Is obesity still a risk factor in renal transplantation?

At our center, since 1982, a body mass index (BMI) of less than 30 has been a prerequisite for placing a patient on the waiting list for renal transplantation. This decision was made because obese transplant recipients seemed to have a less than favorable post-transplant outcome. The aim of this study was to evaluate whether this requirement is still justified. Forty-six patients with a BMI above 30 underwent primary cadaveric renal transplantation between 1972 and 1993. For each of these obese patients, five consecutive non-obese (BMI 20–25) control patients were selected. Patient and graft survival, causes of graft loss, and acute rejection rate were evaluated for the two patient groups before and after the year 1982. Within the first 30 post-transplant days, one patient (2 %) and 11 grafts (24 %) were lost in the group of obese patients whereas seven patients (3 %) and 36 grafts (16 %) were lost in the control group. Among the obese patients, renal circulatory complications were a major cause of graft loss. In the period 1973–1981, the 1-year patient survival rate was 65 % among obese patients versus 75 % among controls from 1982 to 1993, this was 90 % versus 93 %. From 1973 to 1981, the 1-year graft survival rate was 25 % among obese patients versus 53 % among controls (P < 0.05); from 1982 to 1993, it was 68 % versus 84 % (P = NS). Multivariate analysis showed that the immunosuppressive regimen, age of the patient, BMI, and cold ischemia time of the graft had a significant influence on graft survival. The acute rejection rate within the first 30 days was 28 % among obese patients and 35 % among controls (P = NS). We conclude that a BMI below or equal to 30 is still justified as a prerequisite for placement on the waiting list for renal transplantation, for despite an overall improvement, the outcome of renal transplantation in obese patients remains worse than that in non-obese patients. Received: 3 February 1997 Received after revision: 4 April 1997 Accepted: 8 April 1997     

Activated Protein C Reduces Graft Neutrophil Activation in Clinical Renal Transplantation

We studied the role of endogenous activated protein C (APC), the major physiological anti-coagulant with concomitant anti-inflammatory properties, on ischemia/reperfusion (I/R) in 45 patients participating in a larger trial comparing three immunosuppressive protocols in cadaveric renal transplantation: perioperative anti-thymocyte globulin (ATG, Fresenius AG, Bad Homburg, Germany), perioperative basiliximab and conventional triple therapy. Blood samples for assessing plasma APC, protein C, and lactoferrin concentrations, neutrophil CD11b and L-selectin expressions and blood leukocyte differential counts were obtained preoperatively and before reperfusion from central venous cannula, complemented with simultaneous samples from iliac artery and graft vein for calculation of transrenal differences (Delta) of study parameters at 1 and 5 min after reperfusion. Unlike basiliximab or conventional therapy groups, ATG infusion induced a substantial increase in plasma APC concentration (119 [88-144]% before infusion vs. 232 [85-1246]% after infusion, p<0.001), resulting in renal graft sequestration of APC at 1 min after reperfusion (Delta=-72 [-567 to 12]%, p<0.001). Graft APC consumption was associated with transrenal reduction of neutrophil activation markers (L-selectin r=0.7, p=0.01; lactoferrin r=-0.6, p=0.02; CD11b r=-0.8, p=0.001), and with both warm (r=0.6, p=0.01) and cold ischemia time (r=0.6, p=0.02) and donor age (r=0.6, p=0.01). These findings suggest that APC has an anti-inflammatory role in I/R injury in clinical renal transplantation.     

Traumatic deaths in the emergency room: A retrospective analysis of 115 consecutive cases

Objective:   

The aim of the present study was to characterise traumatic deaths occurring in the emergency room (ER) and to assess retrospectively the quality of given emergency care by evaluating whether any of the deaths could be identified as potentially preventable.     

Cervical specimen order and performance measures of Chlamydia trachomatis diagnostic testing

The orders of three endocervical specimens of 3,561 women for Chlamydia trachomatis testing were randomized to determine whether test performance measures of two nucleic acid amplification tests and a DNA probe were affected by swab order. Specimen collection order did not appear to affect the diagnostic accuracy of these tests.     

Characterization of GPRA, a novel G protein-coupled receptor related to asthma

We recently identified a novel positional asthma susceptibility gene, GPRA, which belongs to the G protein-coupled receptor family. In the present studies, we show that isoform specific activation of GPRA-A with its agonist, Neuropeptide S (NPS) resulted in significant inhibition of cell growth. GPRA has several variants due to extensive alternative splicing. We observed that only the full-length variants, GPRA-A and GPRA-B, with 7 transmembrane topology are transported into the plasma membrane, while the truncated proteins retain intracellular compartments. To clarify disease mechanism, we studied co-expression of the variants without finding any indication that truncated variants would inhibit the receptor transport into the plasma membrane. By using in situ hybridization and immunohistochemistry, we detected ubiquitous expression of GPRA-B, and frequent expression of GPRA-A in the epithelia of several organs including bronchi and gastrointestinal tract. Furthermore, we observed aberrant mRNA and protein expression levels of GPRA in the asthmatic bronchi. Finally, we demonstrate that GPRA and NPS are co-expressed in bronchial epithelium. In summary, this study provides evidence that GPRA might have functional relevance in modulating asthma by increased expression levels in the relevant tissues under diseased state and by potential inhibitory effect of GPRA-A activation on cell growth.     

Susceptibility for homeostatic plasticity is down-regulated in parallel with maturation of the rat hippocampal synaptic circuitry

Homeostatic regulation, i.e. the ability of neurons and neuronal networks to adjust their output in response to chronic alterations in electrical activity is a prerequisite for the pronounced functional plasticity in the developing brain. Cellular mechanisms of homeostatic plasticity have mainly been studied in cultured preparations. To understand the developmental time frame and properties of homeostatic plasticity under more physiological conditions, we have here compared the effects of activity deprivation on synaptic transmission in acutely isolated and cultured hippocampal slices at different stages of development. We find that transmission at both glutamatergic and GABAergic synapses is strongly and rapidly (15 h) regulated in the opposite directions in response to inactivity during narrow, separated time windows early in development. Following this critical period of synaptic development, induction of the homeostatic response requires longer periods (40 h) of inactivity. At glutamatergic synapses, activity blockade led to an increase in the amplitude and frequency of mEPSCs, and the threshold for induction of this response was increased during development. In contrast, homeostatic regulation at GABAergic synapses was expressed in a qualitatively distinct manner at different developmental stages. Immature neurons responded rapidly to inactivity by regulating mIPSC frequency, while longer activity blockade led to a decrease in the mIPSC amplitude independent of the neuronal maturation. The susceptibility of immature networks to homeostatic regulation may serve as a safety mechanism against rapid runaway destability during the time of intense remodelling of the synaptic circuitry.     

Endothelial leukocyte adhesion molecule-1-dependent adhesion of colon carcinoma cells to vascular endothelium is inhibited by an antibody to Lewis fucosylated type I carbohydrate chain.

Endothelial leukocyte adhesion molecule-1 (ELAM-1) has been determined to be the mediator of adhesion of colon carcinoma cells to interleukin-1 (IL-1)-activated endothelial cells. To identify ELAM-1 ligand in colon carcinoma cells, we have screened a series of 11 monoclonal antibodies directed to these cells and found that only one MBr8 was able to inhibit the IL-1-induced increment in adhesion of HT29 and of SW948 colon carcinoma lines to endothelial cells. In contrast, MBr8 did not bind to polymorphonuclear cells, monocytes, and lymphocytes and did not inhibit polymorphonuclear adhesion to IL-1-activated endothelial cells. As expected, an ELAM-1 monoclonal antibody strongly inhibited IL-1 induced increment of adhesion of HT29, SW948, and polymorphonuclear cells. As negative control, MG63 osteosarcoma cells were used. These cells adhere more efficiently to IL-1 activated endothelial cells but MBr8 and ELAM-1 monoclonal antibodies did not affect their adhesion. The effect of MBr8 was also tested in an experimental system in vivo. As described previously, radiolabeled HT29 cell retention in the lung of nude mice was increased in animals given IL-1. MBr8 administration to nude mice or pretreatment of tumor cells with it inhibited this effect. These data suggest that cell adhesion to ELAM-1 might be mediated by different, cell type specific, sugar ligands.     

Physiological instability is linked to mortality in primary central nervous system lymphoma: A case–control fMRI study

Primary central nervous system lymphoma (PCNSL) is an aggressive brain disease where lymphocytes invade along perivascular spaces of arteries and veins. The invasion markedly changes (peri)vascular structures but its effect on physiological brain pulsations has not been previously studied. Using physiological magnetic resonance encephalography (MREG_BOLD) scanning, this study aims to quantify the extent to which (peri)vascular PCNSL involvement alters the stability of physiological brain pulsations mediated by cerebral vasculature. Clinical implications and relevance were explored. In this study, 21 PCNSL patients (median 67y; 38% females) and 30 healthy age‐matched controls (median 63y; 73% females) were scanned for MREG_BOLD signal during 2018–2021. Motion effects were removed. Voxel‐by‐voxel Coefficient of Variation (CV) maps of MREG_BOLD signal was calculated to examine the stability of physiological brain pulsations. Group‐level differences in CV were examined using nonparametric covariate‐adjusted tests. Subject‐level CV alterations were examined against control population Z‐score maps wherein clusters of increased CV values were detected. Spatial distributions of clusters and findings from routine clinical neuroimaging were compared [contrast‐enhanced, diffusion‐weighted, fluid‐attenuated inversion recovery (FLAIR) data]. Whole‐brain mean CV was linked to short‐term mortality with 100% sensitivity and 100% specificity, as all deceased patients revealed higher values (n = 5, median 0.055) than surviving patients (n = 16, median 0.028) (p < .0001). After adjusting for medication, head motion, and age, patients revealed higher CV values (group median 0.035) than healthy controls (group median 0.024) around arterial territories (p ≤ .001). Abnormal clusters (median 1.10 × 10⁵mm³) extended spatially beyond FLAIR lesions (median 0.62 × 10⁵mm³) with differences in volumes (p = .0055).     

Artificial Weathering of Contact-Charred Wood—The Effect of Modification Duration,Wood Species and Material Density

A relevant issue with charred exteriors is the inconsistency of the result, which makes service life predictions complicated. Contact charring enables the creation of a very evenly modified surface with accurate control of temperature and modification time, but the weathering properties are questionable. This paper evaluated the effect of the modification time relative to char layer and transition zone thickness, wood species and material density in an artificial weathering test. The results revealed higher color stability in connection to longer modification time, but also an increase in the cracked surface area. Cracking was heavily dependent on the modification regime and increased with increasing char and transition zone thicknesses. Dense spruce had the highest color stability with the most severe modification regime, but char layer thickness varied more than on other wood types. Furthermore, species-dependent cracking patterns affected the final result as the small-scale flaking experienced by birch increased the washing off of char. It is likely an even higher modification temperature with a shorter modification time is needed to produce sufficient weathering resistance suitable for exterior uses.     

Lymphangiogenesis requires Ang2/Tie/PI3K signaling for VEGFR3 cell-surface expression

Vascular endothelial growth factor C (VEGF-C) induces lymphangiogenesis via VEGF receptor 3 (VEGFR3), which is encoded by the most frequently mutated gene in human primary lymphedema. Angiopoietins (Angs) and their Tie receptors regulate lymphatic vessel development, and mutations of the ANGPT2 gene were recently found in human primary lymphedema. However, the mechanistic basis of Ang2 activity in lymphangiogenesis is not fully understood. Here, we used gene deletion, blocking Abs, transgene induction, and gene transfer to study how Ang2, its Tie2 receptor, and Tie1 regulate lymphatic vessels. We discovered that VEGF-C–induced Ang2 secretion from lymphatic endothelial cells (LECs) was involved in full Akt activation downstream of phosphoinositide 3 kinase (PI3K). Neonatal deletion of genes encoding the Tie receptors or Ang2 in LECs, or administration of an Ang2-blocking Ab decreased VEGFR3 presentation on LECs and inhibited lymphangiogenesis. A similar effect was observed in LECs upon deletion of the PI3K catalytic p110α subunit or with small-molecule inhibition of a constitutively active PI3K located downstream of Ang2. Deletion of Tie receptors or blockade of Ang2 decreased VEGF-C–induced lymphangiogenesis also in adult mice. Our results reveal an important crosstalk between the VEGF-C and Ang signaling pathways and suggest new avenues for therapeutic manipulation of lymphangiogenesis by targeting Ang2/Tie/PI3K signaling.