The rodent specific reproductive homeobox (Rhox) gene cluster on the X chromosome has been reported to contain twelve homeobox-containing genes, Rhox1-12.
We have identified a 40 kb genomic region ...within the Rhox cluster that is duplicated eight times in tandem resulting in the presence of eight paralogues of Rhox2 and Rhox3 and seven paralogues of Rhox4. Transcripts have been identified for the majority of these paralogues and all but three are predicted to produce full-length proteins with functional potential. We predict that there are a total of thirty-two Rhox genes at this genomic location, making it the most gene-rich homoeobox cluster identified in any species. From the 95% sequence similarity between the eight duplicated genomic regions and the synonymous substitution rate of the Rhox2, 3 and 4 paralogues we predict that the duplications occurred after divergence of mouse and rat and represent the youngest homoeobox cluster identified to date. Molecular evolutionary analysis reveals that this cluster is an actively evolving region with Rhox2 and 4 paralogues under diversifying selection and Rhox3 evolving neutrally. The biological importance of this duplication is emphasised by the identification of an important role for Rhox2 and Rhox4 in regulating the initial stages of embryonic stem (ES) cell differentiation.
The gene rich Rhox cluster provides the mouse with significant biological novelty that we predict could provide a substrate for speciation. Moreover, this unique cluster may explain species differences in ES cell derivation and maintenance between mouse, rat and human.
We conducted a multicenter study of 101 patients with congenital dysfibrinogenemia (CD) to characterize the incidence of hemorrhagic and thrombotic events as well as complications of pregnancy and ...surgery. At the time of diagnosis, 10.9% and 13.9% had experienced major bleeding and thrombotic events, respectively. During a mean follow-up of 8.8 years after CD diagnosis, the incidence of major bleeding and thrombotic events was 2.5 and 18.7 per 1000 patient-years, respectively, with estimated cumulative incidences at age 50 years of 19.2% and 30.1%. We identified 111 pregnancies with an overall incidence of spontaneous abortions and postpartum hemorrhage of 19.8% and 21.4%, respectively. The risk of postpartum hemorrhage was associated with a previously identified bleeding phenotype (odds ratio, 5.8; 95% CI, 1.2 to 28.0). Among 137 surgical procedures analyzed, 9 (6.5%) were complicated by abnormal bleeding. Propositi vs relatives, sex, mutation hotspots, fibrinogen levels, and activity:antigen ratios were not associated with the risk of thrombotic or bleeding outcomes. In conclusion, the results of our study, the largest in genotyped CD and the first including long-term history, indicate that propositi with CD and their relatives carry not only a high risk of major bleeding, including postpartum hemorrhage, but also of thrombotic event.
•Major bleeding, thrombosis, and postpartum hemorrhage are frequent in propositi and relatives with congenital dysfibrinogenemia.•Hotspot mutations were not predictive of either phenotype or outcome.
The International Tribunal for the Law of the Sea, a judicial institution created by the 1982 United Nations Convention on the Law of the Sea, began its activities on 1 October 1996. Together with ...the Statute of the Tribunal (Annex VI to the Convention), the Rules of the Tribunal, adopted on 28 October 1997, govern the functioning of the Tribunal and the proceedings before it. The objective of this Commentary is to give to legal practitioners and academics a detailed analysis of the provisions contained in the Rules. In doing so, the contributors, who are Judges of the Tribunal or members of its Registry, paid particular attention to the practice and the jurisprudence of the Tribunal as well as to the corresponding provisions in the Rules of the International Court of Justice.
Evidence-based international expert consensus regarding anaesthetic practice in hip/knee arthroplasty surgery is needed for improved healthcare outcomes.
The International Consensus on ...Anaesthesia-Related Outcomes after Surgery group (ICAROS) systematic review, including randomised controlled and observational studies comparing neuraxial to general anaesthesia regarding major complications, including mortality, cardiac, pulmonary, gastrointestinal, renal, genitourinary, thromboembolic, neurological, infectious, and bleeding complications. Medline, PubMed, Embase, and Cochrane Library including Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, NHS Economic Evaluation Database, from 1946 to May 17, 2018 were queried. Meta-analysis and Grading of Recommendations Assessment, Development and Evaluation approach was utilised to assess evidence quality and to develop recommendations.
The analysis of 94 studies revealed that neuraxial anaesthesia was associated with lower odds or no difference in virtually all reported complications, except for urinary retention. Excerpt of complications for neuraxial vs general anaesthesia in hip/knee arthroplasty, respectively: mortality odds ratio (OR): 0.67, 95% confidence interval (CI): 0.57–0.80/OR: 0.83, 95% CI: 0.60–1.15; pulmonary OR: 0.65, 95% CI: 0.52–0.80/OR: 0.69, 95% CI: 0.58–0.81; acute renal failure OR: 0.69, 95% CI: 0.59–0.81/OR: 0.73, 95% CI: 0.65–0.82; deep venous thrombosis OR: 0.52, 95% CI: 0.42–0.65/OR: 0.77, 95% CI: 0.64–0.93; infections OR: 0.73, 95% CI: 0.67–0.79/OR: 0.80, 95% CI: 0.76–0.85; and blood transfusion OR: 0.85, 95% CI: 0.82–0.89/OR: 0.84, 95% CI: 0.82–0.87.
Recommendation: primary neuraxial anaesthesia is preferred for knee arthroplasty, given several positive postoperative outcome benefits; evidence level: low, weak recommendation. Recommendation: neuraxial anaesthesia is recommended for hip arthroplasty given associated outcome benefits; evidence level: moderate-low, strong recommendation. Based on current evidence, the consensus group recommends neuraxial over general anaesthesia for hip/knee arthroplasty.
PROSPERO CRD42018099935.
There is heterogeneity in the names and anatomical descriptions of regional anesthetic techniques. This may have adverse consequences on education, research, and implementation into clinical ...practice. We aimed to produce standardized nomenclature for abdominal wall, paraspinal, and chest wall regional anesthetic techniques.
We conducted an international consensus study involving experts using a three-round Delphi method to produce a list of names and corresponding descriptions of anatomical targets. After long-list formulation by a Steering Committee, the first and second rounds involved anonymous electronic voting and commenting, with the third round involving a virtual round table discussion aiming to achieve consensus on items that had yet to achieve it. Novel names were presented where required for anatomical clarity and harmonization. Strong consensus was defined as ≥75% agreement and weak consensus as 50% to 74% agreement.
Sixty expert Collaborators participated in this study. After three rounds and clarification, harmonization, and introduction of novel nomenclature, strong consensus was achieved for the names of 16 block names and weak consensus for four names. For anatomical descriptions, strong consensus was achieved for 19 blocks and weak consensus was achieved for one approach. Several areas requiring further research were identified.
Harmonization and standardization of nomenclature may improve education, research, and ultimately patient care. We present the first international consensus on nomenclature and anatomical descriptions of blocks of the abdominal wall, chest wall, and paraspinal blocks. We recommend using the consensus results in academic and clinical practice.
Different injection techniques for the quadratus lumborum (QL) block have been described. Data in human cadavers suggest that the transverse oblique paramedian (TOP) QL3 may reach the thoracic ...paravertebral space more consistently than the QL1 and QL2. However, the distribution of injectate in cadavers may differ from that in patients. Hence, we assessed the distribution of the injectate after the QL1, QL2, and TOP QL3 techniques in patients.
Thirty-four patients scheduled for abdominal surgery received QL blocks postoperatively; 26 patients received bilateral and 8 patients received unilateral blocks. Block injections were randomly allocated to QL1, QL2, or TOP QL3 techniques (20 blocks per each technique). The injections consisted of 18 mL of ropivacaine 0.375% with 2 mL of radiopaque contrast, injected lateral or posterior to the QL muscle for the QL1 and QL2 techniques, respectively. For the TOP QL3, the injection was into the plane between the QL and psoas muscles, proximal to the L2 transverse process. Two reviewers, blinded to the allocation, reviewed three-dimensional computed tomography (3D-CT) images to assess the distribution of injectate.
The QL1 block spread in the transversus abdominis plane (TAP), QL2 in the TAP,
posterior aspect of the QL muscle, whereas TOP QL3 spread consistently in the anterior aspect of the QL muscle
occasional spread to the lumbar and thoracic paravertebral areas.
The spread of injectate after QL1, QL2, and QL3 blocks, resulted in different distribution patterns, primarily in the area of injection. The TOP QL3 did not result in consistent interfascial spread toward the thoracic paravertebral space.
We have examined the evolution of the genes at the major human beta-defensin locus and the orthologous loci in a range of other primates and mouse. For the first time these data allow us to examine ...selective episodes in the more recent evolutionary history of this locus as well as the ancient past. We have used a combination of maximum likelihood based tests and a maximum parsimony based sliding window approach to give a detailed view of the varying modes of selection operating at this locus.
We provide evidence for strong positive selection soon after the duplication of these genes within an ancestral mammalian genome. Consequently variable selective pressures have acted on beta-defensin genes in different evolutionary lineages, with episodes both of negative, and more rarely positive selection, during the divergence of primates. Positive selection appears to have been more common in the rodent lineage, accompanying the birth of novel, rodent-specific beta-defensin genes. These observations allow a fuller understanding of the evolution of mammalian innate immunity. In both the rodent and primate lineages, sites in the second exon have been subject to positive selection and by implication are important in functional diversity. A small number of sites in the mature human peptides were found to have undergone repeated episodes of selection in different primate lineages. Particular sites were consistently implicated by multiple methods at positions throughout the mature peptides. These sites are clustered at positions predicted to be important for the specificity of the antimicrobial or chemoattractant properties of beta-defensins. Surprisingly, sites within the prepropeptide region were also implicated as being subject to significant positive selection, suggesting previously unappreciated functional significance for this region.
Identification of these putatively functional sites has important implications for our understanding of beta-defensin function and for novel antibiotic design.
Although our understanding of the regulation of cellular actin and its control during the development of invertebrates is increasing 1–9, the question as to how such actin dynamics are regulated ...differentially across the vertebrate embryo to effect its relatively complex morphogenetic cell movements remains poorly understood. Intercellular signaling that provides spatial and temporal cues to modulate the subcellular localization and activity of actin regulatory molecules represents one important mechanism 10–13. Here we explore whether the localized gene expression of specific actin regulatory molecules represents another developmental mechanism. We have identified a cap1 homolog and a novel guanine nucleotide exchange factor (GEF), quattro (quo), that share a restricted gene expression domain in the anterior mesendoderm of the zebrafish gastrula. Each gene is required for specific cellular behaviors during the anterior migration of this tissue; furthermore, cap1 regulates cortical actin distribution specifically in these cells. Finally, although cap1 and quo are autonomously required for the normal behaviors of these cells, they are also nonautonomously required for convergence and extension movements of posterior tissues. Our results provide direct evidence for the deployment of developmentally restricted actin-regulatory molecules in the control of morphogenetic cell movements during vertebrate development.
Elective caesarean section is performed mainly under spinal anaesthesia using hyperbaric bupivacaine combined with opioids. Despite rapid onset, good quality anaesthesia, bupivacaine provides a long ...duration of motor block and is related to maternal hypotension. Current policies appeal for implementation of enhanced recovery procedures after caesarean section. Hyperbaric prilocaine is an intermediate-acting local anaesthetic known for its efficacy in ambulatory surgery. Evidence on the clinical relevance of intrathecal prilocaine use for caesarean section is currently lacking.
We aimed to investigate whether hyperbaric prilocaine would offer a shorter motor block and recovery than bupivacaine, when comparing equipotent doses. We also assessed the characteristics of sensory block, maternal haemodynamics and side effects for both mother and newborn.
Prospective, randomised, double-blind, controlled, two-centre, clinical trial.
One university teaching hospital and one general teaching hospital in Brussels, Belgium.
American Society of Anesthesiologists' physical status 2 parturients (n = 40) undergoing caesarean section under spinal anaesthesia.
Patients were randomly assigned to receive spinal anaesthesia using hyperbaric prilocaine 50 mg or hyperbaric bupivacaine 10 mg, both given with sufentanil 2.5 μg and morphine 100 μg. An epidural catheter was introduced as a backup in case of failure.
The primary outcome was the motor block regression (modified Bromage scale 1 to 6). Secondary outcomes included sensory block characteristics, first unassisted ambulation, maternal side effects, newborns' parameters and overall satisfaction.
Median IQR motor block was significantly shorter in the hyperbaric prilocaine group (110 104 to 150 min versus 175 135 to 189 min, P = 0.001). First unassisted ambulation was achieved earlier after prilocaine (204.5 177 to 246.5 min versus 314 209.25 to 400 min, P = 0.007), and the incidence of maternal hypotension was significantly higher with bupivacaine (P = 0.033). No supplementary epidural analgesia was needed.
Prilocaine provides shorter motor block, faster recovery and better haemodynamic stability than bupivacaine while offering equivalent surgical anaesthesia.
Clinicaltrials.gov: NCT02973048, EudraCT: 2016-003010-26.
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