Research Spotlight

Zhao, Q., Zhang, L., Hai, B., Wang, J., Baetge, C.L., Deveau, M.A., Kapler, G.M., Feng, J.Q. and Liu, F. (2020). “Transient activation of the Hedgehog-Gli pathway rescues radiotherapy-induced dry mouth via recovering salivary gland resident macrophages.” Cancer Res Sep 30;canres.0503.2020. [Epub ahead of print.].

Full text of this article.

Irreversible hypofunction of salivary glands is a common side effect of radiotherapy for head-and-neck cancer and is difficult to remedy. Recent studies indicate that transient activation of Hedgehog signaling rescues irradiation-impaired salivary function in animal models, but the underlying mechanisms are largely unclear. Here we show in mice that activation of canonical Gli-dependent Hedgehog signaling by Gli1 gene transfer is sufficient to recover salivary function impaired by irradiation. Salivary gland cells responsive to Hedgehog/Gli signaling comprised small subsets of macrophages, epithelial cells and endothelial cells, and their progeny remained relatively rare long after irradiation and transient Hedgehog activation. Quantities and activities of salivary gland resident macrophages were substantially and rapidly impaired by irradiation and restored by Hedgehog activation. Conversely, depletion of salivary gland macrophages by clodronate liposomes compromised the restoration of irradiation-impaired salivary function by transient Hedgehog activation. Single cell RNA sequencing and qRT-PCR of sorted cells indicated that Hedgehog activation greatly enhances paracrine interactions between salivary gland resident macrophages, epithelial progenitors, and endothelial cells through Csf1, Hgf, and C1q signaling pathways. Consistently, expression of these paracrine factors and their receptors in salivary glands decreased following irradiation but were restored by transient Hedgehog activation. These findings reveal that resident macrophages and their pro-repair paracrine factors are essential for the rescue of irradiation-impaired salivary function by transient Hedgehog activation and are promising therapeutic targets of radiotherapy-induced irreversible dry mouth.

Panagiotopoulou, O., Iriarte-Diaz, J., Mehari Abraha, H., Taylor, A.B., Wilshin, S., Dechow, P.C. and Ross, C.F. (2020). “Biomechanics of the mandible of Macaca mulatta during the power stroke of mastication: Loading, deformation, and strain regimes and the impact of food type.” J Hum Evol 147: 102865.

Full text of this article.

Mandible morphology has yet to yield definitive information on primate diet, probably because of poor understanding of mandibular loading and strain regimes, and overreliance on simple beam models of mandibular mechanics. We used a finite element model of a macaque mandible to test hypotheses about mandibular loading and strain regimes and relate variation in muscle activity during chewing on different foods to variation in strain regimes. The balancing-side corpus is loaded primarily by sagittal shear forces and sagittal bending moments. On the working side, sagittal bending moments, anteroposterior twisting moments, and lateral transverse bending moments all reach similar maxima below the bite point; sagittal shear is the dominant loading regime behind the bite point; and the corpus is twisted such that the mandibular base is inverted. In the symphyseal region, the predominant loading regimes are lateral transverse bending and negative twisting about a mediolateral axis. Compared with grape and dried fruit chewing, nut chewing is associated with larger sagittal and transverse bending moments acting on balancing- and working-side mandibles, larger sagittal shear on the working side, and larger twisting moments about vertical and transverse axes in the symphyseal region. Nut chewing is also associated with higher minimum principal strain magnitudes in the balancing-side posterior ramus; higher sagittal shear strain magnitudes in the working-side buccal alveolar process and the balancing-side oblique line, recessus mandibulae, and endocondylar ridge; and higher transverse shear strains in the symphyseal region, the balancing-side medial prominence, and the balancing-side endocondylar ridge. The largest food-related differences in maximum principal and transverse shear strain magnitudes are in the transverse tori and in the balancing-side medial prominence, extramolar sulcus, oblique line, and endocondylar ridge. Food effects on the strain regime are most salient in areas not traditionally investigated, suggesting that studies seeking dietary effects on mandible morphology might be looking in the wrong places.

Russell, D.W., Casey, J.D., Gibbs, K.W., Dargin, J.M., Vonderhaar, D.J., Joffe, A.M., Ghamande, S., Khan, A., Dutta, S., Landsperger, J.S., Robison, S.W., Bentov, I., Wozniak, J.M., Stempek, S., White, H.D., Krol, O.F., Prekker, M.E., Driver, B.E., Brewer, J.M., Wang, L., Lindsell, C.J., Self, W.H., Rice, T.W., Semler, M.W. and Janz, D. (2020). “Protocol and statistical analysis plan for the PREventing cardiovascular collaPse with Administration of fluid REsuscitation during Induction and Intubation (PREPARE II) randomised clinical trial.” BMJ Open 10(9): e036671.

Full text of this article.

INTRODUCTION: Cardiovascular collapse is a common complication during tracheal intubation of critically ill adults. Whether administration of an intravenous fluid bolus prevents cardiovascular collapse during tracheal intubation remains uncertain. A prior randomised trial found fluid bolus administration to be ineffective overall but suggested potential benefit for patients receiving positive pressure ventilation during tracheal intubation. METHODS AND ANALYSIS: The PREventing cardiovascular collaPse with Administration of fluid REsuscitation during Induction and Intubation (PREPARE II) trial is a prospective, multi-centre, non-blinded randomised trial being conducted in 13 academic intensive care units in the USA. The trial will randomise 1065 critically ill adults undergoing tracheal intubation with planned use of positive pressure ventilation (non-invasive ventilation or bag-mask ventilation) between induction and laryngoscopy to receive 500 mL of intravenous crystalloid or no intravenous fluid bolus. The primary outcome is cardiovascular collapse, defined as any of: systolic blood pressure <65 mm Hg, new or increased vasopressor administration between induction and 2 min after intubation, or cardiac arrest or death between induction and 1 hour after intubation. The primary analysis will be an unadjusted, intention-to-treat comparison of the primary outcome between patients randomised to fluid bolus administration and patients randomised to no fluid bolus administration using a χ(2) test. The sole secondary outcome is 28-day in-hospital mortality. Enrolment began on 1 February 2019 and is expected to conclude in June 2020. ETHICS AND DISSEMINATION: The trial was approved by either the central institutional review board at Vanderbilt University Medical Center or the local institutional review board at each trial site. Results will be submitted for publication in a peer-reviewed journal and presented at scientific conferences. TRIAL REGISTRATION NUMBER: NCT03787732.

Goraya, N., Munoz-Maldonado, Y., Simoni, J. and Wesson, D.E. (2020). “Treatment of Chronic Kidney Disease-Related Metabolic Acidosis With Fruits and Vegetables Compared to NaHCO(3) Yields More and Better Overall Health Outcomes and at Comparable Five-Year Cost.” J Ren Nutr Sep 17;S1051-2276(20)30201-6. [Epub ahead of print.].

Full text of this article.

OBJECTIVES: Current guidelines recommend treatment of metabolic acidosis in chronic kidney disease (CKD) with Na(+)-based alkali but base-producing fruits and vegetables (F + V) might yield more and better health outcomes, making the intervention cost-effective. DESIGN AND METHODS: In this post hoc analysis of a clinical trial we randomized 108 macroalbuminuric, nondiabetic CKD stage 3 participants with metabolic acidosis to receive F + V (n = 36) calculated to reduce dietary acid by half, oral NaHCO(3) (HCO(3)(-), n = 36) 0.3 mEq/kg body weight/day, or Usual Care (UC, n = 36) assessed annually for 5 years. We calculated a mean overall health score for the groups as follows: 1 for improved, 0 for no change, and -1 for worsened at 5 years for plasma total CO(2), low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, change in medication dose (reduction = 1, increased = -1, no change = 0), and 1 for met goal and 0 for not meeting goal for estimated glomerular filtration rate (>30 mL/min/1.73 m(2)) and systolic blood pressure (<130 mm Hg). We also assessed the number of participants with cardiovascular disease events (myocardial infarctions + strokes) and group medication and hospitalization costs. RESULTS: Net plasma total CO(2) increase at 5 years was no different between HCO(3)(-) and F + V. Average health scores at 5 years differed among groups (P < .01) with F + V (7.4 [mean] ± 1.6 [standard deviation]) being descriptively larger than HCO(3)(-) and UC (2.9 ± 1.6 and 1.2 ± 1.6, respectively). The number of participants suffering cardiovascular disease events differed among groups (P = .009) with none (0) in F + V, 6 in UC, and 2 in HCO(3)(-). Total 5-year household cost per beneficial health outcome differed among groups (P = .005) with UC being highest and that for HCO(3)(-) and F + V being comparable. CONCLUSIONS: Metabolic acidosis improved comparably with F + V or standard oral NaHCO(3), but F + V yielded ancillary beneficial health outcomes, fewer participants with adverse cardiovascular events, and per-household cost that was comparable to NaHCO(3).

Thayer, K.L., Zweck, E., Ayouty, M., Garan, A.R., Hernandez-Montfort, J., Mahr, C., Morine, K.J., Newman, S., Jorde, L., Haywood, J.L., Harwani, N.M., Esposito, M.L., Davila, C.D., Wencker, D., Sinha, S.S., Vorovich, E., Abraham, J., O’Neill, W., Udelson, J., Burkhoff, D. and Kapur, N.K. (2020). “Invasive Hemodynamic Assessment and Classification of In-Hospital Mortality Risk Among Patients With Cardiogenic Shock.” Circ Heart Fail 13(9): e007099.

Full text of this article.

BACKGROUND: Risk stratifying patients with cardiogenic shock (CS) is a major unmet need. The recently proposed Society for Cardiovascular Angiography and Interventions (SCAI) stages as an approach to identify patients at risk for in-hospital mortality remains under investigation. We studied the utility of the SCAI stages and further explored the impact of hemodynamic congestion on clinical outcomes. METHODS: The CS Working Group registry includes patients with CS from 8 medical centers enrolled between 2016 and 2019. Patients were classified by the maximum SCAI stage (B-E) reached during their hospital stay according to drug and device utilization. In-hospital mortality was evaluated for association with SCAI stages and hemodynamic congestion. RESULTS: Of the 1414 patients with CS, the majority were due to decompensated heart failure (50%) or myocardial infarction (MI; 35%). In-hospital mortality was 31% for the total cohort, but higher among patients with MI (41% versus 26%, MI versus heart failure, P<0.0001). Risk for in-hospital mortality was associated with increasing SCAI stage (odds ratio [95% CI], 3.25 [2.63-4.02]) in both MI and heart failure cohorts. Hemodynamic data was available in 1116 (79%) patients. Elevated biventricular filling pressures were common among patients with CS, and right atrial pressure was associated with increased mortality and higher SCAI Stage. CONCLUSIONS: Our findings support an association between the proposed SCAI staging system and in-hospital mortality among patient with heart failure and MI. We further identify that venous congestion is common and identifies patients with CS at high risk for in-hospital mortality. These findings provide may inform future management protocols and clinical studies.