A mechanistic study of the tremor associated with epidural anaesthesia for intrapartum caesarean delivery

BackgroundIt is not known if the tremor associated with an epidural top-up dose for intrapartum caesarean delivery is thermoregulatory shivering. A tremor is only shivering if it has the same frequency profile as cold stress-induced shivering. Thermoregulatory shivering is a response to a reduction in actual body temperature, whereas non-thermoregulatory shivering may be triggered by a reduction in sensed body temperature. This mechanistic study aimed to compare: 1. the frequency profiles of epidural top-up tremor and cold stress-induced shivering; and 2. body temperature (actual and sensed) before epidural top-up and at the onset of tremor.MethodsTwenty obstetric patients received an epidural top-up for intrapartum caesarean delivery and 20 non-pregnant female volunteers underwent a cold stress. Tremor, surface electromyography, core temperature, skin temperature (seven sites) and temperature sensation votes (a bipolar visual analog score ranging from −50 to +50 mm) were recorded.ResultsThe mean (SD) primary oscillation (9.9 (1.9) Hz) frequency of epidural top-up tremor did not differ from that of cold stress-induced shivering (9.0 (1.6) Hz; P=0.194), but the mean (SD) burst frequency was slower (6.1 (1.2) × 10⁻² Hz vs 6.9 (0.7) × 10⁻² Hz, respectively; P=0.046). Before the epidural top-up dose, the mean (SD) core temperature was 37.6 (0.6) °C. Between the epidural top-up dose and the onset of tremor the mean (SD) core temperature did not change (–0.1 (0.1) °C; P=0.126), the mean (SD) skin temperature increased (+0.4 (0.4) °C; P=0.002) and the mean (SD) temperature sensation votes decreased (−12 (16) mm; P=0.012).ConclusionThese results suggest that epidural top-up tremor is a form of non-thermoregulatory shivering triggered by a reduction in sensed body temperature.     

Retention on ART and predictors of disengagement from care in several alternative community‐centred ART refill models in rural Swaziland

Introduction

A broad range of community‐centred care models for patients stable on anti‐retroviral therapy (ART) have been proposed by the World Health Organization to better respond to patient needs and alleviate pressure on health systems caused by rapidly growing patient numbers. Where available, often a single alternative care model is offered in addition to routine clinical care. We operationalized several community‐centred ART delivery care models in one public sector setting. Here, we compare retention in care and on ART and identify predictors of disengagement with care.

Methods

Patients on ART were enrolled into three community‐centred ART delivery care models in the rural Shiselweni region (Swaziland), from 02/2015 to 09/2016: Community ART Groups (CAGs), comprehensive outreach care and treatment clubs. We used Kaplan–Meier estimates to describe crude retention in care model and retention on ART (including patients who returned to clinical care). Multivariate Cox proportional hazard models were used to determine factors associated with all‐cause attrition from care model and disengagement with ART.

Results

A total of 918 patients were enrolled. CAGs had the most participants with 531 (57.8%). Median age was 44.7 years (IQR 36.3 to 54.4), 71.8% of patients were female, and 62.6% fulfilled eligibility criteria for community ART. The 12‐month retention in ART was 93.7% overall; it was similar between model types (p = 0.52). A considerable proportion of patients returned from community ART to clinical care, resulting in lower 12 months retention in care model (82.2% overall); retention in care model was lowest in CAGs at 70.4%, compared with 86.3% in outreach and 90.4% in treatment clubs (p < 0.001). In multivariate Cox regression models, patients in CAGs had a higher risk of disengaging from care model (aHR 3.15, 95% CI 2.01 to 4.95, p < 0.001) compared with treatment clubs. We found, however, no difference in attrition in ART between alternative model types.

Conclusions

Concurrent implementation of three alternative community‐centred ART models in the same region was feasible. Although a considerable proportion of patients returned back to clinical care, overall ART retention was high and should encourage programme managers to offer community‐centred care models adapted to their specific setting.

     

Combined delivery of dexamethasone and plasmid DNA in an animal model of LPS-induced acute lung injury

Dexamethasone was conjugated to low molecular weight polyethylenimine (2 kDa, PEI2k). Dexamethasone conjugated PEI2k (PEI2k-Dexa) was evaluated as a combined delivery carrier of dexamethasone and plasmid DNA (pDNA) in an animal model of lipopolysaccharide (LPS) induced acute lung injury (ALI). In vitro transfection of L2 lung epithelial cells, PEI2k-Dexa exhibited higher transfection efficiency than PEI2k or a simple mixture of PEI2k and dexamethasone. In addition, the PEI2k-Dexa/pβ-Luc complexes reduced the levels of pro-inflammatory cytokines in LPS activated Raw 264.7 macrophage cells. The anti-inflammatory effect of PEI2k-Dexa was higher than that of controls. The PEI2k-Dexa/pβ-Luc complexes were administered to mice via intratracheal injection. PEI2k-Dexa had higher pDNA delivery efficiency than PEI2k in the lung and decreased TNF-α and IL-6 in the lung homogenates and bronchoalveolar lavage (BAL) fluid compared with the controls. Furthermore, total protein and immunoglobulin M (IgM) concentrations in BAL fluid were reduced by the PEI2k-Dexa/pβ-Luc complexes. The intratracheal injection of the PEI2k-Dexa/pcDNA-EGFP complexes in the ALI model showed higher EGFP expression compared with PEI2k. Hematoxylin and eosin (H&E) staining showed that PEI2k-Dexa reduced inflammatory reaction in the lung. Therefore, PEI2k-Dexa may be useful for combination gene and drug therapy for ALI.     

Functionalized linear poly(amidoamine)s are efficient vectors for intracellular protein delivery

An effective intracellular protein delivery system was developed based on functionalized linear poly(amidoamine)s (PAAs) that form self-assembled cationic nanocomplexes with oppositely charged proteins. Three differently functionalized PAAs were synthesized, two of these having repetitive disulfide bonds in the main chain, by Michael-type polyaddition of 4-amino-1-butanol (ABOL) to cystamine bisacrylamide (CBA), histamine (HIS) to CBA, and ABOL to bis(acryloyl)piperazine (BAP). These water-soluble PAAs efficiently condense β-galactosidase by self-assembly into nanoscaled and positively-charged complexes. Stable under neutral extracellular conditions, the disulfide-containing nanocomplexes rapidly destabilized in a reductive intracellular environment. Cell-internalization and cytotoxicity experiments showed that the PAA-based nanocomplexes were essentially non-toxic. β-Galactosidase was successfully internalized into cells, with up to 94% of the cells showing β-galactosidase activity, whereas the enzyme alone was not taken up by the cells. The results indicate that these poly(amidoamine)s have excellent properties as highly potent and non-toxic intracellular protein carriers, which should create opportunities for novel applications in protein delivery.