Diagnostic Value of High-Sensitivity Cardiac Troponin-I in Patients After Out-of-Hospital Cardiac Arrest.

Knowing the etiology of cardiac arrest (CA) is important for treatment decisions. Results of previous studies on the diagnostic role of cardiac troponin in patients resuscitated from CA are controversial, few studies were done during the era of high-sensitivity cardiac troponin-I (hs-cTnI), and kinetics of hs-cTnI was not thoroughly investigated. We aimed to explore the diagnostic value of hs-cTnI in patients resuscitated from out-of-hospital CA (OHCA). This retrospective study included 201 consecutive patients after OHCA admitted to the intensive cardiac care unit at Rambam Health Care Campus from 2016 to 2021. Patients were divided into 2 groups according to etiology of CA: group 1-patients with definite acute myocardial infarction (AMI), group 2-patients in whom AMI was excluded. Values of hs-cTnI on admission, peak hs-cTnI, and hs-cTnI upslope were compared between patients with AMI and non-AMI. Peak hs-cTnI and hs-cTnI upslope differed significantly between patients with non-AMI versus AMI CA (median 1,424 vs 32,558 ng/L, p <0.0001 and median 109 vs 2,322 ng/L/h, p <0.0001, respectively). Moreover, peak hs-cTnI and hs-cTnI upslope were found to have good discrimination performance between patients with non-AMI and AMI, with area under the curve receiver operating characteristics (ROC) curves of 0.83 and 0.80, respectively. In conclusion, in patients resuscitated from OHCA values of peak hs-cTnI and hs-cTnI upslope could be helpful in the diagnosis of etiology of CA as adjunct to other diagnostic methods.

PTH-Induced Bone Regeneration and Vascular Modulation Are Both Dependent on Endothelial Signaling.

The use of a bone allograft presents a promising approach for healing nonunion fractures. We have previously reported that parathyroid hormone (PTH) therapy induced allograft integration while modulating angiogenesis at the allograft proximity. Here, we hypothesize that PTH-induced vascular modulation and the osteogenic effect of PTH are both dependent on endothelial PTH receptor-1 (PTHR1) signaling. To evaluate our hypothesis, we used multiple transgenic mouse lines, and their wild-type counterparts as a control. In addition to endothelial-specific PTHR1 knock-out mice, we used mice in which PTHR1 was engineered to be constitutively active in collagen-1α+ osteoblasts, to assess the effect of PTH signaling activation exclusively in osteoprogenitors. To characterize resident cell recruitment and osteogenic activity, mice in which the Luciferase reporter gene is expressed under the Osteocalcin promoter (Oc-Luc) were used. Mice were implanted with calvarial allografts and treated with either PTH or PBS. A micro-computed tomography-based structural analysis indicated that the induction of bone formation by PTH, as observed in wild-type animals, was not maintained when PTHR1 was removed from endothelial cells. Furthermore, the induction of PTH signaling exclusively in osteoblasts resulted in significantly less bone formation compared to systemic PTH treatment, and significantly less osteogenic activity was measured by bioluminescence imaging of the Oc-Luc mice. Deletion of the endothelial PTHR1 significantly decreased the PTH-induced formation of narrow blood vessels, formerly demonstrated in wild-type mice. However, the exclusive activation of PTH signaling in osteoblasts was sufficient to re-establish the observed PTH effect. Collectively, our results show that endothelial PTHR1 signaling plays a key role in PTH-induced osteogenesis and has implications in angiogenesis.

Neural crest-derived mesenchymal progenitor cells enhance cranial allograft integration.

Replacement of lost cranial bone (partly mesodermal and partly neural crest-derived) is challenging and includes the use of nonviable allografts. To revitalize allografts, bone marrow-derived mesenchymal stromal cells (mesoderm-derived BM-MSCs) have been used with limited success. We hypothesize that coating of allografts with induced neural crest cell-mesenchymal progenitor cells (iNCC-MPCs) improves implant-to-bone integration in mouse cranial defects. Human induced pluripotent stem cells were reprogramed from dermal fibroblasts, differentiated to iNCCs and then to iNCC-MPCs. BM-MSCs were used as reference. Cells were labeled with luciferase (Luc2) and characterized for MSC consensus markers expression, differentiation, and risk of cellular transformation. A calvarial defect was created in non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice and allografts were implanted, with or without cell coating. Bioluminescence imaging (BLI), microcomputed tomography (µCT), histology, immunofluorescence, and biomechanical tests were performed. Characterization of iNCC-MPC-Luc2 vs BM-MSC-Luc2 showed no difference in MSC markers expression and differentiation in vitro. In vivo, BLI indicated survival of both cell types for at least 8 weeks. At week 8, µCT analysis showed enhanced structural parameters in the iNCC-MPC-Luc2 group and increased bone volume in the BM-MSC-Luc2 group compared to controls. Histology demonstrated improved integration of iNCC-MPC-Luc2 allografts compared to BM-MSC-Luc2 group and controls. Human osteocalcin and collagen type 1 were detected at the allograft-host interphase in cell-seeded groups. The iNCC-MPC-Luc2 group also demonstrated improved biomechanical properties compared to BM-MSC-Luc2 implants and cell-free controls. Our results show an improved integration of iNCC-MPC-Luc2-coated allografts compared to BM-MSC-Luc2 and controls, suggesting the use of iNCC-MPCs as potential cell source for cranial bone repair.

Teriparatide (recombinant parathyroid hormone 1-34) enhances bone allograft integration in a clinically relevant pig model of segmental mandibulectomy.

Massive craniofacial bone loss poses a clinical challenge to maxillofacial surgeons. Structural bone allografts are readily available at tissue banks but are rarely used due to a high failure rate. Previous studies showed that intermittent administration of recombinant parathyroid hormone (rPTH) enhanced integration of allografts in a murine model of calvarial bone defect. To evaluate its translational potential, the hypothesis that rPTH would enhance healing of a mandibular allograft in a clinically relevant large animal model of mandibulectomy was tested. Porcine bone allografts were implanted into a 5-cm-long continuous mandible bone defect in six adult Yucatan minipigs, which were randomized to daily intramuscular injections of rPTH (1.75 µg/kg) and placebo (n = 3). Blood tests were performed on Day 56 preoperation, Day 0 and on Day 56 postoperation. Eight weeks after the surgery, bone healing was analyzed using high-resolution X-ray imaging (Faxitron and micro computed tomography [CT]) and three-point bending biomechanical testing. The results showed a significant 2.6-fold rPTH-induced increase in bone formation (p = 0.02). Biomechanically, the yield failure properties of the healed mandibles were significantly higher in the rPTH group (yield load: p < 0.05; energy to yield: p < 0.01), and the post-yield displacement and energy were higher in the placebo group (p < 0.05), suggesting increased mineralized integration of the allograft in the rPTH group. In contrast to similar rPTH therapy studies in dogs, no signs of hypercalcemia, hyperphosphatemia, or inflammation were detected. Taken together, we provide initial evidence that rPTH treatment enhances mandibular allograft healing in a clinically relevant large animal model.