In Vivo and Ex Vivo Mitochondrial Function in COVID-19 Patients on the Intensive Care Unit

Mitochondrial dysfunction has been linked to disease progression in COVID-19 patients. This observational pilot study aimed to assess mitochondrial function in COVID-19 patients at intensive care unit (ICU) admission (T1), seven days thereafter (T2), and in healthy controls and a general anesthesia group. Measurements consisted of in vivo mitochondrial oxygenation and oxygen consumption, in vitro assessment of mitochondrial respiration in platelet-rich plasma (PRP) and peripheral blood mononuclear cells (PBMCs), and the ex vivo quantity of circulating cell-free mitochondrial DNA (mtDNA). The median mitoVO(2) of COVID-19 patients on T1 and T2 was similar and tended to be lower than the mitoVO(2) in the healthy controls, whilst the mitoVO(2) in the general anesthesia group was significantly lower than that of all other groups. Basal platelet (PLT) respiration did not differ substantially between the measurements. PBMC basal respiration was increased by approximately 80% in the T1 group when contrasted to T2 and the healthy controls. Cell-free mtDNA was eight times higher in the COVID-T1 samples when compared to the healthy controls samples. In the COVID-T2 samples, mtDNA was twofold lower when compared to the COVID-T1 samples. mtDNA levels were increased in COVID-19 patients but were not associated with decreased mitochondrial O(2) consumption in vivo in the skin, and ex vivo in PLT or PBMC. This suggests the presence of increased metabolism and mitochondrial damage

Mitochondrial Oxygenation During Cardiopulmonary Bypass: A Pilot Study

ObjectiveAdequate oxygenation is essential for the preservation of organ function during cardiac surgery and cardiopulmonary bypass (CPB). Both hypoxia and hyperoxia result in undesired outcomes, and a narrow window for optimal oxygenation exists. Current perioperative monitoring techniques are not always sufficient to monitor adequate oxygenation. The non-invasive COMET® monitor could be a tool to monitor oxygenation by measuring the cutaneous mitochondrial oxygen tension (mitoPO2). This pilot study examines the feasibility of cutaneous mitoPO2 measurements during cardiothoracic procedures. Cutaneous mitoPO2 will be compared to tissue oxygenation (StO2) as measured by near-infrared spectroscopy.Design and MethodThis single-center observational study examined 41 cardiac surgery patients requiring CPB. Preoperatively, patients received a 5-aminolevulinic acid plaster on the upper arm to enable mitoPO2 measurements. After induction of anesthesia, both cutaneous mitoPO2 and StO2 were measured throughout the procedure. The patients were observed until discharge for the development of acute kidney insufficiency (AKI).ResultsCutaneous mitoPO2 was successfully measured in all patients and was 63.5 [40.0–74.8] mmHg at the surgery start and decreased significantly (p < 0.01) to 36.4 [18.4–56.0] mmHg by the end of the CPB run. StO2 at the surgery start was 80.5 [76.8–84.3]% and did not change significantly. Cross-clamping of the aorta and the switch to non-pulsatile flow resulted in a median cutaneous mitoPO2 decrease of 7 mmHg (p < 0.01). The cessation of the aortic cross-clamping period resulted in an increase of 4 mmHg (p < 0.01). Totally, four patients developed AKI and had a lower preoperative eGFR of 52 vs. 81 ml/min in the non-AKI group. The AKI group spent 32% of the operation time with a cutaneous mitoPO2 value under 20 mmHg as compared to 8% in the non-AKI group.ConclusionThis pilot study illustrated the feasibility of measuring cutaneous mitoPO2 using the COMET® monitor during cardiothoracic procedures. Moreover, in contrast to StO2, mitoPO2 decreased significantly with the increasing CPB run time. Cutaneous mitoPO2 also significantly decreased during the aortic cross-clamping period and increased upon the release of the clamp, but StO2 did not. This emphasized the sensitivity of cutaneous mitoPO2 to detect circulatory and microvascular changes

A Successful Approach to Kidney Transplantation in Patients With Enteric (Secondary) Hyperoxaluria

Background. Enteric hyperoxaluria due to malabsorption may cause chronic oxalate nephropathy and lead to end-stage renal disease. Kidney transplantation is challenging given the risk of recurrent calcium-oxalate deposition and nephrolithiasis. Methods. We established a protocol to reduce plasma oxalic acid levels peritransplantation based on reduced intake and increased removal of oxalate. The outcomes of 10 kidney transplantation patients using this protocol are reported. Results. Five patients received a living donor kidney and had immediate graft function. Five received a deceased donor kidney and had immediate (n = 1) or delayed graft function (n = 4). In patients with delayed graft function, the protocol was prolonged after transplantation. In 3 patients, our protocol was reinstituted because of late complications affecting graft function. One patient with high-output stoma and relatively low oxalate levels had lost her first kidney transplant because of recurrent oxalate depositions but now receives intravenous fluid at home on a routine basis 3 times per week to prevent dehydration. Patients are currently between 3 and 32 months after transplantation and all have a stable estimated glomerular filtration rate (mean, 51 +/- 21 mL/min per 1.73 m(2)). In 4 of 8 patients who underwent for cause biopsies after transplantation oxalate depositions were found. Conclusions. This is the first systematic description of kidney transplantation in a cohort of patients with enteric hyperoxaluria. Common complications after kidney transplantation impact long-term transplant function in these patients. With our protocol, kidney transplantation outcomes were favorable in this population with unfavorable transplantation prospects and even previous unsuccessful transplants

ETHNIC SEGREGATION AND THE ROLE OF PUBLIC HOUSING IN AMSTERDAM

Dutch cities are characterized by moderate levels of ethnic (and social) segregation if compared with other countries in the Western world. Dutch cities are also famous for their large share of public housing in the total stock. Not surprisingly these two features are frequently supposed to be causally related. However, in this contribution this association is challenged on the basis of a review of existing and well- described segregation situations, and on the basis of an empirical GIS analysis of micro-level data from the Amsterdam population register. Ethnic segregation may also develop within the large public housing secto

Challenges in QCD matter physics - The Compressed Baryonic Matter experiment at FAIR

Substantial experimental and theoretical efforts worldwide are devoted to explore the phase diagram of strongly interacting matter. At LHC and top RHIC energies, QCD matter is studied at very high temperatures and nearly vanishing net-baryon densities. There is evidence that a Quark-Gluon-Plasma (QGP) was created at experiments at RHIC and LHC. The transition from the QGP back to the hadron gas is found to be a smooth cross over. For larger net-baryon densities and lower temperatures, it is expected that the QCD phase diagram exhibits a rich structure, such as a first-order phase transition between hadronic and partonic matter which terminates in a critical point, or exotic phases like quarkyonic matter. The discovery of these landmarks would be a breakthrough in our understanding of the strong interaction and is therefore in the focus of various high-energy heavy-ion research programs. The Compressed Baryonic Matter (CBM) experiment at FAIR will play a unique role in the exploration of the QCD phase diagram in the region of high net-baryon densities, because it is designed to run at unprecedented interaction rates. High-rate operation is the key prerequisite for high-precision measurements of multi-differential observables and of rare diagnostic probes which are sensitive to the dense phase of the nuclear fireball. The goal of the CBM experiment at SIS100 (sqrt(s_NN) = 2.7 - 4.9 GeV) is to discover fundamental properties of QCD matter: the phase structure at large baryon-chemical potentials (mu_B > 500 MeV), effects of chiral symmetry, and the equation-of-state at high density as it is expected to occur in the core of neutron stars. In this article, we review the motivation for and the physics programme of CBM, including activities before the start of data taking in 2022, in the context of the worldwide efforts to explore high-density QCD matter.Comment: 15 pages, 11 figures. Published in European Physical Journal

The role of a firm's absorptive capacity and the technology transfer process in clusters: How effective are technology centres in low-tech clusters?

This paper analyses how the internal resources of small- and medium-sized enterprises determine access (learning processes) to technology centres (TCs) or industrial research institutes (innovation infrastructure) in traditional low-tech clusters. These interactions basically represent traded (market-based) transactions, which constitute important sources of knowledge in clusters. The paper addresses the role of TCs in low-tech clusters, and uses semi-structured interviews with 80 firms in a manufacturing cluster. The results point out that producer–user interactions are the most frequent; thus, the higher the sector knowledge-intensive base, the more likely the utilization of the available research infrastructure becomes. Conversely, the sectors with less knowledge-intensive structures, i.e. less absorptive capacity (AC), present weak linkages to TCs, as they frequently prefer to interact with suppliers, who act as transceivers of knowledge. Therefore, not all the firms in a cluster can fully exploit the available research infrastructure, and their AC moderates this engagement. In addition, the existence of TCs is not sufficient since the active role of a firm's search strategies to undertake interactions and conduct openness to available sources of knowledge is also needed. The study has implications for policymakers and academia

Local therapy of cancer with free IL-2

This is a position paper about the therapeutic effects of locally applied free IL-2 in the treatment of cancer. Local therapy: IL-2 therapy of cancer was originally introduced as a systemic therapy. This therapy led to about 20% objective responses. Systemic therapy however was very toxic due to the vascular leakage syndrome. Nevertheless, this treatment was a break-through in cancer immunotherapy and stimulated some interesting questions: Supposing that the mechanism of IL-2 treatment is both proliferation and tumoricidal activity of the tumor infiltrating cells, then locally applied IL-2 should result in a much higher local IL-2 concentration than systemic IL-2 application. Consequently a greater beneficial effect could be expected after local IL-2 application (peritumoral = juxtatumoral, intratumoral, intra-arterial, intracavitary, or intratracheal = inhalation). Free IL-2: Many groups have tried to prepare a more effective IL-2 formulation than free IL-2. Examples are slow release systems, insertion of the IL-2 gene into a tumor cell causing prolonged IL-2 release. However, logistically free IL-2 is much easier to apply; hence we concentrated in this review and in most of our experiments on the use of free IL-2. Local therapy with free IL-2 may be effective against transplanted tumors in experimental animals, and against various spontaneous carcinomas, sarcomas, and melanoma in veterinary and human cancer patients. It may induce rejection of very large, metastasized tumor loads, for instance advanced clinical tumors. The effects of even a single IL-2 application may be impressive. Not each tumor or tumor type is sensitive to local IL-2 application. For instance transplanted EL4 lymphoma or TLX9 lymphoma were not sensitive in our hands. Also the extent of sensitivity differs: In Bovine Ocular Squamous Cell Carcinoma (BOSCC) often a complete regression is obtained, whereas with the Bovine Vulval Papilloma and Carcinoma Complex (BVPCC) mainly stable disease is attained. Analysis of the results of local IL-2 therapy in 288 cases of cancer in human patients shows that there were 27% Complete Regressions (CR), 23% Partial Regressions (PR), 18% Stable Disease (SD), and 32% Progressive Disease (PD). In all tumors analyzed, local IL-2 therapy was more effective than systemic IL-2 treatment. Intratumoral IL-2 applications are more effective than peritumoral application or application at a distant site. Tumor regression induced by intratumoral IL-2 application may be a fast process (requiring about a week) in the case of a highly vascular tumor since IL-2 induces vascular leakage/edema and consequently massive tumor necrosis. The latter then stimulates an immune response. In less vascular tumors or less vascular tumor sites, regression may require 9–20 months; this regression is mainly caused by a cytotoxic leukocyte reaction. Hence the disadvantageous vascular leakage syndrome complicating systemic treatment is however advantageous in local treatment, since local edema may initiate tumor necrosis. Thus the therapeutic effect of local IL-2 treatment is not primarily based on tumor immunity, but tumor immunity seems to be useful as a secondary component of the IL-2 induced local processes. If local IL-2 is combined with surgery, radiotherapy or local chemotherapy the therapeutic effect is usually greater than with either therapy alone. Hence local free IL-2 application can be recommended as an addition to standard treatment protocols. Local treatment with free IL-2 is straightforward and can readily be applied even during surgical interventions. Local IL-2 treatment is usually without serious side effects and besides minor complaints it is generally well supported. Only small quantities of IL-2 are required. Hence the therapy is relatively cheap. A single IL-2 application of 4.5 million U IL-2 costs about 70 Euros. Thus combined local treatment may offer an alternative in those circumstances when more expensive forms of treatment are not available, for instance in resource poor countries