Target-controlled infusion during MitraClip procedures in deep-sedation with spontaneous breathing.

OBJECTIVE: Percutaneous mitral valve repair with the MitraClip system is an alternative procedure for high-risk patients not suitable for conventional surgery. The MitraClip can be safely performed under general anesthesia (GA) or deep sedation (DS) with spontaneous breathing using a combination of propofol and remifentanil. This study aimed to evaluate the benefits of target-controlled infusion (TCI) of remifentanil and administration of propofol during DS compared with manual administration of total intravenous anesthesia (TIVA) medication during GA in patients undergoing MitraClip. We assessed the impact of these procedures in terms of remifentanil dose, hemodynamic profile, adverse events, and days of hospital stay after the process. PATIENTS AND METHODS: From March 2013 to June 2015 (mean age 73.5 ± 9,54), patients underwent transcatheter MitraClip repair, 27 received DS via TCI and 27 GA with TIVA. RESULTS: Acute procedural success was 100%. DS-TCI group, in addition to a significant reduction of remifentanil dose administrated (249 µg vs. 2865, p < 0.01), resulted in a decrease in vasopressor drugs requirement for hemodynamic adjustments (29.6% vs. 63%, p = 0.03) during the procedure and a reduction of hypotension (p = 0.08). The duration of postoperative hospitalization did not differ between the two groups (5.4 days vs. 5.8 days, p = 0.4). CONCLUSIONS: Administration of remifentanil by TCI for DS in spontaneously breathing patients offers stable anesthesia conditions, with a lower amount of drugs, higher hemodynamic stability, and decreased side effects.

A GLP1 receptor agonist diabetes drug ameliorates neurodegeneration in a mouse model of infantile neurometabolic disease.

Infantile neuroaxonal dystrophy (INAD) is a rare paediatric neurodegenerative condition caused by mutations in the PLA2G6 gene, which is also the causative gene for PARK14-linked young adult-onset dystonia parkinsonism. INAD patients usually die within their first decade of life, and there are currently no effective treatments available. GLP1 receptor (GLP-1R) agonists are licensed for treating type 2 diabetes mellitus but have also demonstrated neuroprotective properties in a clinical trial for Parkinson's disease. Therefore, we evaluated the therapeutic efficacy of a new recently licensed GLP-1R agonist diabetes drug in a mouse model of INAD. Systemically administered high-dose semaglutide delivered weekly to juvenile INAD mice improved locomotor function and extended the lifespan. An investigation into the mechanisms underlying these therapeutic effects revealed that semaglutide significantly increased levels of key neuroprotective molecules while decreasing those involved in pro-neurodegenerative pathways. The expression of mediators in both the apoptotic and necroptotic pathways were also significantly reduced in semaglutide treated mice. A reduction of neuronal loss and neuroinflammation was observed. Finally, there was no obvious inflammatory response in wild-type mice associated with the repeated high doses of semaglutide used in this study.

Performance of seven ECG interpretation programs in identifying arrhythmia and acute cardiovascular syndrome.

BACKGROUND: No direct comparison of current electrocardiogram (ECG) interpretation programs exists. OBJECTIVE: Assess the accuracy of ECG interpretation programs in detecting abnormal rhythms and flagging for priority review records with alterations secondary to acute coronary syndrome (ACS). METHODS: More than 2,000 digital ECGs from hospitals and databases in Europe, USA, and Australia, were obtained from consecutive adult and pediatric patients and converted to 10 s analog samples that were replayed on seven electrocardiographs and classified by the manufacturers' interpretation programs. We assessed ability to distinguish sinus rhythm from non-sinus rhythm, identify atrial fibrillation/flutter and other abnormal rhythms, and accuracy in flagging results for priority review. If all seven programs' interpretation statements did not agree, cases were reviewed by experienced cardiologists. RESULTS: All programs could distinguish well between sinus and non-sinus rhythms and could identify atrial fibrillation/flutter or other abnormal rhythms. However, false-positive rates varied from 2.1% to 5.5% for non-sinus rhythm, from 0.7% to 4.4% for atrial fibrillation/flutter, and from 1.5% to 3.0% for other abnormal rhythms. False-negative rates varied from 12.0% to 7.5%, 9.9% to 2.7%, and 55.9% to 30.5%, respectively. Flagging of ACS varied by a factor of 2.5 between programs. Physicians flagged more ECGs for prompt review, but also showed variance of around a factor of 2. False-negative values differed between programs by a factor of 2 but was high for all (>50%). Agreement between programs and majority reviewer decisions was 46-62%. CONCLUSIONS: Automatic interpretations of rhythms and ACS differ between programs. Healthcare institutions should not rely on ECG software "critical result" flags alone to decide the ACS workflow.

Cardiac resynchronization therapy: a comparison among left ventricular bipolar, quadripolar and active fixation leads.

We evaluated the performance of 3 different left ventricular leads (LV) for resynchronization therapy: bipolar (BL), quadripolar (QL) and active fixation leads (AFL). We enrolled 290 consecutive CRTD candidates implanted with BL (n = 136) or QL (n = 97) or AFL (n = 57). Over a minimum 10 months follow-up, we assessed: (a) composite technical endpoint (TE) (phrenic nerve stimulation at 8 V@0.4 ms, safety margin between myocardial and phrenic threshold <2V, LV dislodgement and failure to achieve the target pacing site), (b) composite clinical endpoint (CE) (death, hospitalization for heart failure, heart transplantation, lead extraction for infection), (c) reverse remodeling (RR) (reduction of end systolic volume >15%). Baseline characteristics of the 3 groups were similar. At follow-up the incidence of TE was 36.3%, 14.3% and 19.9% in BL, AFL and QL, respectively (p < 0.01). Moreover, the incidence of RR was 56%, 64% and 68% in BL, AFL and QL respectively (p = 0.02). There were no significant differences in CE (p = 0.380). On a multivariable analysis, "non-BL leads" was the single predictor of an improved clinical outcome. QL and AFL are superior to conventional BL by enhancing pacing of the target site: AFL through prevention of lead dislodgement while QL through improved management of phrenic nerve stimulation.

Molecular-based upconversion in homo/heterogeneous liquids and in micro/nanostructured solid materials.

Radiation upconversion can be an elegant and efficient strategy to minimize waste in energy harvesting and storage processes. The upconversion based on triplet-triplet annihilation processes of molecular dyes is a very versatile approach, but it requires a systematic photophysical characterization of the systems to optimize the upconversion yields and develop materials for technological applications. This paper represents an overview of the work carried out in our laboratories for the study and characterization of a molecular dye pair, 2,3,7,8,12,13,17,18-octaethyl-21H,23H-porphyrin platinum(ii) (PtOEP) and 1,3,6,8-tetraphenylpyrene (TPPy), suitable as the sensitizer and emitter, respectively, in a triplet-triplet annihilation based upconversion process. The investigation has been carried out in various media with increasing complexity. First, we used the dye pair to characterize the UC-efficiencies in homogeneous solvents of different viscosities and in oil-in-water microemulsions; then we explored the possibility to achieve upconversion in solid materials, like nanostructured silica matrices and liquid filled microcapsules. The possibility to achieve upconversion emission even in confined and rigid media has been confirmed and can inspire further applications of the process.

Ultrasound prenatal diagnosis of inguinal scrotal hernia and contralateral hydrocele.

Fetal inguinal scrotal hernia is a rare condition resulting in an abnormal embryonic process of the tunica vaginalis. We report a case of ultrasound prenatal diagnosis of inguinal scrotal hernia associated with contralateral hydrocele in a woman at 37 weeks of gestation, referred to our clinic for a scrotal mass. Differential diagnosis includes hydrocele, teratoma, hemangiomas, solid tumours of testis, bowel herniation, and testicular torsion. Bowel peristalsis is an important ultrasound sign and it allowed us to make diagnosis of inguinal scrotal hernia. Diagnosis was confirmed at birth and a laparoscopic hernia repair was performed without complications on day 10. During surgery, a bilateral defect of canal inguinal was seen and considered as the cause of scrotal inguinal hernia and contralateral hydrocele observed in utero.

Glucose-6-phosphate dehydrogenase in barley roots: kinetic properties and localisation of the isoforms.

Two different isoforms of glucose-6-phosphate dehydrogenase (Glc6PDH; EC 1.1.1.49) have been partially purified from barley (Hordeum vulgare L., cv. Alfeo) roots. The procedure included an ammonium sulfate step, Q-Sepharose and Reactive Blue agarose chromatography, and led to 60-fold and 150-fold purification for the two enzymes, respectively. The Glc6PDH 1 isoform accounts for 17% of total activity of the enzyme in roots, and is very sensitive to the effects of NADP+/NADPH ratio and dithiothreitol; the Glc6PDH 2 isoform is less affected by reducing power and represents 83% of the total activity. The isoforms showed distinct pH optima, isoelectric points, Km for glucose-6-phosphate and a different electrophoretic mobility. The kinetic properties for the two enzymes were affected by ATP and metabolites. Both enzymes are inhibited to different extents by ATP when magnesium is omitted from the assay mixture, whereas the addition of ATP-Mg2+ had no effect on Glc6PDH activities. The Glc6PDH isoforms are usually present in the plastids and cytosol of plant cells. To verify the intracellular locations of the enzymes purified from barley roots, Glc6PDH was purified from isolated barley root plastids; this isoform showed kinetic parameters coincident with those found for Glc6PDH 1, suggesting a plastid location; the enzyme purified from the soluble fraction had kinetic parameters resembling those of Glc6PDH 2, confirming that this isoform is present in the cytosol of barley roots.

Pulmonary alveolus formation: critical period, retinoid regulation and plasticity.

Pulmonary alveoli, the lung's gas-exchange structures, are formed in part by subdivision (septation) of the saccules that constitute the gas-exchange region of the immature lung. Although little is known about the regulation of septation, relatively recent studies show: (1) all-trans retinoic acid (RA) treatment of newborn rats increases septation and prevents the inhibition of septation produced by treatment of newborn rats with dexamethasone, a glucocorticosteroid hormone; (2) treatment with RA of adult rats that have elastase-induced emphysema increases lung elastic recoil, induces the formation of alveoli, and increases volume-corrected alveolar surface area; and (3) in tight-skin mice, which have a genetic failure of septation, and in rats in which septation had previously been prevented by treatment with dexamethasone, treatment with RA partially rescues the failed septation. These findings raise the possibility that treatment with RA will induce the formation of alveoli in humans with pulmonary emphysema.

Retinoic acid receptor-beta: an endogenous inhibitor of the perinatal formation of pulmonary alveoli.

Pulmonary alveoli are formed, in part, by subdivision (septation) of the gas-exchange saccules of the immature lung. Septation is developmentally regulated, and failure to septate at the appropriate time is not followed by delayed spontaneous septation. We report retinoic acid receptor (RAR) beta knockout mice exhibit premature septation; in addition, they form alveoli twice as fast as wild-type mice during the period of septation but at the same rate as wild-type mice thereafter. Consistent with the perinatal effect of RARbeta knockout, RARbeta agonist treatment of newborn rats impairs septation. These results 1) identify RARbeta as the first recognized endogenous signaling that inhibits septation, 2) demonstrate premature onset of septation may be induced, and 3) show the molecular signaling regulating alveolus formation differs during and after the period of septation. Suppressing perinatal RARbeta signaling by RARbeta antagonists may offer a novel, nonsurgical, means of preventing, or remediating, failed septation in prematurely born children.

Retinoic acid treatment partially rescues failed septation in rats and in mice.

Pulmonary alveoli are formed in part by subdivision (septation) of the gas-exchange saccules of the immature lung. Septation results in smaller, more numerous structures (alveoli) and is developmentally regulated in mammals including humans, rats, and mice; if it fails to occur at the appropriate time, there is no spontaneous post hoc septation nor has there been a means of inducing septation after it has failed to occur. We measured lung volume, the volume of individual alveoli, and alveolar surface area and calculated alveolar number in neonatal rats in which septation had been blocked by treatment with a glucocorticosteroid hormone and in adult tight-skin mice that have a genetic failure of septation. We tested the hypothesis that treatment with all-trans retinoic acid induces post hoc septation. In both models of failed septation, hence in two species, and in immature and adult animals, treatment with all-trans retinoic acid induced post hoc septation, offering the possibility of a similar effect in premature infants.

Gene expression of cellular retinoid-binding proteins: modulation by retinoic acid and dexamethasone in postnatal rat lung.

In rats, septation of gas-exchange saccules occurs during the first 2 postnatal weeks; dexamethasone (DEX) treatment irreversibly impairs septation, and treatment with all-trans retinoic acid (RA) prevents the DEX-induced inhibition of septation. Cellular retinoic acid-binding protein I (CRABP I) and cellular retinol-binding protein I (CRBP I) are important modulators of the cellular metabolism of retinoids. In the present study, therefore, we measured the mRNA concentration of CRABP I and CRBP I in lungs of neonatal rats. In untreated rats, CRABP I and CRBP I mRNA peaked at postnatal d 8, indicating that CRABP I and CRBP I are developmentally regulated at least in part at a pretranslational level during lung septation. Daily treatment of 3- to 8-d-old rats with RA (500 microg/kg/d) had no effect on the level of CRABP I mRNA; treatment with DEX (0.25 microg/d) from d 4 to 8 caused a decrease in CRABP I mRNA that was not prevented by concomitant treatment with RA. These findings suggest that a decrease in CRABP I expression may be important in the DEX-induced block of septation but not in the prevention by RA of DEX-induced inhibition of septation. RA treatment caused an increase of CRBP I mRNA; conversely, treatment with DEX caused a decrease in CRBP I mRNA that was prevented by concomitant treatment with RA. These data suggest CRBP I may play a role in RA-induced septation, in the inhibition of septation caused by DEX, and in the ability of RA to prevent DEX-blocked septation.

Retinoic acid treatment abrogates elastase-induced pulmonary emphysema in rats.

Pulmonary emphysema is a common disease in which destruction of the lung's gas-exchange structures (alveoli) leads to inadequate oxygenation, disability and frequently death; lung transplantation provides its only remediation. Because treatment of normal rats with all-trans-retinoic acid increases the number of alveoli, we tested whether a similar effect would occur in rats with emphysema. Elastase was instilled into rat lungs, producing changes characteristic of human and experimental emphysema: increased lung volume reflecting a loss of lung elastic recoil, larger but fewer alveoli and diminished volume-corrected alveolar surface area due to destruction of alveolar walls. Treatment with all-trans-retinoic acid reversed these changes providing nonsurgical remediation of emphysema and suggesting the possibility of a similar effect in humans.

Postnatal treatment with retinoic acid increases the number of pulmonary alveoli in rats.

Dexamethasone, a glucocorticosteroid hormone, inhibits the formation of alveoli; retinoids and glucocorticosteroid hormones can be mutually antagonistic. These observations led us to test the hypothesis that the administration of retinoic acid to postnatal rats would prevent the low alveolar number and the low body mass-specific gas-exchange surface area (Sa) produced by treatment with dexamethasone. We used serial lung sections to distinguish alveoli from alveolar ducts and stereological procedures that allow quantitation of alveoli uninfluenced by their size, shape, or distribution. Treatment with retinoic acid prevented the low number of alveoli and the low body mass-specific Sa caused by treatment with dexamethasone. In otherwise untreated rats, retinoic acid caused a 50% increase in the number of alveoli, but without an increase in Sa, suggesting the action of a regulatory mechanism to prevent unneeded Sa. These findings provide the first experimental support for the possibility that, in individuals with too few alveoli for adequate gas exchange, treatment with a pharmacological agent may provide preventative or remedial therapy.

Formation of pulmonary alveoli and gas-exchange surface area: quantitation and regulation.

New morphometric procedures allow selection of alveoli for analysis in an unbiased manner and then to determine the volume of individual alveoli. The latter, together with the easily measured lung volume, allows the calculation of alveolar number. These new techniques have greatly increased the rigor of the study of the formation of alveoli and the manner in which this process is regulated. This review deals mainly with work based on these new morphometric methods that explore the regulation of the formation of alveoli and hence the size of the lung's gas-exchange surface area. We expect that continued application of these methods, buttressed with experiments at the cellular and molecular level, will result in a fundamental understanding of how the formation of alveoli and the size of the gas-exchange surface area is regulated. This new information holds the promise of translation into the induction of the formation of alveoli for therapeutic purposes.

Estrogen modulates the dimensions of the lung's gas-exchange surface area and alveoli in female rats.

Sexually mature virgin female rats and mice have a higher mass-specific gas-exchange surface area (Sa) and smaller alveoli than same-aged males even though mass-specific oxygen consumption (VO2) is the same, within species, in both sexes (G. D. Massaro, J. P. Mortola, and D. Massaro. Proc. Natl. Acad. Sci. USA 92: 1105-1107, 1995). We now report that rats subjected to ovariectomy at age 21 days had, at age 59 days, a smaller mass-specific Sa and larger alveoli than sham-ovariectomized rats; these differences were not due to differences in VO2 and were prevented by estrogen therapy. Furthermore, sham-ovariectomized rats treated with estrogen had smaller and more alveoli than sham-operated females not given estrogen. Androgenization of newborn female rats did not alter mass-specific Sa or alveolar size. Male mice genetically deficient in androgen receptors had the same mass-specific Sa as normal male littermates. We conclude that estrogen is responsible for the sexual dimorphism of the lung's gas-exchange region and induces the formation of smaller, more numerous alveoli in otherwise untreated female rats.

Sexual dimorphism in the architecture of the lung's gas-exchange region.

The lung's only vital function is to provide sufficient gas-exchange surface area (Sa) to meet the organism's needs for oxygen uptake (VO2) and carbon dioxide elimination. A direct linear relation between Sa and VO2 and an inverse linear relation between the size of the lung's gas-exchange units and the species mass-specific VO2 are strongly conserved across species. Within species, Sa increases in response to prolonged (weeks) elevation of VO2. We now report sex-dependent deviations from these relationships that seem to anticipate the need for increased gas-exchange capacity engendered in females by the metabolic demands of pregnancy and lactation. We found that although VO2 almost doubled in rats during pregnancy and lactation, Sa was the same in age-matched virgin, pregnant, and lactating females. However, at the onset of sexual maturity, virgin female rats and mice had higher mass-specific Sa than males of the same species although mass-specific VO2 was identical, within species, in both sexes. In addition, even though mass-specific VO2 was identical in males and females, alveoli were 30% and 50% smaller in female rats and mice, respectively, than males of the same species. We suggest the greater mass-specific Sa and smaller alveoli in females in spite of identical mass-specific VO2 as males were selected for evolutionarily; they help females meet the metabolic demands of reproduction without adding to the energy demands of these periods a requirement to form additional lung.

Pertussis toxin treatment alters manganese superoxide dismutase activity in lung. Evidence for lung oxygen toxicity in air-breathing rats.

Exposure of rats to hyperoxia or to treatment with endotoxin, increases lung manganese superoxide dismutase (MnSOD) gene expression. However, the paths by which these environmental signals are transduced into enhanced MnSOD gene expression are unknown. We now provide evidence that heterotrimeric G proteins are involved in the hyperoxia-induced increase in lung MnSOD gene expression but that pertussis toxin-sensitive G proteins are not involved in the endotoxin-induced elevation of lung MnSOD gene expression. We also show that treating rats with pertussis toxin decreased lung MnSOD activity approximately 50%. This decline in MnSOD activity occurred without a change in the lung activity of copper-zinc SOD, catalase, or glutathione peroxidase. In air-breathing rats, the pertussis toxin-induced decrease in MnSOD activity was associated with the development of lung edema, pleural effusion with a high concentration of protein, and biochemical evidence of lung oxygen toxicity. Compared to air-breathing rats, maintenance of pertussis toxin-treated rats under hypoxic or hyperoxic conditions respectively decreased or increased intrathoracic fluid. Endotoxin treatment elevated lung MnSOD activity and protected pertussis toxin-treated rats from an increase in intrathoracic fluid.

Postnatal lung growth: evidence that the gas-exchange region grows fastest at the periphery.

The site(s) at which the gas-exchange region enlarges after alveoli are formed from the saccules of the immature lung is unclear; however, this information might be important to studies of the regulation of lung growth. Although aware of important assumptions on which it rests, we undertook this study to test the idea that the lung's gas-exchange region enlarges more rapidly in the immediate subpleural region than more centrally. To label the interstitium of the gas-exchange region, rats were provided silver-containing water from age 23 to 135 days (112 days). Some were killed at age 135 days, others 51 days after silver exposure ended (age 186 days). We considered silver grains that formed in the interstitium as a marker of lung present or formed during silver exposure; tissue added after exposure would diminish the numerical density of grains and the fastest growing sites would have the lowest grain density. Rats killed on the 112th day of silver exposure had a silver grain density in their immediate subpleural gas-exchange matrix that was 28% lower than in their more central gas-exchange matrix. Rats killed 51 days after silver exposure ended had a grain density in the immediate subpleural region that was 65% lower than in the central matrix of the gas-exchange region. The grain density in the rats killed 51 days after silver exposure ended was 33% lower in the central matrix and 67% lower in the peripheral matrix than in the respective regions of rats killed on day 112 of exposure.(ABSTRACT TRUNCATED AT 250 WORDS)

Formation of alveoli in rats: postnatal effect of prenatal dexamethasone.

We administered a glucocorticosteroid (dexamethasone) or its diluent to pregnant rats on gestation days 17, 18, and 19. In male offspring we determined the lung's gas exchange surface area (S(a)), the average volume (v) of gas exchange saccules at age 2 days and alveoli at age 14 days, and their number (N) on these days. S(a), v, and N at 2 days and v at 14 days were not affected by the prenatal administration of dexamethasone. However, S(a) and N were lower in 14-day-old pups from dexamethasone-treated dams than in pups from diluent-treated dams. In separate experiments we found the responsiveness to prenatal dexamethasone, as a depressor of the postnatal increase in S(a), appeared earlier in female than male fetuses; it was present in female but not in male fetuses on days 16-18 and was found in male fetuses on days 17-19. We conclude 1) prenatal administration of dexamethasone diminishes the postnatal increase in S(a), 2) responsiveness to this action of dexamethasone occurs earlier in gestation in female than in male fetuses, and 3) prenatal dexamethasone does not effect the postnatal volume of an average alveolus but diminishes their number in male pups.