Oxygen Transport and Venous Admixture in the Extremely Obese. Influence of Anaesthesia and Artificial Ventilation with and without Positive End-Expiratory Pressure

Eight extremely obese patients (mean weight 136 kg) were studied when awake and breathing air, and during anaesthesia with controlled ventilation (oxygen fraction in inspirate (Fi o₂): 0.5). During anaesthesia, the patients were first studied with zero end-expiratory pressure (ZEEP) ventilation. Then two different positive end-expiratory pressures (PEEP) were applied, 10 cmH₂O and 15 cmH₂O₂ in order to study the effect of an increase in functional residual capacity (FRC). Arterial oxygenation and oxygen availability, as well as cardiac output (Q_t) and venous admixture (Q_s/Q_t) were studied. With the institution of anaesthesia and ZEEP, the alveolar arterial oxygen tension difference (P(A-a)o₂) rose from 3.5 ± 1.1 to 28.4 ± 2.6 kPa, and the oxygen availability fell from 1346 ± 222 to 1039 ± 239 ml/min, due to the additive effect of an increase in Q_s/Q_t from 10 ± 4 to 21 ± 5% and a fall in Q_T, from 7.7 ± 1.2 to 5.5 ± 1.1 l/min. With increasing levels of PEEP, despite a fall in P(A-a)o₂, there was a reduction in oxygen availability. This was due to simultaneous reduction in Q_s/Q_t and Q_T. At a PEEP of 15cmH₂O, the P(A-a)o₂ was 21.2 ± 7.1 kPa, oxygen availability 862 ± 170 ml/min, Q_s/Q_t 13 ± 4 and Q_T 4.4 ± 0.6 I. It is concluded that PEEP ventilation significantly reduces Q_s/Q_t in extremely obese patients during anaesthesia and should be used in these patients if there is arterial hypoxemia despite a high Fi o₂     

Airway Closure and Distribution of Inspired Gas in the Extremely Obese, Breathing Spontaneously and During Anaesthesia with Intermittent Positive Pressure Ventilation

Airway closure (closing capacity, CC), FRC, total efficiency of ventilation (lung clearance index, LCI) and distribution of inspired gas (nitrogen washout delay percentage, NWOD) were determined by nitrogen washout techniques and arterial Po₂ and Pco₂ measured by standard electrodes in 10 extremely obese subjects, prior to and during anaesthesia and artificial ventilation. CC was normal, but because of small FRC, airway closure occurred within a tidal breath in 9 out of 10 subjects during spontaneous breathing, when awake. Po₂ was reduced, the hypoxaemia correlating to the magnitude of airway closure. LCI was normal, but NWOD was borderline. During anaesthesia, CC was unaltered but FRC was further reduced, so that in nine subjects airway closure occurred above FRC and tidal volume together. A marked increase in relative hypoxaemia was recorded. LCI and NWOD rose, indicating less efficient and less even ventilation. It is concluded that airway closure reasonably explains the marked hypoxaemia in obese subjects during anaesthesia, and that it may also be the reason for the uneven distribution of inspired gas.     

Is heart rate in fish a sensitive indicator to evaluate acute effects of β-blockers in surface water?

We have investigated if propranolol, a non-selective β-blocker present in sewage effluents, affects heart rate in rainbow trout. During a 48 h exposure to a very high concentration of propranolol (70.9 μg/L) no effects on heart rate were found. After a subsequent intravenous injection of propranolol, heart rate remained unaffected in pre-exposed fish but was significantly lowered in naïve fish. Other studies have reported effects on the reproduction of fish by propranolol dissolved in water at much lower concentrations. The present study suggests that physiological systems under homeostatic control, like heart rate, may not be particularly sensitive despite being direct targets.     

Chapter 23: International Standard reagents for harmonization of HPV serology and DNA assays--an update

International reference materials such as International Standard reagents facilitate quality assurance of essential biopharmaceutical products and related in vitro diagnostic tests. Standardization of antibody and DNA measurements and harmonization of laboratory procedures are key to the success of cancer prevention strategies through screening methods as well as for development and implementation of vaccination against the human papillomavirus (HPV). The WHO supported the preparation and initial analysis of a panel of candidate serological and DNA reference reagents aimed at facilitating inter-laboratory comparisons and detection of HPV worldwide. Two international collaborative studies assessed the performance of various HPV antibody and HPV-DNA detection assays and examined the feasibility of generating HPV antibody and DNA standard reagents. These studies showed that improvement in performance and comparability of assays is urgently needed and that the use of the same International Standard reference reagent could significantly improve performance and comparability. It is hoped that the establishment of International Units and International Standards for HPV antibody and DNA analysis will be pursued with high priority.     

A truncated analogue of CCL2 mediates anti-fibrotic effects on murine fibroblasts independently of CCR2

The truncated [1+9-76] CCL2 analogue, also known as 7ND, has been described in numerous reports as an anti-inflammatory and anti-fibrotic agent in a wide spectrum of animal models, e.g. models of cardiovascular disease, graft versus host disease and bleomycin-induced pulmonary fibrosis. 7ND has been reported to function as a competitive inhibitor of CCL2 signaling via CCR2 in human in vitro systems. In contrast, the mechanistic basis of 7ND action in animal models has not been previously reported. Here we have studied how 7ND interacts with CCL2 and CCR2 of murine origin. Surprisingly, 7ND was shown to be a weak inhibitor of murine CCL2/CCR2 signaling and displaced murine CCL2 (JE) from the receptor with a K(i)>1 μM. Using surface plasmon resonance, we found that 7ND binds murine CCL2 with a K(d) of 670 nM, which may indicate that 7ND inhibits murine CCL2/CCR2 signaling by a dominant negative mechanism rather than by competitive binding to the CCR2 receptor. In addition we observed that sub-nanomolar levels of 7ND mediate anti-fibrotic effects in CCR2 negative fibroblasts cultured from fibrotic lung of bleomycin-induced mice. Basal levels of extracellular matrix proteins were reduced (collagen type 1 and fibronectin) as well as expression levels of α-smooth muscle actin and CCL2. Our conclusion from these data is that the previously reported effects of 7ND in murine disease models most probably are mediated via mechanisms independent of CCR2.     

Systolic blood pressure increases in patients with atrial fibrillation regaining sinus rhythm after electrical cardioversion

Direct current (DC) cardioversion is used to convert persistent atrial fibrillation (AF) to sinus rhythm (SR), but there is limited knowledge about how blood pressure (BP) is affected by conversion to SR. We sought to evaluate how BP changed in AF patients who converted to SR, compared to patients still in AF. In this retrospective registry analysis, we included a total of 487 patients, treated with DC cardioversion for persistent AF. We obtained data regarding medical history, medication, BP, and electrocardiogram the day before and 7 days after cardioversion. Systolic BP increased by 9 (±16) mm Hg (P < 0.01) and diastolic BP decreased by 3 (±9) mm Hg (P < 0.01) after conversion to SR. In the group of patients with restored SR, there was a 40% increase in the proportion of patients with a hypertensive BP level (≥140/90 mm Hg) after DC cardioversion compared to before. Patients still in AF had no significant change in BP. Systolic BP increases and diastolic BP slightly decreases when persistent AF is converted to SR. The underlying mechanisms explaining these findings are not known, but may involve either hemodynamic changes that occur when SR is restored, an underestimation of systolic BP in AF, or a combination of both. Our findings suggest that an increased attention to BP levels after a successful cardioversion is warranted.     

Pulmonary vascular endothelial growth factor-C in development and lung injury in preterm infants

RATIONALE: In mice, vascular endothelial growth factor-C (VEGF-C) plays an important role in development of the lymphatic system and in pathogenesis of pulmonary inflammation. Its role in development of the lymphatic system in human lung and in lung injury in newborns remains unclear. OBJECTIVES: We studied the role of VEGF-C in developing human lung, and in acute and chronic lung injury in preterm infants. METHODS: Included in the immunohistochemistry study were 10 fetuses, 15 control neonates without primary lung disease, 15 preterm infants with respiratory distress syndrome, and 8 infants with bronchopulmonary dysplasia. Tracheal aspirate fluid samples of intubated very-low-birth-weight infants during Postnatal Weeks 1-5 were analyzed with ELISA. RESULTS: Bronchiolar staining for VEGF-C was observed in all 48 samples. Alveolar epithelial staining was seen in most fetuses (8/10). In addition, staining was observed in alveolar macrophages in bronchopulmonary dysplasia (4/8), and late respiratory distress syndrome (2/7). VEGF receptor-3 (VEGFR-3) staining was observed in lymphatic endothelium adjacent to vascular endothelium. VEGF-C was expressed consistently in tracheal aspirate fluid, being highest during the first 2 postnatal days. Antenatal administration of glucocorticoids was associated with higher VEGF-C in tracheal aspirate fluid. CONCLUSIONS: The pattern of pulmonary VEGF-C and VEGFR-3 protein expression and consistent VEGF-C protein appearance in tracheal aspirate fluid in human preterm infants indicate a role for VEGF-C in the physiologic development of the lymphatic system of the lung.     

The mosaic genome structure of the Wolbachia wRi strain infecting Drosophila simulans

The obligate intracellular bacterium Wolbachia pipientis infects around 20% of all insect species. It is maternally inherited and induces reproductive alterations of insect populations by male killing, feminization, parthenogenesis, or cytoplasmic incompatibility. Here, we present the 1,445,873-bp genome of W. pipientis strain wRi that induces very strong cytoplasmic incompatibility in its natural host Drosophila simulans. A comparison with the previously sequenced genome of W. pipientis strain wMel from Drosophila melanogaster identified 35 breakpoints associated with mobile elements and repeated sequences that are stable in Drosophila lines transinfected with wRi. Additionally, 450 genes with orthologs in wRi and wMel were sequenced from the W. pipientis strain wUni, responsible for the induction of parthenogenesis in the parasitoid wasp Muscidifurax uniraptor. The comparison of these A-group Wolbachia strains uncovered the most highly recombining intracellular bacterial genomes known to date. This was manifested in a 500-fold variation in sequence divergences at synonymous sites, with different genes and gene segments supporting different strain relationships. The substitution-frequency profile resembled that of Neisseria meningitidis, which is characterized by rampant intraspecies recombination, rather than that of Rickettsia, where genes mostly diverge by nucleotide substitutions. The data further revealed diversification of ankyrin repeat genes by short tandem duplications and provided examples of horizontal gene transfer across A- and B-group strains that infect D. simulans. These results suggest that the transmission dynamics of Wolbachia and the opportunity for coinfections have created a freely recombining intracellular bacterial community with mosaic genomes.