Supporting play exploration and early developmental intervention versus usual care to enhance development outcomes during the transition from the neonatal intensive care unit to home: a pilot randomized controlled trial

Background While therapy services may start in the Neonatal Intensive Care Unit (NICU) there is often a gap in therapy after discharge. Supporting Play Exploration and Early Development Intervention (SPEEDI) supports parents, helping them build capacity to provide developmentally supportive opportunities starting in the NICU and continuing at home. The purpose of this single blinded randomized pilot clinical trial was to evaluate the initial efficacy of SPEEDI to improve early reaching and exploratory problem solving behaviors. Methods Fourteen infants born very preterm or with neonatal brain injury were randomly assigned to SPEEDI or Usual Care. The SPEEDI group participated in 5 collaborative parent, therapist, and infant interventions sessions in the NICU (Phase 1) and 5 at home (Phase 2). Parents provided daily opportunities designed to support the infants emerging motor control and exploratory behaviors. Primary outcome measures were assessed at the end of the intervention, 1 and 3 months after the intervention ended. Reaching was assessed with the infant supported in an infant chair using four 30 s trials. The Early Problem Solving Indicator was used to evaluate the frequency of behaviors during standardized play based assessment. Effect sizes are including for secondary outcomes including the Test of Infant Motor Performance and Bayley Scales of Infant and Toddler Development. Results No group differences were found in the duration of toy contact. There was a significant group effect on (F1,8 = 4.04, p = 0.08) early exploratory problem-solving behaviors with infants in the SPEEDI group demonstrating greater exploration with effect sizes of 1.3, 0.6, and 0.9 at the end of the intervention, 1 and 3 months post-intervention. Conclusions While further research is needed, this initial efficacy study showed promising results for the ability of SPEEDI to impact early problem solving behaviors at the end of intervention and at least 3 months after the intervention is over. While reaching did not show group differences, a ceiling effect may have contributed to this finding. This single blinded pilot RCT was registered prior to subject enrollment on 5/27/14 at ClinicalTrials.Gov with number NCT02153736

Paraneoplastic SIADH and Dermatomyositis in Cervical Cancer: A Case Report and Literature Review

We present the first known case of a patient with cervical squamous cell carcinoma complicated by paraneoplastic syndromes of both dermatomyositis and inappropriate secretion of antidiuretic hormone (SIADH). The patient in this case presented with generalized body pain and vaginal bleeding. Her cervical cancer was diagnosed as stage IIB by physical exam, imaging, and cervical biopsy, her dermatomyositis was confirmed by muscle and skin biopsy, and her SIADH was diagnosed based on laboratory findings

The Stargazin-Related Protein {gamma}7 Interacts with the mRNA-Binding Protein Heterogeneous Nuclear Ribonucleoprotein A2 and Regulates the Stability of Specific mRNAs, Including CaV2.2

The role(s) of the novel stargazin-like {gamma}-subunit proteins remain controversial. We have shown previously that the neuron-specific {gamma}7 suppresses the expression of certain calcium channels, particularly CaV2.2, and is therefore unlikely to operate as a calcium channel subunit. We now show that the effect of {gamma}7 on CaV2.2 expression is via an increase in the degradation rate of CaV2.2 mRNA and hence a reduction of CaV2.2 protein level. Furthermore, exogenous expression of {gamma}7 in PC12 cells also decreased the endogenous CaV2.2 mRNA level. Conversely, knockdown of endogenous {gamma}7 with short-hairpin RNAs produced a reciprocal enhancement of CaV2.2 mRNA stability and an increase in endogenous calcium currents in PC12 cells. Moreover, both endogenous and expressed {gamma}7 are present on intracellular membranes, rather than the plasma membrane. The cytoplasmic C terminus of {gamma}7 is essential for all its effects, and we show that {gamma}7 binds directly via its C terminus to a heterogeneous nuclear ribonucleoprotein (hnRNP A2), which also binds to a motif in CaV2.2 mRNA, and is associated with native CaV2.2 mRNA in PC12 cells. The expression of hnRNP A2 enhances CaV2.2 IBa, and this enhancement is prevented by a concentration of {gamma}7 that alone has no effect on IBa. The effect of {gamma}7 is selective for certain mRNAs because it had no effect on {alpha}2{delta}-2 mRNA stability, but it decreased the mRNA stability for the potassium-chloride cotransporter, KCC1, which contains a similar hnRNP A2 binding motif to that in CaV2.2 mRNA. Our results indicate that {gamma}7 plays a role in stabilizing CaV2.2 mRNA

Molecular profiling of malignant peripheral nerve sheath tumors associated with neurofibromatosis type 1, based on large-scale real-time RT-PCR

BACKGROUND: Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder with a complex range of clinical symptoms. The hallmark of NF1 is the onset of heterogeneous (dermal or plexiform) benign neurofibromas. Plexiform neurofibromas can give rise to malignant peripheral nerve sheath tumors (MPNSTs), and the underlying molecular mechanisms are largely unknown. RESULTS: To obtain further insight into the molecular pathogenesis of MPNSTs, we used real-time quantitative RT-PCR to quantify the mRNA expression of 489 selected genes in MPNSTs, in comparison with plexiform neurofibromas. The expression of 28 (5.7%) of the 489 genes was significantly different between MPNSTs and plexiform neurofibromas; 16 genes were upregulated and 12 were downregulated in MPNSTs. The altered genes were mainly involved in cell proliferation (MKI67, TOP2A, CCNE2), senescence (TERT, TERC), apoptosis (BIRC5/Survivin, TP73) and extracellular matrix remodeling (MMP13, MMP9, TIMP4, ITGB4). More interestingly, other genes were involved in the Ras signaling pathway (RASSF2, HMMR/RHAMM) and the Hedgehog-Gli signaling pathway (DHH, PTCH2). Several of the down-regulated genes were Schwann cell-specific (L1CAM, MPZ, S100B, SOX10, ERBB3) or mast cell-specific (CMA1, TPSB), pointing to a depletion and/or dedifferentiation of Schwann cells and mast cells during malignant transformation of plexiform neurofibromas. CONCLUSION: These data suggest that a limited number of signaling pathways, and particularly the Hedgehog-Gli signaling pathway, may be involved in malignant transformation of plexiform neurofibromas. Some of the relevant genes or their products warrant further investigation as potential therapeutic targets in NF1

Assessing Opportunities to Improve Sedation/Analgesia Use in Neonatal Patients on ECMO

Background: Sedation is used during ECMO to prevent agitation. Analgesia is used to dampen pain perception as neonatal procedural pain related stress is associated with later altered neurodevelopment with poorer perceptual reasoning and visual perception. Common sedatives/analgesics used during ECMO are opiates and benzodiazepines. Studies have shown that lipophilic drugs such as Fentanyl and Midazolam are significantly sequestered in the circuit suggesting opportunities to improve delivery for pain. Hypothesis and Methods: We hypothesized opportunities to improve sedation/analgesia drug treatment in ECMO patients. Using a retrospective analysis of all neonatal patients receiving ECMO between 2015-2020, we aimed to assess the relationship between sedative/analgesia type and dose and clinical complications. We identified patient demographics, medication type, dose used, days to wean, length of hospital stay, mortality, medical complications at discharge and MRI results. Results: 49 patients were included, mean gestational age 37.6 wks ±3.6. Seventeen (35%) infants died. Race was not associated with mortality. All patients received Fentanyl and Midazolam with one patient who also received Morphine infusion. Fentanyl and Midazolam dose during ECMO was associated with risk for oxygen at discharge 296 vs 517 mcg/kg/days for Fentanyl (p=0.04), and 358 vs 2598 mcg/kg/days for Midazolam (p=0.002) as well as need for feeding tube at discharge 272 vs 420 mcg/kg/days for Fentanyl (p=0.049) and 1.03 vs 1.60 mg/kg/days for Midazolam(p=0.04). Risk for abnormal MRI was increased with Fentanyl ECMO dose exposure (p=0.016). Male gender was associated with greater fentanyl dose exposure by 27% (p=0.038). Conclusion: Fentanyl and Midazolam increased dose exposure was associated with increased risk for later neurological clinical complications in infants undergoing ECMO. Further studies are needed to assess serum drug concentrations in ECMO patients to better understand development of drug tolerance, circuit sequestration and dose exposure to adjust the therapeutic range of sedation and analgesia use

Predictors of Circuit Health in Neonatal Patients Receiving Extracorporeal Membrane Oxygenation

Background: Clot formation is the most common mechanical complication of ECMO and can lead to oxygenator failure and the need for subsequent circuit changes. The goals of this study were to identify early indicators of circuit failure to alert providers of ECMO circuit health. Hypothesis: We hypothesized that patient-specific circuit parameters can predict circuit health to identify risk of early circuit failure in neonate ECMO patients. Using a retrospective chart analysis ECMO flow parameters and clotting factors were identified during the 48 hours prior to ECMO circuit change through the 24 hours post circuit change. Statistical analysis included non-parametric Mann-Whitney U-test. Results: There was a significant increase in maximum and mean delta-p prior to need for circuit changes compared to those without (p=0.011 and p=0.0128 respectively) and a significant increase in the maximum RPM and mean RPM (p=0.0043 and p=0.0057 respectively). There was a significant increase in mean plasma free hemoglobin (hgb) (p=0.0209); however, the maximum plasma free hgb was not significant (p=0.0569). No differences were notable for sweep and venous pressure in those with circuit changes. Furthermore, clotting parameters were not found to be significant, including ACT, heparin, platelet count, fibrinogen, PT, PTT, INR, AT III (%), anti-Xa. Conclusion: Changes in Delta-p, RPM, and flow may be valuable predictors of early circuit impairment in neonates on ECMO. Sweep, venous pressure and clotting parameters may not reliable predictors of circuit health.https://scholarscompass.vcu.edu/gradposters/1167/thumbnail.jp

Determinants of the voltage dependence of G protein modulation within calcium channel β subunits

CaVβ subunits of voltage-gated calcium channels contain two conserved domains, a src-homology-3 (SH3) domain and a guanylate kinase-like (GK) domain with an intervening HOOK domain. We have shown in a previous study that, although Gβγ-mediated inhibitory modulation of CaV2.2 channels did not require the interaction of a CaVβ subunit with the CaVα1 subunit, when such interaction was prevented by a mutation in the α1 subunit, G protein modulation could not be removed by a large depolarization and showed voltage-independent properties (Leroy et al., J Neurosci 25:6984–6996, 2005). In this study, we have investigated the ability of mutant and truncated CaVβ subunits to support voltage-dependent G protein modulation in order to determine the minimal domain of the CaVβ subunit that is required for this process. We have coexpressed the CaVβ subunit constructs with CaV2.2 and α2δ-2, studied modulation by the activation of the dopamine D2 receptor, and also examined basal tonic modulation. Our main finding is that the CaVβ subunit GK domains, from either β1b or β2, are sufficient to restore voltage dependence to G protein modulation. We also found that the removal of the variable HOOK region from β2a promotes tonic voltage-dependent G protein modulation. We propose that the absence of the HOOK region enhances Gβγ binding affinity, leading to greater tonic modulation by basal levels of Gβγ. This tonic modulation requires the presence of an SH3 domain, as tonic modulation is not supported by any of the CaVβ subunit GK domains alone

Predictors of Circuit Health in Neonatal Patients Receiving Extracorporeal Membrane Oxygenation (ECMO)

To identify predictors of neonatal ECMO circuit health, a retrospective analysis of circuit functional pressure and flow parameters as well as infant clotting values were collected 48 h prior to and 24 h post circuit change. Circuit impairment was defined as need for partial or total circuit change. Statistical analysis used multivariate statistics and non-parametric Mann–Whitney U-test with possible non-normality of measurements. A total of 9764 ECMO circuit and clotting values in 21 circuits were analyzed. Circuit delta-P mean, and maximum values increased from 8.62 to 48.59 mmHg (p \u3c 0.011) and 16.00 to 53.00 mmHg (p \u3c 0.0128) respectively prior to need for circuit change. Maximum and mean Pump Flow Revolutions per minute (RPM) increased by 75% (p \u3c 0.0043) and 81% (p \u3c 0.0057), respectively. Mean plasma free hemoglobin (pfHb) increased from 26.45 to 76.00 mg/dl, (p \u3c 0.0209). Sweep, venous pressure, and clotting parameters were unaffected. ECMO circuit delta-P, RPM, and pfHb were early predictors of circuit impairment