maturation at that time. We therefore conclude that the postnatal enhancement of renal mitochondrial oxidative capacity might depend on protein synthesis de novo and on changes in the adenine nucleotide concentrations.

Effect of maternal hyperglycemia on NaK ATPase activity in fetal rat kidney.

The effect of moderate hyperglycemia on renal ATP production and ATPase activity of rat fetus was investigated using the experimental procedure of maternal continuous infusion of glucose during the last 5 days of gestation. Glucose-infused mothers and their fetuses showed a high level of glycemia (8.8 and 5.5 mM, respectively) and a high level of insulinemia (3 times higher than in controls). No change in either ATP or ADP concentration was detectable but an increase in NaK ATPase activity occurred without any change in Mg ATPase activity. These modifications should be the result of an enhanced Na/glucose cotransport leading to an enhanced extrusion of Na at the basolateral membrane. These results indicate that immature kidney is able to increase NaK ATPase activity to maintain Na homeostasis.

A stereochemical relationship could explain the origin of the genetic code.

A stereochemical analysis has been carried out to investigate the possible complementarity between an RNA double helix containing thymine instead of uracil and two growing peptide chains. It is found that the optimal interactions follow the rules of the genetic code. The nature of the interaction could allow a mechanism for aminoacyl-RNA formation which could have given rise to the tRNA ancestors. Some theoretical implications are discussed.

An automated Western blot analysis using the phastsystem.

We have developed a rapid, automated method for preparing Western blots of very small amounts of proteins, utilizing a commercially available electrophoresis system (Phastsystem, Pharmacia). This system has been adapted to transfer to nitrocellulose experimental samples that were initially separated in the same system by gradient-sodium dodecyl sulfate gel electrophoresis. The developing unit of the Phastsystem has permitted automation of all the necessary steps including incubation with antibodies, saturation of nonspecific binding sites, and washing. The total elapsed time for protein separation, transfer, and staining is about 6 to 7 h.

Pefloxacin in the treatment of nosocomial lower respiratory tract infections in intensive care patients.

Pefloxacin was used to treat nosocomial pulmonary infections in 46 mechanically ventilated patients. All patients had one or more underlying diseases and were given pefloxacin at a dose of 800 mg or 1200 mg daily in two or three divided doses. The commonest bacterial isolates were Staphylococcus aureus, Pseudomonas aeruginosa and enterobacteria. Of these patients, 33 (72%) showed a favourable response, one patient relapsed and 12 (26%) were considered failures. Superinfections occurred in 10 (22%). Of the 62 isolated potential pathogens, 53 (85%) were completely eradicated. Side effects were mild and treatment was withdrawn in only three patients. Pefloxacin can be considered as a possible therapeutic agent for the treatment of nosocomial pulmonary infections.

Purification and characterization of a 32-kDa phospholipase A2 inhibitory protein (lipocortin) from human peripheral blood mononuclear cells.

A 32-kDa protein was isolated from human monocytes after calcium precipitation and chromatography. The protein activity was assessed by the inhibition of soluble phospholipase A2 (PLA2). This in vitro inhibitory effect on phospholipases A2 was found only with negatively charged phospholipids. The protein was also able to inhibit cellular PLA2 in mouse thymocytes. The biochemical properties and amino acid composition strongly suggest that the protein shares similarities with endonexin. Using a neutralizing monoclonal antibody against rat lipocortin, we found a cross-reactivity with the 32-kDa protein. According to the biochemical and immunological properties, we propose to relate this PLA2 inhibitory protein from human monocytes to lipocortin.

Lipocortin inhibition of extracellular and intracellular phospholipases A2 is substrate concentration dependent.

Hydrolysis of Escherichia coli membrane phospholipids by pancreatic phospholipase A2 was inhibited by lipocortin from human monocytes in a substrate dependent manner. Inhibition was completely overcome at substrate concentrations above 250 microM. Lipocortin also inhibited partially purified preparations of two intracellular phospholipases A2 isolated from rat liver mitochondria and rat platelets when these enzymes were assayed at low micromolar concentrations of phosphatidylethanolamine. Inhibition gradually decreased with increasing substrate concentrations both for pancreatic and platelet phospholipase A2 and became completely abolished above 15 and 50 microM phosphatidylethanolamine, respectively.

The use of VEPs for CNS monitoring during continuous cardiopulmonary bypass and circulatory arrest.

Cerebral function was monitored with the use of visual evoked potentials (VEPs) in 16 infants (mean age 9.9 +/- 4.3 months) during surgery for congenital cardiac anomalies. While hypothermia was employed in all patients, half (8) remained on continuous cardiopulmonary bypass (CCB) while the rest were cooled to lower temperatures before the induction of circulatory stasis and venous exsanguination (CA), i.e., profound hypothermic circulatory arrest (PHCA). VEPs were recorded before, during and after surgical intervention. Latency changes occurred in both the N100 and P145 components of the VEP as a function of systemic temperature during cooling in both groups. Differences in the VEPs were found between the two groups post-operatively, with the most interesting result being a greater increase in P145 latency in the CA group after rewarming. To the extent that VEPs reflect neurological status, our findings suggested that CCB was associated with less perturbation in acute neurological status than PHCA, and shorter arrest times and lower temperatures during CA were associated with the most favourable post-operative VEPs. Hence, intraoperative monitoring of VEPs appeared to be useful as an objective measure of the short-term effects of various cardiopulmonary procedures on neurophysiological function.

Steady-state levels of pefloxacin and its metabolites in patients with severe renal impairment.

Twenty patients (aged 26-70 years) with severely impaired renal function received pefloxacin twice daily for 5 days as 12 mg.kg-1 administered as a 1 h i.v. infusion, or 800 mg administered as tablets. On Day 5 the minimal and maximal plasma concentrations were 5.9 and 11.5 mg.l-1 respectively, after oral administration. The steady-state level of the N-desmethyl metabolite ranged from 0.9 (infusion) to 1.2 mg.l-1 (oral route), and that of the N-oxide metabolite ranged from 6.2 (infusion) to 9.0 mg.l-1 (oral route). The minimal concentration of unchanged drug was related to the age of the patients (infusion), but the N-oxide concentration was influenced by the degree of renal impairment (both routes). The pefloxacin levels were similar to those achieved in healthy subjects, but reduced renal function leads accumulation of its biotransformation products, especially of the N-oxide metabolite which lacks antibacterial activity.

["In vitro" glass fiber filtration of sperm (author's transl)]. / La filtration "in vitro" du sperme sur laine de verre.

Filtering sperm through glass fiber has been suggested as a method for improving its fecundity before homologous artificial insemination. Various technical modification of this procedure have enabled good results to be obtained on spermatozoid mobility but at the expense of a marked drop in numbers: sperm counts per ml are diminished by a half. A comparative in vitro study of the penetration of filtered and non-filtered sperm into the cervical mucus showed that glass fiber filtration produced generally no great improvement, and may indeed reduce penetration into the cervical mucus to a marked degree in some cases.