Non-invasive ventilation in neuromuscular diseases: should we use higher levels of ventilatory support?

PURPOSE: In patients with COPD, one of the leading indications for domiciliary non-invasive ventilation (NIV), a major paradigm shift has been observed over the past decade in the method for adjusting NIV settings, with the use of sufficient ventilatory support to achieve a significant reduction in PaCO2. Whether this approach may be relevant to other populations, especially slowly progressive neuromuscular diseases (NMD), is unknown. METHODS: This study was conducted as a post hoc analysis from a previously published randomized controlled trial (NCT03458507). Patients with NMD treated with domiciliary NIV were stratified according to the level of ventilatory support: high-level tidal volume (HLVT; mL/kg of predicted body weight [PBW]) or high-level pressure support (HLPS), defined as a value above median value of the whole population (> 6.8 mL/kgPBW or 9.0 cmH2O, respectively). Primary outcome was mean nocturnal transcutaneous CO2 pressure (PtcCO2). Secondary outcomes included adherence to NIV, leaks, and side effects. RESULTS: Of a total of 26 patients, 13 were exposed to HLVT, with significantly lower nocturnal PtcCO2 (respectively 40.5 ± 4.2 vs. 46.3 ± 3.9 mmHg, p = 0.002). A linear correlation between VT (mL/kgPBW) and mean nocturnal PtcCO2 was evidenced (r = - 0.59, 95%CI [- 0.80; - 0.25], p = 0.002). No significant impact of HLVT was found on secondary outcomes. CONCLUSION: Despite the lack of power of this post hoc analysis, our results suggest that higher levels of ventilatory support are correlated with lower PtcCO2 in patients with NMD. Further studies are desirable to assess the extent to which the level of assistance influences PaCO2 evolution in patients with slowly progressive NMD, as well as in restrictive thoracic disorders.

An anticoagulant dermatan sulfate proteoglycan circulates in the pregnant woman and her fetus.

Investigation of the in vitro ability of plasma from pregnant women to inhibit exogenous thrombin (25 nM) demonstrated that heparin cofactor II inhibited more thrombin (3.0 +/- 0.7 nM, mean +/- SD) than plasma from women 3-5 d postpartum (1.9 +/- 0.5 nM) or plasma from nonpregnant adults (1.5 +/- 0.4 nM). Levels of heparin cofactor II were only slightly increased over normal in both pregnant and postpartum women and did not account for the observed increase in thrombin bound to heparin cofactor II. Assay of pregnancy plasma for dermatan sulfate anticoagulant activity demonstrated the presence of activity equivalent to 0.23 +/- 0.02 micrograms/ml of porcine mucosal dermatan sulfate. This activity could not be demonstrated in normal adult plasma or plasma from women on the contraceptive pill. The mass of dermatan sulfate in pregnancy and umbilical cord plasmas was increased over adult control plasma by 0.20 micrograms/ml (53%) and 0.29 micrograms/ml (76%), respectively. The glycosaminoglycan-containing fraction of plasma was isolated and an assay for anticoagulant dermatan sulfate confirmed its presence in both pregnancy and cord plasmas but minimal activity in adult plasma. Gel chromatography of isolated fractions from both pregnancy and cord plasmas revealed a polydisperse, active species with apparent Mr 150,000 D. Reductive elimination decreased the apparent Mr of the active species on gel chromatography to 31,000 D for cord and 21,000 D for pregnancy products. This confirmed the presence of an anticoagulant active dermatan sulfate proteoglycan circulating in the plasmas of pregnant women at term and fetuses at delivery.

Perfluorooctanoic acid: relationship between repeated inhalation exposures and plasma PFOA concentration in the rat.

A large database exists describing the pharmacokinetic behavior of perfluorooctanoic acid (PFOA) following oral exposure. The objective of this study was to examine the concentration- and time-dependence of the pharmacokinetics of inhaled PFOA in rat plasma to determine equivalent inhalation and oral (from literature values) exposure levels. The study was comprised of two separate experiments: a single 6-h inhalation exposure and repeated inhalation exposures for 3 weeks (6h per day, 5 days per week). In both experiments, male and female rats were exposed nose-only to aerosol atmospheres of either 0, 1, 10, or 25mg/m(3) PFOA. In the single exposure experiment, blood was drawn via the tail vein pre-exposure, four times concurrent to exposure, and six times post-exposure up to 24h. In the repeated exposure experiment, blood was collected immediately before and after exposure 3 days per week. Plasma PFOA concentrations were quantitated by liquid chromatography-mass spectrometry (LC-MS). Following the single exposures, plasma PFOA concentrations were directly proportional to airborne concentrations in both male and female rats. Elimination of PFOA from the plasma was sex-dependent, with female rats eliminating PFOA much more rapidly than male rats. Following repeated PFOA exposure, there was little daily PFOA carryover observed in plasma samples from female rats, while males demonstrated an accumulative pattern over the 3-week period. Peak post-exposure PFOA plasma concentrations in female rats averaged 1, 2, and 4 microg/mL when exposed to 1, 10, and 25mg/m(3) PFOA, respectively, and returned to baseline levels by the time of the next pre-exposure sample collection. Male rats reached steady state plasma concentrations of 8, 21, and 36 microg/mL (ppm) after 3 weeks of exposure to 1, 10, and 25mg/m(3) PFOA, respectively. These results demonstrate that the pharmacokinetic properties of inhaled PFOA in male and female rats are similar to those observed in male and female rats following oral dosing with PFOA. It is thus possible to use this internal dose metric (plasma PFOA) for route-to-route dose extrapolation, with inhalation exposures of 1, 10, and 25mg/m(3) PFOA corresponding to oral doses of approximately 0.3, 1.0, and 2.0mg/kg in rats.

Stalled replication forks within heterochromatin require ATRX for protection.

Expansive growth of neural progenitor cells (NPCs) is a prerequisite to the temporal waves of neuronal differentiation that generate the six-layered neocortex, while also placing a heavy burden on proteins that regulate chromatin packaging and genome integrity. This problem is further reflected by the growing number of developmental disorders caused by mutations in chromatin regulators. ATRX gene mutations cause a severe intellectual disability disorder (α-thalassemia mental retardation X-linked (ATRX) syndrome; OMIM no. 301040), characterized by microcephaly, urogenital abnormalities and α-thalassemia. Although the ATRX protein is required for the maintenance of repetitive DNA within heterochromatin, how this translates to disease pathogenesis remain poorly understood and was a focus of this study. We demonstrate that Atrx(FoxG1Cre) forebrain-specific conditional knockout mice display poly(ADP-ribose) polymerase-1 (Parp-1) hyperactivation during neurogenesis and generate fewer late-born Cux1- and Brn2-positive neurons that accounts for the reduced cortical size. Moreover, DNA damage, induced Parp-1 and Atm activation is elevated in progenitor cells and contributes to their increased level of cell death. ATRX-null HeLa cells are similarly sensitive to hydroxyurea-induced replication stress, accumulate DNA damage and proliferate poorly. Impaired BRCA1-RAD51 colocalization and PARP-1 hyperactivation indicated that stalled replication forks are not efficiently protected. DNA fiber assays confirmed that MRE11 degradation of stalled replication forks was rampant in the absence of ATRX or DAXX. Indeed, fork degradation in ATRX-null cells could be attenuated by treatment with the MRE11 inhibitor mirin, or exacerbated by inhibiting PARP-1 activity. Taken together, these results suggest that ATRX is required to limit replication stress during cellular proliferation, whereas upregulation of PARP-1 activity functions as a compensatory mechanism to protect stalled forks, limiting genomic damage, and facilitating late-born neuron production.

Amino acid substitutions in structurally related proteins. A pattern recognition approach. Determination of a new and efficient scoring matrix.

Amino acid substitutions in evolutionarily related proteins have been studied from a structural point of view. We consider here that an amino acid al in a protein p1 has been replaced by the amino acid a2 in the structurally similar protein p2 if, after superposition of the p1 and p2 structures, the a1 and a2 C alpha atoms are no more than 1.2 A apart. Thirty-two proteins, grouped in 11 classes, have been analysed by this method. This produced 2860 amino acid pairs (substitutions), which were analysed by multi-dimensional statistical methods. The main results are as follows: (1) according to the observed exchangeability of amino acid side-chains, only four groups (strong clusters) could be delineated; (i) Ile and Val, (ii) Leu and Met, (iii) Lys, Arg and Gln, and (iv) Tyr and Phe. The other residues could not be classified. (2) The matrix of distances between amino acids, or scoring matrix, determined from this study, is different from any other published matrix. (3) Except for the distance matrices based on the chemical properties of amino acid side-chains, which can be grouped together, all other published matrices are different from one another. (4) The distance matrix determined in this study seems to be very efficient for aligning distantly related protein sequences.

The effects of dermatan sulfate at submicrogram/ml concentrations on in vitro thrombin generation.

Dermatan sulfate is an antithrombotic glycosaminoglycan which has been shown to be effective in preventing deep venous thrombosis in general surgery patients when present at concentrations less than 1 microgram/ml. It has also been found to circulate physiologically in similar concentrations in pregnant women at term and in cord blood. We investigated the ability of dermatan sulfate added to plasma at 0.2, 0.5 and 1.0 microgram/ml to inhibit thrombin generation initiated by low concentrations of recombinant human tissue factor in defibrinated plasma. A dose dependent decrease in thrombin potential was demonstrated at therapeutically relevant concentrations of dermatan sulfate (0.5 and 1.0 microgram/ml) but there was no induction of a lag phase in thrombin generation. We were unable to demonstrate a significant effect on thrombin potential of dermatan sulfate at a concentration similar to that found in pregnancy plasma (0.2 microgram/ml). This indicates that either the dermatan sulfate concentration found in pregnancy plasma is not physiologically relevant or that our experimental system (which lacks platelets and fibrin) does not accurately reflect physiologic conditions. The effect on the thrombin potential was somewhat greater at the lowest concentration of tissue factor and amounted to a maximum inhibition of approximately 50% at 1 microgram/ml dermatan sulfate. A dose dependent increase in formation of thrombin-heparin cofactor II complexes and a decrease in thrombin-antithrombin complex formation with increasing dermatan sulfate concentration were observed at all dermatan sulfate concentrations. Prothrombin consumption was not changed by any dose of dermatan sulfate. We conclude that dermatan sulfate, at the concentrations tested, catalyses inhibition of free thrombin by heparin cofactor II but not efficiently enough to inhibit prothrombinase formation.

Circulating dermatan sulfate and heparan sulfate/heparin proteoglycans in children undergoing liver transplantation.

The liver produces dermatan sulfate (DS), heparan sulfate (HS) and heparin glycosaminoglycans (GAG) and in the presence of hepatic disease, tissue levels of the DS GAG increase dramatically. We hypothesized that in children undergoing liver transplantation plasma levels of DS would be increased. Plasma from children undergoing liver transplantation were tested preoperative, intra operative and post operative at 24-48 h, and 1-3 weeks. Fluctuating levels of DS, HS and heparin anticoagulant activity were detected at all timepoints. The anticoagulant activity was purified and gel chromatography of the material displayed a mean Mr 110,000 D. Reductive elimination decreased the mean Mr 24,000 D indicating the activity resides on a proteoglycan (PG). The purified material was subjected to further chromatography and two peaks of anticoagulant activity resolved, compatible with at least two separate PGs, one with DS GAG chains and the additional PG(s) with HS and heparin GAG chains.

Inhibition of thrombin by antithrombin III and heparin cofactor II in vivo.

The critical role of thrombin in the pathogenesis of venous and arterial thrombosis, and the effectiveness of glycosaminoglycans as antithrombotic drugs are well known. Antithrombin III is a major inhibitor of thrombin and augmentation of its inhibitory actions by heparin is the basis for the clinical uses of heparin. Recent clinical and experimental studies have demonstrated that another glycosaminoglycan, dermatan sulfate, is an effective antithrombotic drug. Dermatan sulfate catalyses the inhibition of thrombin by heparin cofactor II. The concentrations of heparin cofactor II are higher in the plasmas of individuals with congenital antithrombin III deficiency and pregnant women than controls. The role of heparin cofactor II as a physiologic thrombin inhibitor is unknown. Enzyme-linked immunosorbent assays were used to quantify thrombin-heparin cofactor II and thrombin-antithrombin III endogenous to the plasmas of adult antithrombin III-Hamilton deficient subjects, their siblings with normal antithrombin III levels, pregnant women at term and 3 to 5 days after delivery. Both thrombin-antithrombin III and thrombin-heparin cofactor II complexed with vitronectin were detected in all the plasmas. Significantly, the concentrations of thrombin-heparin cofactor II-vitronectin were higher in the plasmas of congenital antithrombin III deficient subjects and in pre- and post-delivery plasmas than those of normal subjects. In addition, the concentrations of thrombin-heparin cofactor II decreased 3 to 5 days after delivery, reflecting the disappearance of the catalytically active dermatan sulfate elaborated by the placenta. Thus, heparin cofactor II normally inactivates thrombin in vivo, with its role increasing in conditions associated with high levels of heparin cofactor II and/or dermatan sulfate.

Anticoagulant dermatan sulfate proteoglycan (decorin) in the term human placenta.

Normal pregnancy is characterized by increased in vivo thrombin generation. A greater proportion of endogenously generated thrombin is complexed to heparin cofactor II in plasma from pregnant women compared to plasma from nonpregnant ones. The increase in thrombin-heparin cofactor II complexes suggests that the site of the additional thrombin generation is relatively rich in dermatan sulfate. We postulated that the site of thrombin generation may be the placenta since endogenous thrombin generation returns rapidly to normal after delivery. This report describes the isolation and characterization of placental dermatan sulfate proteoglycan from villous tissue of the term human placenta. Placental dermatan sulfate was isolated by guanidine HCI extraction and anion exchange chromatography. The isolated material was found to have anticoagulant activity with a relative activity of approximately 40% of that of a porcine mucosal dermatan sulfate which is undergoing clinical trial as an antithrombotic agent. The dermatan sulfate was present as a proteoglycan with a molecular mass of 90-150 kD. Upon degradation with chondroitin ABC lyase, the core protein was demonstrated to be a doublet with molecular masses of 42 and 44 kD. This core protein reacted with antiserum against the core protein of decorin on Western analysis. The role of this placental dermatan sulfate in local regulation of thrombin in the placenta warrants further study.

Inflammatory cell availability affects ozone-induced lung damage.

Identifying whether or not neutrophils have a role to play in the early stages of acute lung epithelial injury brought about by inhalation of reactive substances continues to be a major area of investigation. In this study, the availability of circulating neutrophils was manipulated by treatment with either cyclophosphamide or rabbit antiserum against rat neutrophils, prior to exposures to air, a single high ozone exposure of 1 or 2 ppm for 3 h, or a continuous exposure to 0.8-1.0 ppm for up to 48 h. Although cyclophosphamide treatment resulted in undetectable levels of neutrophils in the blood, the recovery of tissue marginated-interstitial neutrophils of 1 x 10(6) cells by collagenase tissue digestion was not significantly diminished at the onset of air and ozone exposures. Cyclophosphamide treatment alone did not cause any permeability damage to air-exposed rat lungs, but did ameliorate ozone-induced increases in bronchoalveolar lavage (BAL) neutrophil and albumin recoveries after both short-term and 1 d of continuous ozone exposure. In contrast to cyclophosphamide, antiserum treatment resulted in greater than a 90% decrease in neutrophil recoveries from both blood and lung tissue at the onset of air and ozone exposures. Antiserum treatment also abrogated ozone-induced neutrophil accumulations in lung lavageable spaces following both single and continuous ozone exposures, but did not significantly affect ozone-associated lung permeability damage indicated by unaltered BAL fluid albumin recoveries. These data demonstrated that under experimental conditions when neutrophils remain within lung tissue marginated and interstitial pools, reduction in circulating blood neutrophil availability is associated with a concomitant decrease in ozone-induced lung damage.

[Acquired pseudohypoparathyroidism/(PHP) in adult coeliac disease (MCA)]. / Pseudo-hypoparathyroïdie (php) acquise au cours d'une maladie coeliaque de l'adulte (mca)

One case of chronic hypocalcemia and hyperphosphatemia, with an adult coeliac disease, hight P.T.H. level, very low rate of cyclic A.M.P. in urine, and normal rate of cyclid A.M.P. in plasma is described. It is the question of the pseudohypoparathyroidism acquirec as a result of an adult coeliac disease, because of after seven months of diet without gluten the clinical and biological improvement was observed with the increase of the cyclic-AMP clearance into the normal level and its great reactivity on the administration of exogenous PTH. We think to bring an additional analysis of the trouble of renal receptivity to parathyroid hormone.

[Radioimmunological determination of calcitonin (TCT) in the course of thyroid tumor pathology (84 cases)]. / Dosage radioimmunologique de la calcitonine (T.C.T.) au cours de la pathologie tumorale thyroidienne (84 cas)

The dosage of calcitonin was done in 13 thyroid carcinoma and 71 begnin thyroid tumors. In one case, the preoperative diagnosis of medullary thyroid carcinoma (M.T.C.) was alloved; in one another case of M.T.C. the repeatted dosage allows the evolution survey and the exploration of the family; in a third case, the dosage allows to doubt the diagnosis of M.T.C. in post-mortem. In 71 cases of begnin thyroid tumors, the calcitonin immunoassay is in the normal range. The interest and limits of the preoperative dosage was drawn of this experience.

[Anesthesia in the management of pyloric stenosis. Evaluation of the combination of propofol-halogenated anesthetics]. / Anesthésie pour sténose du pylore. Evaluation de l'association propofol-anesthésiques halogénés.

This study was aimed at evaluating haemodynamic changes during an anaesthetic sequence for full stomach, using propofol as induction agent and volatile anaesthetics for maintenance of anaesthesia in infants scheduled for surgical cure of hypertrophic pyloric stenosis. After correction of preoperative blood electrolyte and metabolic disturbances with appropriate i.v. hydrating solutions, anaesthesia was induced with propofol and suxamethonium. Infants were divided in two groups according to the volatile anaesthetic agent used for maintenance of anaesthesia after tracheal intubation: halothane (n = 16) or isoflurane (n = 15). The two groups were identical regarding weight (4.28 +/- 0.6 vs 4.14 +/- 0.76 kg), age (1.6 +/- 0.9 vs 1.5 +/- 0.6 months), preinduction heart rate (155 +/- 22 vs 151 +/- 22 b.min-1) and systolic-diastolic arterial pressure (96 +/- 18/58 +/- 12 vs 105 +/- 16/67 +/- 15 mmHg). Propofol and suxamethonium doses were identical, 3.9 +/- 1 mg.kg-1 and 1.3 +/- 0.6 mg.kg-1 respectively in halothane group, vs 4.3 +/- 0.8 mg.kg-1 and 1.3 +/- 0.4 mg.kg-1 in isoflurane group. Heart rate did not change after induction of anaesthesia, while arterial blood pressure decreased significantly (p < 0.001). However, blood pressure remained within the normal range for age throughout the procedure. Mean duration of surgery was shorter in halothane group (64 +/- 16 vs 79 +/- 17 min, p < 0.05), however time-interval from the end of surgery to tracheal extubation (12 +/- 6 vs 15 +/- 8 min) was short and identical in the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Behavioral reactions of the bat Carollia perspicillata to abrupt changes in gravity.

As part of an ongoing survey of the behavioral responses of vertebrates to abrupt changes in gravity, we report here on the reactions of bats (Carollia perspicillata) exposed to altered gravity during parabolic aircraft flight. In microgravity, mammals typically behave as if they were upside-down and exhibit repetitive righting reflexes, which often lead to long axis rolling. Since bats, however, normally rest upside-down, we hypothesized that they would not roll in microgravity. Only one of three specimens attempted to fly during microgravity. None rolled or performed any righting maneuvers. During periods of microgravity the bats partially extended their forearms but kept their wings folded and parallel to the body. Between parabolas and occasionally during microgravity the bats groomed themselves. Both the extended limbs and autogrooming may be stress responses to the novel stimulus of altered gravity. This is the first behavioral record of Chiroptera in microgravity.

A prospective, randomized trial comparing a transparent dressing and a dry gauze on the exit site of long term central venous catheters of hemodialysis patients.

The objective of this study was to assess the risk of bacteremia, estimate the cost and evaluate the quality of life by using a transparent dressing (TD) versus (vs) a dry gauze (DG) on the exit site of long term central I.V. catheters (LTCC) of hemodialysis patients. This 6-months preliminary study was conducted on 58 patients (pts) randomized to receive DG replaced 3 times/week (29 pts) or TD replaced every 7 days (29 pts). Data on patients, conditions of the exit site, local infection, bacteremia, quality of life and cost related to each type of dressing were collected. Two pts in the DG group experienced bacteremia related to their LTCC vs 1 pt in the group TD. A total of 7 (DG) vs 13 (TD) pts experienced skin condition changes at the catheter exit site. Some skin reactions, erythema and pruritus, did occur initially in the group TD and was due in part to insufficient drying time of the skin preparation solution. The estimated individual, weekly costs for using the DG was $7.60 vs $4.72 Canadian dollars for the TD. The SF-36trade mark scores did not show a significant difference between the 2 groups during the study (3.8 (PCS), 6.4 (MCS) at study end). Although this study was statistically underpowered, it suggests that the incidence of bacteremia was not increased with the use of a TD. Moreover, the use of a TD allowed fewer dressing changes, lowered total treatment costs, with no observed unfavorable impact on the quality of life and without significant local complications of the exit site. Based on the positive results observed in this pilot study, further study is warranted to examine the cost effectiveness of long-term use of TD dressings on dialysis catheter exit sites.

[The impact of suicide on the caregiver]. / L'impact du suicide sur l'aidant.

Suicide ("the killing of one's self") raises one crucial question: what does the manifest desire of death bring out in oneself and in others? For those providing care and support who are confronted with the voluntary death of a client or patient, the question is particularly difficult to address. Using the story of a suicide in an institution, the authors reveal the nature of defense mechanisms at play within the group of caregivers. Whether it be a traumatic daze, denial, guilt or depression, these individual and collective reactions to the event hinder the mourning process and threaten cohesion within the institution. Members of an "institution in crisis" must try to relieve their tensions by refraining from withdrawal, banalities, being haunted by suicide and implementing pseudo-solutions. The purpose of such an exercise is especially to avoid the cancellation or displacement of necessary thought process about the origins, implications and consequences of a suicide taking place within an institution. The authors discuss the founding principles and guidelines for group exploration of these phenomena. Without this coming-to-terms with the crisis, the authors point out that the institution could find itself in a rut where discussion focuses only on when and where things went wrong, and how it turned its back on a suffering patient.

[Latex hypersensitivity: a foreseeable accident?]. / Hypersensibilité au latex: un accident prévisible?

This paper describes another case of severe anaphylactic reaction due to allergy to natural rubber during anaesthesia in a child without known risk factors. The day after surgery the child reported that he experienced a few months ago an impressive skin reaction of both face and lips after inflating a latex balloon. It is suggested to try to detect latex allergy during the preoperative visit in all patients by including questions about latex sensitivity such as previous skin reactions or respiratory symptoms after wearing latex gloves or after inflating toy balloons. Patients in whom latex sensitivity is suspected should be tested appropriately in order to perform the planned surgery in a latex-free environment.