Spontaneous effort causes occult Pendelluft during mechanical ventilation

In the injured lung, local negative pleural pressure generated by diaphragmatic contraction is not uniformly transmitted, but is concentrated in dependent lung. This causes Pendelluft (using EIT), with shift of air from non-dependent to dependent lung regions. Thus, during lung-protective ventilation with strictly limited tidal volume, the presence of strong inspiratory effort can result in a hidden, local over-stretch of the dependent lung

Age at first birth in women is genetically associated with increased risk of schizophrenia

Prof. Paunio on PGC:n jäsenPrevious studies have shown an increased risk for mental health problems in children born to both younger and older parents compared to children of average-aged parents. We previously used a novel design to reveal a latent mechanism of genetic association between schizophrenia and age at first birth in women (AFB). Here, we use independent data from the UK Biobank (N = 38,892) to replicate the finding of an association between predicted genetic risk of schizophrenia and AFB in women, and to estimate the genetic correlation between schizophrenia and AFB in women stratified into younger and older groups. We find evidence for an association between predicted genetic risk of schizophrenia and AFB in women (P-value = 1.12E-05), and we show genetic heterogeneity between younger and older AFB groups (P-value = 3.45E-03). The genetic correlation between schizophrenia and AFB in the younger AFB group is -0.16 (SE = 0.04) while that between schizophrenia and AFB in the older AFB group is 0.14 (SE = 0.08). Our results suggest that early, and perhaps also late, age at first birth in women is associated with increased genetic risk for schizophrenia in the UK Biobank sample. These findings contribute new insights into factors contributing to the complex bio-social risk architecture underpinning the association between parental age and offspring mental health.Peer reviewe

Ventilator-induced lung injury: The role of gene activation

10.1097/MCC.0b013e32834e7d00Current Opinion in Critical Care18116-22COCC

Preemptive analgesia. Clinical evidence of neuroplasticity contributing to postoperative pain.

Recent evidence suggests that surgical incision and other noxious perioperative events may induce prolonged changes in central neural function that later contribute to postoperative pain. The present study tested the hypothesis that patients receiving epidural fentanyl before incision would have less pain and need fewer analgesics post-operatively than patients receiving the same dose of epidural fentanyl after incision. Thirty patients (ASA physical status 2) scheduled for elective thoracic surgery through a posterolateral thoracotomy incision were randomized to one of two groups of equal size and prospectively studied in a double-blind manner. Epidural catheters were placed via the L2-L3 or L3-L4 interspaces preoperatively, and the position was confirmed with lidocaine. Group 1 received epidural fentanyl (4 micrograms/kg, in 20 ml normal saline) before surgical incision, followed by epidural normal saline (20 ml) infused 15 min after incision. Group 2 received epidural normal saline (20 ml) before surgical incision, followed by epidural fentanyl (4 micrograms/kg, in 20 ml normal saline) infused 15 min after incision. No additional analgesics were used before or during the operation. Anesthesia was induced with thiopental (3-5 mg/kg) and maintained with N2O/O2 and isoflurane. Paralysis was achieved with pancuronium (0.1 mg/kg). Postoperative analgesia consisted of patient-controlled intravenous morphine. Visual analogue scale pain scores were significantly less in group 1 (2.6 +/- 0.44) than in group 2 (4.7 +/- 0.58) 6 h after surgery (P less than 0.05), by which time plasma fentanyl concentrations had decreased to subtherapeutic levels (less than 0.15 ng/ml) in both groups

Thames estuary - Establishing a robust flood system model to support engineering investment decisions

The Environment Agency is currently planning its long-term approach to Flood Risk Management within the Thames Estuary. This is a significant and multi-dimensional challenge. Adapting and managing existing defences, barriers, gates and pumps as well as building new ones are likely to have a significant role as part of this future. This paper explores the initial development and first application of a system model capable of supporting a risk-based targeting of investment. The paper demonstrates how a regional system analysis tool – based on the RASP High Level analysis framework - can be used to provide an assessment of both flood risk and the performance of different response strategies under future scenarios. The practical issues explored in this paper include: Data gathering – including hierarchical approaches to the use of data and the attribution of data uncertainties. Defence performance analysis – how national scale and local analysis of defence failure can be integrated. Quantifying the individual defence contribution to risk (within the context of over 480km of defences within the tidal Thames) The paper concludes with a practical insight to the use and utility of system models in the context of an active and complex decision making process

Continuous positive airway pressure causes lung injury in a model of sepsis.

Continuous positive airway pressure, aimed at preventing pulmonary atelectasis, has been used for decades to reduce lung injury in critically ill patients. In neonatal practice, it is increasingly used worldwide as a primary form of respiratory support due to its low cost and because it reduces the need for endotracheal intubation and conventional mechanical ventilation. We studied the anesthetized in vivo rat and determined the optimal circuit design for delivery of continuous positive airway pressure. We investigated the effects of continuous positive airway pressure following lipopolysaccharide administration in the anesthetized rat. Whereas neither continuous positive airway pressure nor lipopolysaccharide alone caused lung injury, continuous positive airway pressure applied following intravenous lipopolysaccharide resulted in increased microvascular permeability, elevated cytokine protein and mRNA production, and impaired static compliance. A dose-response relationship was demonstrated whereby higher levels of continuous positive airway pressure (up to 6 cmH(2)O) caused greater lung injury. Lung injury was attenuated by pretreatment with dexamethasone. These data demonstrate that despite optimal circuit design, continuous positive airway pressure causes significant lung injury (proportional to the airway pressure) in the setting of circulating lipopolysaccharide. Although we would currently avoid direct extrapolation of these findings to clinical practice, we believe that in the context of increasing clinical use, these data are grounds for concern and warrant further investigation

Multimodal analgesia before thoracic surgery does not reduce postoperative pain

Several reports have suggested that preoperative nociceptive block may reduce postoperative pain, analgesic requirements, or both, beyond the anticipated duration of action of the analgesic agents. We have investigated, in a double-blind, placebo-controlled study, pre-emptive analgesia and the respiratory effects of preoperative administration of a multimodal antinociceptive regimen. Thirty patients undergoing thoracotomy were allocated randomly to two groups. Before surgery, the treatment group (n = 15) received morphine 0.15 mg kg−1 i.m. with perphenazine 0.03mg kg−1 i.m. and a rectal suppository of indomethacin 100 mg, while the placebo group (n = 15) received midazolam 0.05mg kg−1 i.m. and a placebo rectal suppository. After induction of anaesthesia, the treatment group received intercostal nerve block with 0.5% bupivacaine and adrenaline 1:200000 (3 ml) in the interspace of the incision and in the two spaces above and two spaces below. The placebo group received identical injections but with normal saline only. The treatment group consumed significantly less morphine by patient-controlled analgesia in the first 6 h after operation, but the total dose of morphine consumed on days 2 and 3 after surgery was significantly greater in the treatment group. There were no differences between the groups in postoperative VAS scores (at rest or after movement), Paco2 values or postoperative spirometry. However, pain thresholds to pressure applied at the side of the chest contralateral to the site of incision decreased significantly from preoperative values on days 1 and 2 after surgery in both groups. The results of this study do not support the preoperative use of this combined regimen for post-thoracotomy pain

Potent antimicrobial effect induced by disruption of chloride homeostasis

Artificial transmembrane ion transporters have proposed applicability to medicinal chemistry, where perturbation of normal cellular homeostasis has already been shown to induce apoptosis in mammalian cells; however, this effect has not been observed in bacteria. In this study, we report the synthesis and structural characterization of a new class of fluorescent anionophores that effectively kill Gram-positive bacteria by disrupting normal Na+ and Cl- concentrations.The so-called "squindoles"take advantage of both NH and CH hydrogen-bonding interactions to bind chloride with high affinity and act as efficient anion transporters, as measured by lipid vesicle transport assays. The most active transporter shows potent inhibitory activity against Staphylococcus aureus (SA) and methicillin-resistant Staphylococcus aureus (MRSA). Cell-based as-says and label-free quantitative proteomic profiling suggest that the mode of action is directly related to the anion-transport ability, whereby an influx of chloride into bacterial cells significantly affects their proteome and induces several known stress responses