Aims In clinical studies on cell therapy for acute myocardial infarction (MI), cells are usually applied by intracoronary infusion with balloon (IC/B). To test the utility of balloon occlusion, ...mononuclear bone marrow cell (MNC) retention after intracoronary infusion without balloon (IC/noB) was compared with IC/B and intramyocardial (IM) injection. Methods and results Four hours after LAD ligation in male pigs, reperfusion was allowed (confirmed by coronary angiography). Five days later, 1 × 108 autologous 111Indium-labelled MNC were injected IC/noB (n = 4), IC/B (n = 4), or IM (n = 4). At 1 h the fraction of injected MNC that was detected in the heart was 4.1 ± 1.1% after IC/noB injection, 6.1 ± 2.5% after IC/B injection (P = 0.19), and 20.7 ± 2.3% after IM injection (P < 0.001 vs. IC/noB and IC/B). At 24 h it was 3.0 ± 0.6% (IC/noB), 3.3 ± 0.5% (IC/B, P = 0.43), and 15.0 ± 3.1% (IM, P < 0.001 vs. IC/noB and IC/B). Dynamic scintigrammes during each of four consecutive IC/B injections showed a rapid 19.6 ± 8.0% cell loss during balloon inflation (no-flow period, phase 1) and a rapid 36.6 ± 17.8% cell loss after balloon deflation (re-flow period, phase 2). After each of four consecutive IC/noB injections the peak cell deposit was lower, followed by one phase of rapid cell loss (30.9 ± 11.0% after 6 min). After IM injection only a slow linear cell loss was observed (9.7% per h). In histology, PKH-67 labelled cells only rarely had passed the endothelial barrier after 24 h after IC injection, while they were exclusively found in the interstitium after IM injection. Conclusion The observation of a similar cell persistence after IC injections with and without balloon occlusion suggests that the balloon procedures currently applied in clinical studies are not necessary for cell deposit. If longer term persistence of cells plays a role for the clinical benefit of cardiac cell therapy, IM injection may be superior to IC applications.
To determine the survival and evolution of pulmonary hypertension (PH) associated with bronchopulmonary dysplasia (BPD) in extremely premature born infants beyond 36 weeks postmenstrual age (PMA).
A ...single-centre retrospective cohort study from a university hospital.
Extremely preterm (gestational age <30 weeks and/or birth weight <1000 g) infants, born between 2012 and 2017, in the University Medical Center Groningen with confirmed PH at/beyond 36 weeks PMA.
Survival, mortality rate and PH resolution. Patient characteristics, treatment, presence and evolution of PH were collected from patient charts.
Twenty-eight infants were included. All had BPD, while 23 (82%) had severe BPD and 11 infants (39%) died. Survival rates at 1, 3 and 7 months from 36 weeks PMA were 89%, 70% and 58%, respectively. In 16 of the 17 surviving infants, PH resolved over time, with a resolution rate at 1 and 2 years corrected age of 47% and 79%, respectively. At 2.5 years corrected age, the resolution rate was 94%.
These extremely preterm born infants with PH-BPD had a survival rate of 58% at 6 months corrected age. Suprasystemic pulmonary artery pressure was associated with poor outcome. In the current study, infants surviving beyond the corrected age of 6 months showed excellent survival and resolution of PH in almost all cases. Prospective follow-up studies should investigate whether resolution of PH in these infants can be improved by multi-modal therapies, including respiratory, nutritional and cardiovascular treatments.
Background: The tumor vasculature is increasingly recognized as a target for cancer therapy. We developed and evaluated recombinant fusion proteins targeting the coagulation-inducing protein soluble ...tissue factor (sTF) to the luminal tumor endothelial antigen vascular cell adhesion molecule 1 (VCAM-1, CD106). Methods: We generated fusion proteins consisting of sTF fused to antibody fragments directed against mouse or human VCAM-1 and characterized them in vitro by flow cytometry, surface plasmon resonance, and two-stage coagulation assays. Their therapeutic effects were tested in three human xenograft tumor models: L540rec Hodgkin lymphoma, Colo677 small-cell lung carcinoma, and Colo677/HDMEC small-cell lung carcinoma with human vasculature. Toxicity was analyzed by histologic examination of organs and determination of laboratory blood parameters. Results: The fusion proteins bound VCAM-1 with nanomolar affinities and had the same coagulation activity as an sTF standard. Xenograft tumor–bearing mice treated with fusion protein (FP) alone or in combination with lipopolysaccharide (FP/L) or doxorubicin (FP/D) exhibited tumor-selective necrosis (L540rec tumors: 74% tumor necrosis 95% confidence interval {CI} = 55% to 93% with FP/L versus 13% tumor necrosi1s 95% CI = 4% to 22% with vehicle; Colo677 tumors: 26% 95% CI = 16% to 36% with FP versus 8% 95% CI = 2% to 14% with vehicle); tumor growth delay (Colo677/HDMEC: mean tumor weights after 3 days = 42 mg in FP-treated mice versus 71 mg in vehicle-treated mice, difference = 29 mg, 95% CI = 8 to 100, Mann–Whitney P = .008); and some tumor regressions (one of seven FP-treated Colo677 tumor–bearing mice and two of seven FP/D-treated mice). The fusion protein was well tolerated. Conclusions: Recombinant tissue factor–based fusion proteins directed against an intraluminal tumor endothelial cell marker induce tumor-selective intravascular coagulation, tumor tissue necrosis, and tumor growth delay.
To characterize different phenotypes of early pulmonary hypertension (PH) in preterm infants and their respective associations with bronchopulmonary dysplasia (BPD) and survival.
A prospective cohort ...study in a tertiary university medical center from June 2016 until March 2019. Infants with a gestational age <30 weeks and/or a birth weight <1000 g were included. Echocardiographic assessment for PH was performed at 3-10 days after birth. Subsequent development of BPD at 36 weeks postmenstrual age and mortality were assessed.
Early PH was identified in 55% of 104 included infants, including 21% with persistent PH of the newborn (PPHN), 61% with flow-associated PH, and 18% PH without shunt. Only PPHN was associated with placental fetal vascular malperfusion, lower gestational age, and low Apgar score. Both PPHN and flow PH were associated with the development of BPD. Early PH was associated with poorer survival, driven by PPHN.
Early PH is highly prevalent (55%) in preterm infants and associated with the development of BPD, independent of the phenotype of PH. Infants with PPHN had the poorest survival. Early PH presents in various phenotypes characterized by differences in etiology, pathophysiology, and associated long-term sequelae.
Abstract Background In times of organ shortage, use of marginal cadaveric livers has become increasingly important to reduce pressing organ demand and rising death rates while awaiting donations. ...Indisputably, fatty change in donor livers is a risk factor for poor initial function after orthotopic transplantation. However, identifying and rejecting marginal from good donor livers is one of the most difficult surgical tasks. Unfortunately, a liver biopsy with rapid histological diagnosis is rarely performed to identify marginal livers. Methods From 2005 to 2008, we investigated 36 livers of organ donors, which were explanted but not transplanted or underwent liver wedge biopsy during organ donation. All livers underwent standard surgical procedures and were allocated by Eurotransplant International Foundation. After unsuccessful allocation, explanted livers were photographically documented, formalin-fixed, and analyzed histopathologically. Results Seven livers were classified as good organ quality by the surgeon (19.4%); 15 were acceptable (41.6%); and 14 poor (39%). In 63.8% of livers, a frozen section was performed; 6/36 cases (16.7%) showed macrovesicular and microvesicular steatosis of less than 30%. In addition, all six cases fulfilled two or less extended donor criteria, as defined by the German Medical Association. Conclusion More marginal livers from cadaveric organ donors could have been transplanted. To extend the transplant pool of liver grafts, liver biopsies should be performed in all cases of acceptable and poor livers. If frozen section analysis is performed, a wedge liver biopsy should be taken from at least two different segments of the liver to validate the histological results.
Keratins 8 and 18 (K8 and K18) are the cytoskeletal intermediate filament proteins of adult hepatocytes. Murine models indicate that mutations in the K8- and K18-encoding genes predispose to liver ...injury. Moreover, studies showed an association of K8/K18 variants with human acute and chronic liver diseases. However, only little is known about a putative association of K8/K18 variants with cryptogenic hepatitis, a frequent liver disease of enigmatic etiology, often necessitating liver transplantation. Therefore, we analyzed whether K8 variants associate with cryptogenic hepatitis in a German cohort of patients in comparison to control blood bank donors. Genomic DNA isolated from liver biopsies of cryptogenic hepatitis patients or peripheral blood of healthy donors was analyzed for K8 variants by PCR amplification and direct DNA sequencing. We identified 8 novel heterozygous or homozygous amino acid-altering K8 variants in 5 of 62 cryptogenic hepatitis patients (8.1 %) and in none of 67 controls (
P
= 0.02). Previously described K8 variants p.G62C and p.R341H were found at similar incidence in cryptogenic hepatitis patients and controls. Hence, they were considered as polymorphisms not associated with liver disease progression. In conclusion, previously undescribed K8 variants associate with cryptogenic hepatitis in a German cohort of patients, possibly predisposing carriers to the development of liver disease.
Recently, we showed that manual stimulation (MS) of denervated vibrissal muscles enhanced functional recovery following facial nerve cut and suture (FFA) by reducing poly-innervation at the ...neuro-muscular junctions (NMJ). Although the cellular correlates of poly-innervation are established, with terminal Schwann cells (TSC) processes attracting axon sprouts to “bridge” adjacent NMJ, molecular correlates are poorly understood. Since quantitative RT-PCR revealed a rapid increase of IGF-1 mRNA in denervated muscles, we examined the effect of daily MS for 2 months after FFA in IGF-1
+/− heterozygous mice; controls were wild-type (WT) littermates including intact animals. We quantified vibrissal motor performance and the percentage of NMJ bridged by S100-positive TSC. There were no differences between intact WT and IGF-1
+/− mice for vibrissal whisking amplitude (48° and 49°) or the percentage of bridged NMJ (0%). After FFA and handling alone (i.e. no MS) in WT animals, vibrissal whisking amplitude was reduced (60% lower than intact) and the percentage of bridged NMJ increased (42% more than intact). MS improved both the amplitude of vibrissal whisking (not significantly different from intact) and the percentage of bridged NMJ (12% more than intact). After FFA and handling in IGF-1
+/− mice, the pattern was similar (whisking amplitude 57% lower than intact; proportion of bridged NMJ 42% more than intact). However, MS did not improve outcome (whisking amplitude 47% lower than intact; proportion of bridged NMJ 40% more than intact). We conclude that IGF-I is required to mediate the effects of MS on target muscle reinnervation and recovery of whisking function.
Three anti TNF-α agents have currently been approved for the treatment of moderate-to-severe or complicated Crohn's disease (CD): infliximab, certolizumab and adalimumab. Infliximab is effective in ...CD, but for reasons linked to its chimeric structure, response to treatment may be lost overtime and as a result, it can sometimes be unable to provide long term durable treatment of CD. Adalimumab, a fully human anti TNF-α antibody, demonstrates similar treatment efficacy as infliximab and certolizumab, and can easily be self-administered at home.
A literature search in the Cochrane, MEDLINE, PUBMED, Ovid MEDLINER® and EMBASE databases has been performed on the efficacy, safety and the impact adalimumab has on the quality of life and natural history of CD. Abstracts presented at the DDW, UEGW and ECCO Congresses have also been reviewed as well as references from review articles, meta-analysis studies and published RCTs.
Adalimumab induced remission of CD in 64% of patients, and maintained remission in more than 80% of initial responders. Adalimumab did not significantly increase the risk of adverse events compared with conventional medication up to 3 years of follow-up. Adalimumab reduces more than 50% the risk for hospitalisation and surgery due to CD. It is also effective for fistula closure, for the healing of the mucosa, and improving quality of life.
Adalimumab is effective in the induction and maintenance of clinical remission in CD and is generally well tolerated. It has been proved to have a positive impact by improving quality of life of patients, and reducing the need for hospitalisation and surgery due to CD. According to the European Crohn's and Colitis Organisation (ECCO), infliximab or adalimumab can be used for the treatment of fistulizing CD.
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