Utility of nociceptive flexion reflex threshold and bispectral index to predict movement responses under propofol anaesthesia

Introduction: The nociceptive flexion reflex threshold (NFRT) is a promising tool to monitor analgesia during general anaesthesia. Clinical studies have shown that the NFRT allows to predict movement responses to painful stimuli under a combined anaesthetic regime of sedative and opioid agents. Experimental studies indicated that the NFRT is also able to predict such movement responses under an exclusively sedative regime like propofol mono-anaesthesia. Therefore, we performed this study to investigate the ability of the NFRT to predict movement responses to painful stimuli in patients during a clinical propofol mono-anaesthesia.

Methods: We investigated 140 cardiac surgery patients during their postoperative phase under propofol mono-anaesthesia. NFRT and bispectral index (BIS) were determined in each patient right before endotracheal suctioning or painful electrical test stimulation. Prediction probabilities were calculated to quantify how accurate each measure is able to predict movement responses to the stimuli.

Results: The 124 patients included in the analysis received a median propofol dosage of 3.2 (2.5–3.9) [median (IQR)] mg/kg/h. The included patients showed 287 movement responses after a total of 725 investigated stimuli. The prediction probabilities for positive movement responses were 0.63 (95%CI: 0.59–0.67) for the NFRT and 0.69 (95%CI: 0.65–0.73) for the BIS.

Conclusions: The NFRT allows the prediction of movement responses under propofol mono-anaesthesia, which confirms its utility as a monitor to predict movement responses under general anaesthesia. The BIS allows an even more accurate prediction, although it does not reflect the physiological structures of movement suppression, but correlates closely with the dose of propofol.

Trial registration: German clinical trial register (DRKS00003062, Deutsches Register Klinischer Studien).     

Human complement factor I does not require cofactors for cleavage of synthetic substrates

Complement factor I (fI) plays a major role in the regulation of the complement system. It circulates in an active form and has very restricted specificity, cleaving only C3b or C4b in the presence of a cofactor such as factor H (fH), complement receptor type 1, membrane cofactor protein, or C4-binding protein. Using peptide-7-amino-4-methylcoumarin derivatives, we investigated the substrate specificity of fI. There is no previous report of synthetic substrate cleavage by fI, but five substrates were found in this study. A survey of 15 substrates and a range of inhibitors showed that fI has specificity similar to that of thrombin, but with much lower catalytic activity than that of thrombin. fI amidolytic activity has a pH optimum of 8.25, typical of serine proteases and is insensitive to ionic strength. This is in contrast to its proteolytic activity within the fI-C3b-fH reaction, in which the pH optimum for C3b cleavage is <5.5 and the reaction rate is highly dependent on ionic strength. The rate of cleavage of tripeptide 7-amino-4-methylcoumarins by fI is unaffected by the presence of fH or C3(NH(3)). The amidolytic activity is inhibited by the synthetic thrombin inhibitor Z-D-Phe-Pro-methoxypropylboroglycinepinanediol ester, consistent with previous reports, and by benzenesulfonyl fluorides such as Pefabloc SC. Suramin inhibits fI directly at concentration of 1 mM. Within a range of metal ions tested, only Cr(2+) and Fe(3+) were found to inhibit both the proteolytic and amidolytic activity of fI.     

Evidence for phosphatidylinositol-3-OH-kinase (PI3-kinase) involvement in Cd-mediated oxidative effects on hemocytes of mussels

This study investigated phosphatidylinositol-3-OH-kinase (PI3-kinase) involvement in the induction of cadmium-mediated oxidative effects on hemocytes of mussel Mytilus galloprovincialis. PI3-kinase was investigated with the use of wortmannin, a specific covalent inhibitor of PI3-kinase. Moreover, phorbol-myristate acetate (PMA), a well-known protein kinase C (PKC)-mediated NADPH oxidase and nitric oxide (NO) synthase stimulator, was also used for elucidating PI3-kinase involvement during the respiratory burst process in challenge hemocytes. According to the results, cells pre-treated with non-toxic concentrations of wortmannin (1 and/or 50 nM, as revealed by neutral red retention assay) for 15 min, showed a significant attenuation of cadmium ability (at concentration of 50 μM) to promote cell death, superoxide anion (O(2)(-)) production, NO generation and lipid peroxidation (in terms of malondialdehyde equivalents). On the other hand, wortmannin-treated cells showed a significant attenuation of PMA ability to induce NO generation but not O(2)(-) production. These findings reveal that PI3-kinase could lead to a PKC-independent induction of NO synthase activity in cells faced with pro-oxidants, such as cadmium, while its activation could be fundamental for the regulation of NAPDH oxidase activity, probably through a PKC-dependent signaling pathway.     

Effects of bisphosphonates on keratinocytes and fibroblasts having a role in the development of osteonecrosis of the jaw

Bisphosphonates (BPs) have became the treatment of choice for the prevention of skeletal complications in cancer patients with bone metastases as well as in patients suffering from osteoporosis, Paget's disease and rheumatoid arthritis. Osteonecrosis of the jaw (ONJ) is a recently described complication associated with the use of BPs in which the key finding is exposed necrotic bone in the oral cavity. Often, the precipitating event appears to be a dental invasive procedure. We recently provided evidence that ONJ is associated with dental extractions and use of dentures. It has been reported that the primary lesion lies in the bone and it is related to over-suppression of bone turnover, but it is unclear why such a lesion should present with loss of the soft tissue covering the jawbone. We propose that BP could be impairing molecular signalling not only of osteoblasts and osteoclasts but also of fibroblasts and keratinocytes, via cell to cell endocrine and paracrine interactions in a double manner. Such an impairment would result to fibroblast and keratinocyte impaired multiplication, proliferation and migration thereby leading to defective mucosal wound healing. This provides an open entry point for the oral flora to reach the underlying jawbone which is considered to have poor metabolic and immune properties when under BP treatment. We demonstrate that ONJ is associated with mucosal damage, which could be mediated via BP induced soft tissue toxicity. BPs have been reported to promote keratinocyte and fibroblast apoptosis and to impair various cellular activities like apoptosis, RANK, RANK-L and OPG signalling, bone morphogenetic protein signalling, growth factor signalling, immune homeostasis and wound healing. We discuss potential consequences of the above hypothesis for practitioners and investigators.     

Wolbachia symbiosis and insect immune response

Bacterial intraceUular symbiosis is very common in insects, having significant consequences in promoting the evolution of life and biodiversity. The bacterial group that has recently attracted particular attention is Wolbachia pipientis which probably represents the most ubiquitous endosymbiont on the planet. W. pipientis is a Gram-negative obligatory intracellular and maternally transmitted a-proteobacterium, that is able to establish symbiotic associations with arthropods and nematodes. In arthropods, Wolbachia pipientis infections have been described in Arachnida, in Isopoda and mainly in Insecta. They have been reported in almost all major insect orders including Diptera, Coleoptera, Hemiptera, Hymenoptera, Orthoptera and Lepidoptera. To enhance its transmission, W. pipientis can manipulate host reproduction by inducing parthenogenesis, feminization, male killing and cytoplasmic incompatibility. Several polymerase chain reaction surveys have indicated that up to 70% of all insect species may be infected with W. pipientis. How does W. pipientis manage to get established in diverse insect host species？ How is this intracellular bacterial symbiont species so successful in escaping the host immune response？ The present review presents recent advances and ongoing scientific efforts in the field. The current body of knowledge in the field is summarized, revelations from the available genomic information are presented and as yet unanswered questions are discussed in an attempt to present a comprehensive picture of the unique ability of W. pipientis to establish symbiosis and to manipulate reproduction while evading the host＇s immune system.