Time Dependence in Mixture Toxicity with Soft Electrophiles: 1. Combined Effects of Selected S<Subscript>N</Subscript>2- and S<Subscript>N</Subscript>Ar-Reactive Agents with a Nonpolar Narcotic

Frequently the toxicity of an organic chemical mixture is close to dose-additive, even when the agents are thought to induce toxicity at different molecular sites of action. These findings appear to conflict with the hypothesis that a strictly dose-additive combined effect will be observed for agents sharing a single molecular site of toxic action within the organism. In this study, several S_N2-reactive (α-halogen) or S_NAr-reactive (halogenated dinitrobenzene) soft electrophiles were tested with a model nonpolar narcotic (NPN) to determine the toxicity of the combinations. A sham combination of the model NPN (3-methyl-2-butanone) was also tested as a positive control. The study design incorporated time-dependent toxicity (TDT) determinations at 15, 30, and 45 minutes using a Microtox (Vibrio fischeri) protocol that included testing seven duplicated concentrations for each single agent and mixture per combination. Additionally, in chemico reactivity was determined for each compound using thiol in glutathione as a model nucleophile. The model NPN alone lacked reactivity and TDT. The S_N2-reactive agents individually showed varying levels of both reactivity and TDT alone, while the S_NAr-reactive chemicals alone were reactive and had toxicity that was fully time-dependent between 15 and 45 minutes of exposure. Data analyses indicated that the sham combination was dose additive, as expected, whereas three of four S_N2:NPN combinations showed effects close to that predicted for dose addition but with some differences. The fourth S_N2:NPN combination, which included an α-halogen with full TDT, showed a less-than-dose-additive combined effect as did both of the S_NAr:NPN pairings. By incorporating TDT values, shapes of the dose-response curves, chemical reactivity data with thiol, reactive mechanisms for the soft electrophiles, and quantitative structure activity relationship information on whether the toxicity of the individual soft electrophiles did or did not exceeded that predicted for baseline narcosis, the results suggested that the α-halogens elicited two toxic effects at the concentrations tested (reactivity and narcotizing effects), whereas toxicity induced by the halogenated dinitrobenzenes was essentially limited to reactive effects. Collectively, these results provide experimental evidence consistent with previous explanations as to why binary mixtures of industrial organic chemicals often show combined effects that are close to dose additive, even when the chemicals are thought to induce toxicity at different molecular sites of action.     

Inpatient care of small and sick newborns: a multi-country analysis of health system bottlenecks and potential solutions

Background

The Every Newborn Action Plan (ENAP) and Ending Preventable Maternal Mortality targets cannot be achieved without high quality, equitable coverage of interventions at and around the time of birth. This paper provides an overview of the methodology and findings of a nine paper series of in-depth analyses which focus on the specific challenges to scaling up high-impact interventions and improving quality of care for mothers and newborns around the time of birth, including babies born small and sick.

Methods

The bottleneck analysis tool was applied in 12 countries in Africa and Asia as part of the ENAP process. Country workshops engaged technical experts to complete a tool designed to synthesise "bottlenecks" hindering the scale up of maternal-newborn intervention packages across seven health system building blocks. We used quantitative and qualitative methods and literature review to analyse the data and present priority actions relevant to different health system building blocks for skilled birth attendance, emergency obstetric care, antenatal corticosteroids (ACS), basic newborn care, kangaroo mother care (KMC), treatment of neonatal infections and inpatient care of small and sick newborns.

Results

The 12 countries included in our analysis account for the majority of global maternal (48%) and newborn (58%) deaths and stillbirths (57%). Our findings confirm previously published results that the interventions with the most perceived bottlenecks are facility-based where rapid emergency care is needed, notably inpatient care of small and sick newborns, ACS, treatment of neonatal infections and KMC. Health systems building blocks with the highest rated bottlenecks varied for different interventions. Attention needs to be paid to the context specific bottlenecks for each intervention to scale up quality care. Crosscutting findings on health information gaps inform two final papers on a roadmap for improvement of coverage data for newborns and indicate the need for leadership for effective audit systems.

Conclusions

Achieving the Sustainable Development Goal targets for ending preventable mortality and provision of universal health coverage will require large-scale approaches to improving quality of care. These analyses inform the development of systematic, targeted approaches to strengthening of health systems, with a focus on overcoming specific bottlenecks for the highest impact interventions.

     

Neonatal testicular torsion--a lost cause?

Twenty-four neonates presented with signs of testicular ischaemia over a 13-year period. They had a mean birth weight of 3.706 kg. The right testicle was affected in 13, the left in 9 and there was bilateral torsion in 2 babies. Two babies had no twist in the cord, but the testicles were nonviable macroscopically and microscopically. Twenty-one babies had primary exploration revealing necrotic testes in all patients and they underwent orchidectomies. The other three babies had conservative management and the affected testes had atrophied on follow-up. Sixteen babies had contralateral orchidopexy. Doppler ultrasound scans were reported as normal in 2 of 13 babies who had scans. No testes were salvaged following surgery. CONCLUSION: The incidence of testicular torsion in the neonatal period was calculated as 6.1 per 100,000 live births. No testis was salvaged following surgery in our series of 24 patients. This dismal outcome underlines that immediate surgical exploration, although commonly performed, rarely saves torted testes.     

Repeated attempts improve tracheal tube insertion time using the intubating laryngeal airway in a mannequin

Study ObjectiveTo determine if repeated performance of endotracheal tube insertion via the intubating laryngeal airway (ILA) would shorten insertion time in mannequins.DesignProspective study.SettingClinical Skills Laboratory, Department of Anesthesia, Toronto Western Hospital.Participants65 department anesthesiologists.MeasurementsAfter a video training session, anesthesiologists with no previous experience with the ILA performed 5 consecutive ILA-guided tracheal tube intubations on a mannequin. Each participant completed Task 1: insertion of an ILA; Task 2: blind insertion of a tracheal tube through the ILA, and Task 3: removal of the ILA. The time required for each task and the total intubation time for the three tasks over the 5 attempts were recorded. These times were compared using repeated-measures analysis of variance. The success rate among the 5 attempts was compared using Chi-Square analyses.Main ResultsA total of 65 anesthesiologists performed 5 ILA-guided tracheal intubations each. Total intubation time decreased from the first to the fifth attempt (92.6 ± 22.7 sec, 74.5 ± 19.2 sec, 66.5 ± 16.5 sec, 65.9 ± 19.9 sec, and 60.8 ± 16.3 sec; P < 0.001). Significant differences in intubation times were noted between the first and second, and the second and third attempts (P < 0.001 and P = 0.02, respectively). The success rate did not change over the 5 attempts (84.6%, 89.2%, 84.6%, 89.2%, and 90.8%; P = 0.737).ConclusionsTotal intubation time decreased by 34% (92.6 to 60.8 sec) over the 5 attempts in mannequins. The success rate ranged from 84.6% to 90.8% and did not differ significantly over the 5 attempts.     

Maternal germline-specific effect of DNA ligase I on CTG/CAG instability

The instability of (CTG)?(CAG) repeats can cause >15 diseases including myotonic dystrophy, DM1. Instability can arise during DNA replication, repair or recombination, where sealing of nicks by DNA ligase I (LIGI) is a final step. The role of LIGI in CTG/CAG instability was determined using in vitro and in vivo approaches. Cell extracts from a human (46BR) harbouring a deficient LIGI (～3% normal activity) were used to replicate CTG/CAG repeats; and DM1 mice with >300 CTG repeats were crossed with mice harbouring the 46BR LigI. In mice, the defective LigI reduced the frequency of CTG expansions and increased CTG contraction frequencies on female transmissions. Neither male transmissions nor somatic CTG instability was affected by the 46BR LigI - indicating a post-female germline segregation event. Replication-mediated instability was affected by the 46BR LIGI in a manner that depended upon the location of Okazaki fragment initiation relative to the repeat tract; on certain templates, the expansion bias was unaltered by the mutant LIGI, similar to paternal transmissions and somatic tissues; however, a replication fork-shift reduced expansions and increased contractions, similar to maternal transmissions. The presence of contractions in oocytes suggests that the DM1 replication profile specific to pre-meiotic oogenesis replication of maternal alleles is distinct from that occurring in other tissues and, when mediated by the mutant LigI, is predisposed to CTG contractions. Thus, unlike other DNA metabolizing enzymes studied to date, LigI has a highly specific role in CTG repeat maintenance in the maternal germline, involved in mediating CTG expansions and in the avoidance of maternal CTG contractions.