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Prospective observational study. To evaluate patient-reported outcomes after navigation-guided minimally invasive hybrid lumbar interbody fusion (nMIS-HLIF) for decompression and fusion in degenerative spondylolisthesis (Meyerding grade I-II). Posterior lumbar interbody fusion (PLIF) and transforaminal lumbar interbody fusion (TLIF) are well-known standard procedures for lumbar spinal fusion. nMIS-HLIF is a navigation-guided combined percutaneous and open procedure that combines the advantages of PLIF and TLIF procedures for the preparation of a single-port endoscopic approach. 33 patients underwent nMIS-HLIF. Core outcome measure index (COMI), oswestry disability index (ODI), numeric rating scale (NRS) back, NRS leg, and short form health-36 (SF-36) were collected preoperatively and at follow-up of 6 weeks, 3 months, 6 months, and 1 year. The impact of body mass index (BMI) was also analyzed. Computed tomography reconstruction was used to assess realignment and verify fused facet joints and vertebral bodies at the 1-year follow-up. 28 (85%) completed the 1-year follow-up. The median BMI was 27.6 kg/m(2), age 69 yrs. The mean reduction in listhesis was 8.4% (P < .01). BMI was negatively correlated with listhesis reduction (P = .032). The improvements in the NRS back, NRS leg, ODI, and COMI scores were significant at all times (P P < .01). The SF-36 parameters of bodily pain, physical functioning, physical component summary, role functioning/physical functioning, and social functioning improved (P < .003). The complication rate was 15.2% (n = 5), with durotomy (n = 3) being the most frequent. To reduce the complication rate and allow transitioning to a fully endoscopic approach, expandable devices have been developed. The outcomes of nMIS-HLIF are comparable to the current standard open and minimally invasive techniques. A high BMI hinders this reduction. The nMIS-HLIF procedure is appropriate for learning minimally invasive dorsal lumbar stabilization. The presented

Objectives: The most important goal of surgical treatment for spinal degeneration, in addition to eliminating the underlying pathology, is to preserve the biomechanically relevant structures. If degeneration destroys biomechanics, the single segment must either be surgically stabilized or functionally replaced by prosthetic restoration. This study examines how software-based presurgical simulation affects device selection and device development. Methods: Based on videofluoroscopic motion recordings and pixel-precise processing of the segmental motion patterns, a software-based surrogate functional model was validated. It characterizes the individual movement of spinal segments relative to corresponding cervical or lumbar spine sections. The single segment-based motion of cervical or lumbar spine of individual patients can be simulated, if size-calibrated functional X-rays of the relevant spine section are available. The software plug-in biokinemetric triangle has been then integrated into this software to perform comparative segmental motion analyses before and after treatment in two cervical device studies: the correlation of implant-induced changes in the movement geometry and patient-related outcome was examined to investigate, whether this surrogate model could provide a guideline for implant selection and future implant development. Results: For its validation in 253 randomly selected patients requiring single-level cervical (n=122) or lumbar (n=131) implant-supported restoration, the biokinemetric triangle provided significant pattern recognition in comparable investigations (p<0.05) and the software detected device-specific changes after implant-treatment (p<0.01). Subsequently, 104 patients, who underwent cervical discectomy, showed a correlation of the neck disability index with implant-specific changes in their segmental movement geometry: the preoperative simulation supported the best choice of surgical implants, since the best outcome resulted from restr

Immunomodulation by adipose-tissue-derived stem cells (ADSCs) is of special interest for the alleviation of damaging inflammatory responses in central nervous system injuries. The present study explored the effects of cerebrospinal fluid (CSF) from traumatic brain injury (TBI) patients on this immunomodulatory potential of ADSCs. CSF conditioning of ADSCs increased messenger RNA levels of both pro- and anti-inflammatory genes compared to controls. Exposure of phorbol-12-myristate-13-acetate-differentiated THP1 macrophages to the secretome of CSF-conditioned ADSCs downregulated both proinflammatory (cyclooxygenase-2, tumor necrosis factor alpha) and anti-inflammatory (suppressor of cytokine signaling 3, interleukin-1 receptor antagonist, and transforming growth factor beta) genes in these cells. Interleukin-10 expression was elevated in both naive and conditioned secretomes. ADSC secretome treatment, further, induced macrophage maturation of THP1 cells and increased the percentage of CD11b(+), CD14(+), CD86(+), and, to a lesser extent, CD206(+) cells. This, moreover, enhanced the phagocytic activity of CD14(+) and CD86(+) cells, though independently of pre-conditioning. Secretome exposure, finally, also induced a reduction in the percentage of CD192(+) adherent cells in cultures of peripheral blood mononuclear cells (PBMCs) from both healthy subjects and TBI patients. This limited efficacy (of both naive and pre-conditioned secretomes) suggests that the effects of lymphocyte-monocyte paracrine signaling on the fate of cultured PBMCs are strongest upon adherent cell populations.

BACKGROUND: Conventional surgical approaches used in the management of thoracic disc herniation (TDH) are associated with high morbidity. The development of minimally invasive and mini-open approaches has consistently improved patient outcomes. OBJECTIVE: To report our experience and outcomes of patients with symptomatic TDHs who underwent discectomy and partial corpectomy using the mini-open retropleural (MORP) approach as well as provide a detailed and illustrated technical description of the approach. METHODS: Retrospective chart review was performed on all patients with symptomatic TDHs who underwent a MORP approach at a tertiary academic center between 2011 and 2019. Patient demographic, clinical, and imaging data were examined (n = 33). The surgical technique is illustrated and described in detail. RESULTS: Discectomy of the herniated thoracic discs was successfully achieved in all patients using the MORP approach. Calcified discs were present in 63.6% (n = 21) of patients. Immediate instrumentation and fusion were performed in 30.3% (n = 10) of patients, which were among the earlier cases in this series. Symptomatic pleural effusions and cerebrospinal fluid leakage occurred in 6.1% (n = 2) and 9.1% (n = 3), respectively. No patient required chest tube placement. CONCLUSION: The MORP approach described in this manuscript is feasible and safe in achieving discectomy in patients with symptomatic TDHs. Compared to conventional open and other minimally invasive approaches, patients undergoing the MORP approach may have better outcomes with lower complication rates.

Objectives Genetic engineering of human-induced pluripotent stem cell-derived neural stem cells (hiPSC-NSC) may increase the risk of genomic aberrations. Therefore, we asked whether genetic modification of hiPSC-NSCs exacerbates chromosomal abnormalities that may occur during passaging and whether they may cause any functional perturbations in NSCs in vitro and in vivo. Materials and Methods The transgenic cassette was inserted into the AAVS1 locus, and the genetic integrity of zinc-finger nuclease (ZFN)-modified hiPSC-NSCs was assessed by the SNP-based karyotyping. The hiPSC-NSC proliferation was assessed in vitro by the EdU incorporation assay and in vivo by staining of brain slices with Ki-67 antibody at 2 and 8 weeks after transplantation of ZFN-NSCs with and without chromosomal aberration into the striatum of immunodeficient rats. Results During early passages, no chromosomal abnormalities were detected in unmodified or ZFN-modified hiPSC-NSCs. However, at higher passages both cell populations acquired duplication of the entire long arm of chromosome 1, dup(1)q. ZNF-NSCs carrying dup(1)q exhibited higher proliferation rate than karyotypically intact cells, which was partly mediated by increased expression ofAKT3located on Chr1q. Compared to karyotypically normal ZNF-NSCs, cells with dup(1)q also exhibited increased proliferation in vivo 2 weeks, but not 2 months, after transplantation. Conclusions These results demonstrate that, independently of ZFN-editing, hiPSC-NSCs have a propensity for acquiring dup(1)q and this aberration results in increased proliferation which might compromise downstream hiPSC-NSC applications.

OBJECTIVE: For effective minimally invasive lumbar decompression, we changed the routine of segmental decompression. Using a high-speed drill or an ultrasound knife, we created a working channel, starting at the base of the spinous process of the upper vertebra slightly above the disc level, to target and decompress the contralateral recess, and termed it the translaminar crossover decompression (TCD). We evaluated the feasibility and compared the outcomes of a navigation-guided endoscopic translaminar crossover approach for segmental decompression (eTCD) in elderly patients with microscopic decompression using the same approach (mTCD). METHODS: A total of 740 elderly patients were enrolled in a prospective cohort study. Of the 740 patients, 297, who had undergone mTCD, and 253, who had undergone eTCD, completed a 1-year follow-up visit. In addition to the surgical data, numerical rating scales (NRSs) for back and leg pain, the Core Outcome Measures Index and Oswestry Disability Index were recorded preoperatively and 3, 6, and 12 months after surgery. The MacNab criteria were supplemented by qualitative assessment of the patients' postoperative pain-free walking distance. RESULTS: A comparison of the preoperative and postoperative clinical scores showed significant improvement after TCD in both cohorts (P < 0.01): Oswestry Disability Index, from 50.3% +/- 12.6% to 15.5% +/- 7.43%; NRS (back), from 6.9 +/- 1.9 to 2.5 +/- 1.3; NRS (leg), from 8.0 +/- 0.85 to 1.6 +/- 0.33; Core Outcome Measures Index (back), from 7.8 +/- 2.0 to 2.7 +/- 1.5. No statistically significant differences were found in the outcomes between the 2 cohorts. CONCLUSIONS: TCD inherently eliminated central stenosis and facilitated decompression of both recesses via mutual undercutting, with preservation of facet joint integrity.

Pathophysiological conditions, such as myocardial infarction and mechanical overload affect the mammalian heart integrity, leading to a stiffened fibrotic tissue. With respect to the pathophysiology of cardiac fibrosis but also in the limelight of upcoming approaches of cardiac cell therapy it is of interest to decipher the interaction of cardiomyocytes with fibrotic matrix. Therefore, we designed a hydrogel-based model to engineer fibrotic tissue in vitro as an approach to predict the behavior of cardiomyocytes facing increased matrix rigidity. Here, we generated pure induced pluripotent stem cell-derived cardiomyocytes and cultured them on engineered polyacrylamide hydrogels matching the elasticities of healthy as well as fibrotic cardiac tissue. Only in cardiomyocytes cultured on matrices with fibrotic-like elasticity, transcriptional profiling revealed a substantial up-regulation of a whole panel of cardiac fibrosis-associated transcripts, including collagen I and III, decorin, lumican, and periostin. In addition, matrix metalloproteinases and their inhibitors, known to be essential in cardiac remodeling, were found to be elevated as well as insulin-like growth factor 2. Control experiments with primary cardiac fibroblasts were analyzed and did not show comparable behavior. In conclusion, we do not only present a snapshot on the transcriptomic fingerprint alterations in cardiomyocytes under pathological conditions but also provide a new reproducible approach to study the effects of fibrotic environments to various cell types. STATEMENT OF SIGNIFICANCE: The ageing population in many western countries is faced with an increasing burden of ageing-related diseases such as heart failure which is associated with cardiac fibrosis. A deeper understanding of the interaction of organotypic cells with altered extracellular matrix mechanical properties is of pivotal importance to understand the underlying mechanisms. Here, we present a strategy to combine hydrogel matrices, info:eu-repo/semantics/published

Pluripotent stem cells have demonstrated the potential to generate large numbers of functional cardiomyocytes (CMs) from different cell sources. Besides Wnt signaling, additional pathways are involved in early cardiac development and function. To date however, no study exists showing the effects of perturbing the canonical Wnt pathway using nonhuman primate embryonic stem (ES) cells. In this study, we investigated the effect of canonical Wnt inhibition during differentiation of nonhuman primate ES cell-derived CMs under defined, growth factor conditions. Rhesus monkey ES (rES) cells were differentiated into spontaneously beating CMs in the absence (control) or presence (treated) of Wnt inhibitor Dickkopf1 (DKK1), vascular endothelial growth factor, and basic fibroblast growth factor combined or added in a sequential manner during differentiation. Quantification and functional characterization of CMs were assessed by molecular and electrophysiological techniques. Analysis revealed no difference in average ratio of spontaneously beating clusters in both control and treated groups. However, the percentage of CMs was significantly reduced and the expressions of specific cardiac markers tested were also decreased in the treated group. Interestingly, we found that in CMs obtained from treated group, beta-adrenergic receptors (beta-ARs) were less expressed, their function was altered and electrophysiological studies revealed differences in action potential responsiveness to beta-AR stimulation. We demonstrated that the Wnt/beta-catenin pathway inhibitor, DKK1 associated with other growth factors repressed functional expression of beta-ARs in rES cell-derived CMs. Thus, control of this pathway in each cell line and source is important for proper basic research and further cell therapy applications.

Background and purpose: Based on the fact that traumatic brain injury is associated with mitochondrial dysfunction we aimed at localization of mitochondrial defect and attempted to correct it by thiamine. Experimental approach: Interventional controlled experimental animal study was used. Adult male Sprague-Dawley rats were subjected to lateral fluid percussion traumatic brain injury. Thiamine was administered 1 h prior to trauma; cortex was extracted for analysis 4 h and 3 d after trauma. Key results: Increased expression of inducible nitric oxide synthase (iNOS) and tumor necrosis factor receptor 1 (TNF-R1) by 4 h was accompanied by a decrease in mitochondrial respiration with glutamate but neither with pyruvate nor succinate. Assays of TCA cycle flux-limiting 2-oxoglutarate dehydrogenase complex (OGDHC) and functionally linked enzymes (glutamate dehydrogenase, glutamine synthetase, pyruvate dehydrogenase, malate dehydrogenase and malic enzyme) indicated that only OGDHC activity was decreased. Application of the OGDHC coenzyme precursor thiamine rescued the activity of OGDHC and restored mitochondrial respiration. These effects were not mediated by changes in the expression of the OGDHC sub-units (E1k and E3), suggesting post-translational mechanism of thiamine effects. By the third day after TBI, thiamine treatment also decreased expression of TNF-R1. Specific markers of unfolded protein response did not change in response to thiamine. Conclusion and implications: Our data point to OGDHC as a major site of damage in mitochondria upon traumatic brain injury, which is associated with neuroinflammation and can be corrected by thiamine. Further studies are required to evaluate the pathological impact of these findings in clinical settings.

Nitric oxide (NO) has frequently been associated with secondary damage after brain injury. However, average NO levels in different brain regions before and after traumatic brain injury (TBI) and its role in post-TBI mitochondrial dysfunction remain unclear. In this comprehensive profiling study, we demonstrate for the first time that basal NO levels vary significantly in the healthy cortex (0.44 +/- 0.04 mu M), hippocampus (0.26 +/- 0.03 mu M), and cerebellum (1.24 +/- 0.08 mu M). Within 4 h of severe lateral fluid percussion injury, NO levels almost doubled in these regions, thereby preserving regional differences in NO levels. TBI-induced NO generation was associated with inducible NO synthase (iNOS) increase in ipsilateral but not in contralateral regions. The transient NO increase resulted in a persistent tyrosine nitration adjacent to the injury site. Nitrosative stress-associated cell loss via apoptosis and receptor-interacting serine/threonine-protein kinase 3 (RIPK3)-mediated necrosis were also observed in the ipsilateral cortex, despite high levels of NO in the contralateral cortex. NO-mediated impairment of mitochondrial state 3 respiration dependent on complex I substrates was transient and confined to the ipsilateral cortex. Our results demonstrate that NO dynamics and associated effects differ in various regions of the injured brain. A potential association between the observed mitochondrial electron flow through complex I, but not complex II, and the modulation of TBI induced NO levels in different brain regions has to be prospectively analyzed in more detail.

First description of MIS-VLIF, a minimally invasive lumbar stabilization, to evaluate its safety and feasibility in patients suffering from weak bony conditions (lumbar spondylodiscitis and/or osteoporosis). After informed consent, 12 patients suffering from lumbar spondylodiscitis underwent single level MIS-VLIF. Eight of them had a manifest osteoporosis, either. Pre- and postoperative clinical status was documented using numeric rating scale (NRS) for leg and back pain. In all cases, the optimal height for the cage was preoperatively determined using software-based range of motion and sagittal balance analysis. CT scans were obtained to evaluate correct placement of the construct and to verify fusion after 6 months. Since 2013, 12 patients with lumbar pyogenic spondylodiscitis underwent MIS-VLIF. Mean surgery time was 169 +/- 28 min and average blood loss was less than 400 ml. Postoperative CT scans showed correct placement of the implants. Eleven patients showed considerable postoperative improvement in clinical scores. In one patient, we observed screw loosening. After documented bony fusion in the CT scan, the fixation system was removed in two cases to achieve lower material load. The load-bearing trajectories (vectors) of MIS-VLIF are different from those of conventional coaxial pedicle screw implantation. The dorsally converging construct combines the heads of the dorsoventral pedicle screws with laminar pedicle screws following cortical bone structures within a small approach. In case of lumbar spondylodiscitis and/or osteoporosis, MIS-VLIF relies on cortical bony structures for all screw vectors and the construct does not depend on conventional coaxial pedicle screws in the presence of inflamed, weak, cancellous or osteoporotic bone. MIS-VLIF allows full 360 degrees lumbar fusion including cage implantation via a small, unilateral dorsal midline approach.

Transplantation of stem cell-derived cardiomyocytes is one of the most promising therapeutic approaches after myocardial infarction, as loss of cardiomyocytes is virtually irreversible by endogenous repair mechanisms. In myocardial scars, transplanted cardiomyocytes will be in immediate contact with cardiac fibroblasts. While it is well documented how the electrophysiology of neonatal cardiomyocytes is modulated by cardiac fibroblasts of the same developmental stage, it is unknown how adult cardiac fibroblasts (aCFs) affect the function of embryonic stem cell-derived cardiomyocytes (ESC-CMs). To investigate the effects of aCFs on ESC-CM electrophysiology, we performed extra-and intracellular recordings of murine aCF-ESC-CM cocultures. We observed that spontaneous beating behaviour was highly irregular in aCF-ESC-CM cocultures compared to cocultures with mesenchymal stem cells (coefficient of variation of the interspike interval: 40.5 +/- 15.2% versus 9.3 +/- 2.0%, p = 0.008) and that action potential amplitude and maximal upstroke velocity (V-max) were reduced (amplitude: 52.3 +/- 1.7 mV versus 65.1 +/- 1.5 mV, V-max: 7.0 +/- 1.0 V/s versus 36.5 +/- 5.3 V/s), while action potential duration (APD) was prolonged (APD50: 25.6 +/- 1.0 ms versus 16.8 +/- 1.9 ms, p < 0.001; APD90: 52.2 +/- 1.5 ms versus 43.3 +/- 3.3 ms, p < 0.01) compared to controls. Similar changes could be induced by aCF-conditioned medium. We conclude that the presence of aCFs changes automaticity and induces potentially proarrhythmic changes of ESC-CM electrophysiology.