Oversizing lung allografts deteriorates outcomes in patients with pulmonary fibrosis.

BACKGROUND: Lung transplantation is the only curative treatment for patients with end-stage pulmonary fibrosis. It is still under debate whether over- or undersizing of lung allografts is preferably performed regarding the postoperative outcome. We therefore analyzed our data using predicted total lung capacity to compare size mismatches. METHODS: Patient records were retrospectively reviewed. Three groups were formed, 1 including patients with a donor-recipients pTLC ratio (DRPR) of <1.0 (undersized group), the second with a DRPR of ≥1.0 and <1.1 (size-matched group), and the third group with a DRPR of ≥1.1 (oversized group). Outcomes were evaluated using chi-square test and Kruskall-Wallis test as well as Kaplan-Meier analysis, competing risk analysis, and multivariable analysis, respectively. RESULTS: Between January 2010 and May 2023, among the 1501 patients transplanted at our institution, 422 (28%) patients were included, 26 (2%) patients forming the oversized group (median DRPR: 1.14), 101 (7%) patients forming the size-matched group (median DRPR: 1.03), and 296 (20%) patients forming the undersized group (median DRPR: 0.92). Patients from the oversized group had a higher PGD grade 3 rate at 24 (p < 0.001), 48 (p < 0.001), and 72 (p = 0.039) hours after transplantation as well as a higher in-hospital mortality compared to the undersized group (p = 0.033). The long-term survival was also better in the undersized group compared to the oversized group (p = 0.011) and to the size-matched group (p = 0.01). CONCLUSIONS: Oversizing lung allografts more than 10% deteriorated early postoperative outcomes and long-term survival in patients with pulmonary fibrosis.

Lungs From Donors ≥70 Years of Age for Transplantation-Do Long-Term Outcomes Justify Their Use?

Donor shortages have led transplant centers to extend their criteria for lung donors. Accepting lung donors ≥70 years of age has previously shown good short-term outcomes; however, no mid- and long-term outcome data on these extended criteria donors has been published to date. In this study, all patients who underwent lung transplantation between 06/2010 and 12/2019 were included in the analysis, and the outcomes were compared between patients receiving organs from donors <70 years of age and patients transplanted with lungs from donors ≥70 years of age. Among the 1,168 lung-transplanted patients, 62 patients received lungs from donors ≥70 years of age. The recipient age of those receiving older organs was significantly higher, and they were more likely to suffer from obstructive lung disease. Older donors were exposed to significantly shorter periods of mechanical ventilation prior to donation, had higher Horowitz indices, and were less likely to have smoked. The postoperative time on mechanical ventilation, time on ICU, and total hospital stay were comparable. The overall survival as well as CLAD-free survival showed no differences between both groups in the follow-up period. Utilization of lungs from donors ≥70 years of age leads to excellent mid- and long-term results that are similar to organs from younger donors when the organs from older donors are carefully preselected.

Lung transplantation despite preformed donor-specific antihuman leukocyte antigen antibodies: a 9-year single-center experience.

Pretransplant allosensitization to human leukocyte antigens (HLA) increases the recipient's waiting list time and mortality in lung transplantation. Rather than waiting for crossmatch-negative donors, since 2013, recipients with preformed donor-specific antiHLA antibodies (pfDSA) have been managed with repeated IgA- and IgM-enriched intravenous immunoglobulin (IgGAM) infusions, usually in combination with plasmapheresis before IgGAM and a single dose of antiCD20 antibody. This retrospective study presents our 9-year experience with patients transplanted with pfDSA. Records of patients transplanted between February 2013 and May 2022 were reviewed. Outcomes were compared between patients with pfDSA and those without any de novo donor-specific antiHLA antibodies. The median follow-up time was 50 months. Of the 1,043 patients who had undergone lung transplantation, 758 (72.7%) did not develop any early donor-specific antiHLA antibodies, and 62 (5.9%) patients exhibited pfDSA. Among the 52 (84%) patients who completed treatment, pfDSA was cleared in 38 (73%). In pfDSA vs control patients and at 8-year follow-up, respectively, graft survival (%) was 75 vs 65 (P = .493) and freedom from chronic lung allograft dysfunction (%) was 63 vs 65 (P = .525). In lung transplantation, crossing the preformed HLA-antibody barrier is safe using a treatment protocol based on IgGAM. Patients with pfDSA have a good 8-year graft survival rate and freedom from chronic lung allograft dysfunction, similar to control patients.

Impact of total ischaemic time and disease severity class on graft function after bilateral lung transplantation.

OBJECTIVES: Total ischaemic time (IT) is considered a limiting factor in lung transplantation. In this retrospective study, we investigate effects of IT and disease burden on outcomes after bilateral lung transplantation. METHODS: A total of 1298 patients undergoing bilateral lung transplantation between January 2010 and May 2022 (follow-up 100%, median 54 months) were included. Pre-transplant diseases' severity (recipient body mass index, recipient age, previous lung transplantation, Tacrolimus immunosuppression, preoperative recipient extracorporeal membrane oxygenation support, lung volume reduction) for graft failure was individually calculated and-as IT-categorized. Vice versa adjusted Cox models were calculated. Considering competing risks, we assessed cumulative incidences of airway obstructive complications and chronic lung allograft dysfunction with death as competing risk factors for primary graft dysfunction were assessed by binary logistic regression. RESULTS: Higher disease burden significantly accelerated chronic lung allograft dysfunction and death occurrence (P < 0.001); IT did not. IT-adjusted disease burden strata showed 50% graft survival differences at 11 years after transplantation (range 24-74%), disease burden-adjusted IT strata 18% for all and 6% (54-60%) among those above 7 h. All significant primary graft dysfunction risk factors were diagnoses related, IT was not significantly important and odds ratios did not increase with IT. CONCLUSIONS: The eventual graft survival disadvantage that results from an IT between 7 and at least 11 h is negligible in contrast to frequent recipients' disease-based risk levels.

Towards High Surface Area α-Al2O3-Mn-Assisted Low Temperature Transformation.

When impregnated with manganiferous precursors, γ-Al2O3 may be converted into α-Al2O3 under relatively mild and energy-saving conditions. In this work, a manganese assisted conversion to corundum at temperatures as low as 800 °C is investigated. To observe the alumina phase transition, XRD and solid-state 27Al-MAS-NMR are applied. By post-synthetical treatment in concentrated HCl, residual manganese is removed up to 3 wt.-%. Thereby, α-Al2O3 with a high specific surface area of 56 m2 g-1 is obtained after complete conversion. Just as for transition alumina, thermal stability is an important issue for corundum. Long-term stability tests were performed at 750 °C for 7 days. Although highly porous corundum was synthesized, the porosity decreased with time at common process temperatures.

Minimally Invasive Mitral Valve Surgery in the Elderly.

BACKGROUND: The minimally invasive mitral valve procedure warrants minimal surgical trauma and might influence the postoperative course positively, especially in old patients. In this retrospective study, we reviewed our experience in minimally invasive mitral valve surgery (miMVS) in patients aged ≥ 75 years. METHODS: In this retrospective cohort study, based on propensity score matching, we compared patients aged ≥75 years with patients aged <75 years who underwent miMVS. The primary endpoint was 30-day mortality. Secondary endpoints were myocardial infarction, stroke, and renal failure. RESULTS: Between January 2011 and February 2021, 761 patients underwent miMVS at our institution. After propensity score matching, a study group (≥75 years, n = 189) and a control group (<75 years, n = 189) were formed. Preoperatively patients ≥75 years more often suffered from NYHA III heart failure (60 vs. 46%; p = 0.013). Their valves were more often frequently replaced (48 vs. 32%; p < 0.001), and their postoperative ventilation time was longer (13 hours vs. 11 hours; p < 0.001). There were no statistically significant differences regarding postoperative stroke (3 vs. 0.6%; p = 0.16), myocardial infarction (0 vs. 1%; p = 0.32), renal insufficiency with new dialysis (5 vs. 4%; p = 0.62), and 30-day mortality (4 vs. 2%; p = 0.56). CONCLUSION: miMVS results in satisfactory early postoperative outcomes in elderly patients.

Does donor-recipient age mismatch have an influence on outcome after lung transplantation? A single-centre experience.

OBJECTIVES: Lack of organ donors demands transplantation of older lung allografts for recipients between 0 and 50 years. So far, it has not yet been investigated whether donor-recipient age mismatch affects long-term outcome. METHODS: Records of patients aged between 0 and 50 years were retrospectively reviewed. Donor-recipient age mismatch was calculated subtracting recipient age from donor age. Multivariable Cox regression analyses was performed to assess donor-recipient age mismatch regarding the end points' overall patient mortality, mortality conditioned to hospital discharge, biopsy-confirmed rejection and chronic lung allograft dysfunction. Furthermore, we performed competing risk analysis to analyse if age mismatch affects biopsy-confirmed rejection and CLAD while death being a competing risk. RESULTS: Between January 2010 and September 2021, out of 1363 patients who underwent lung transplantation at our institution, 409 patients fulfilled the eligibility criteria and were included. Age mismatch ranged between 0 and 56 years. Multivariable analysis revealed that donor-recipient age mismatch does not affect overall patient mortality (P = 0.19), biopsy-confirmed rejection (P = 0.68) and chronic lung allograft dysfunction (P = 0.42). There was no difference seen in CLAD (P = 0.166) and biopsy-confirmed rejection (P = 0.944) with the competing risk death (P = 0.765 and P = 0.851; respectively). CONCLUSIONS: Age mismatch between recipients and donors of lung allografts does not affect long-term outcomes after lung transplantation.

Lung transplant and severe coronary artery disease: results from a single-centre experience.

OBJECTIVES: The management of severe coronary artery disease at the time of a lung transplant remains a challenge. We analysed the short- and long-term outcomes of lung transplant recipients with severe coronary artery disease. METHODS: Records of adult patients who received transplants at our institution between April 2010 and February 2021 were reviewed retrospectively. Severe coronary artery disease was defined as coronary stenosis ≥70% (main stem ≥50%) seen on the coronary angiographic scans performed before or at the time of listing. Patient characteristics, perioperative and long-term outcomes were compared between patients with and without severe coronary artery disease. RESULTS: Among 896 patients who received lung transplants who had undergone coronary angiography before the transplant, 77 (8.5%) had severe coronary artery disease; the remaining 819 (91.5%) did not. Patients with severe coronary artery disease were older (p < 0.0001), more often male (p < 0.0001) and received transplants more often for pulmonary fibrosis (p = 0.0007). The median (interquartile range) follow-up was 46 (20-76) months. At the Cox multivariable analysis, severe coronary artery disease was not associated with death. Patients with pretransplant percutaneous transluminal coronary angioplasty and patients with coronary artery bypass graft surgery concomitant to a transplant had survival equivalent to that of patients without severe coronary artery disease (p = 0.513; p = 0.556). CONCLUSIONS: Severe coronary artery disease was not associated with decreased survival after a lung transplant. Concomitant coronary artery bypass graft surgery and pretransplant percutaneous transluminal coronary angioplasty can be used for revascularization.

Chronic unilateral arm lymphedema correlates with increased intima-media thickness in the brachial artery.

Drainage of the arterial wall via adventitial lymphatic vessels has been shown to play a pivotal role for vessel wall homeostasis. Also, retrograde cholesterol transport is ensured via this route, but no studies exist to demonstrate that lymphatic stasis would represent a mechanism to initiate atherosclerotic lesion formation in human arteries. To test this hypothesis, we embarked on a simple clinical experiment, assessing wall thickness in limb arteries with lymphedema after surgical intervention, with the contralateral limb serving as control. Using ultrasound imaging, the differential thickness was assessed separately for the three arterial wall layers. The potential of disease progression by lymphostasis was addressed by depiction of longitudinal results according to the time after lymph dissection.

Indications and outcome after lung transplantation in children under 12 years of age: A 16-year single center experience.

OBJECTIVE: Paediatric lung transplantation poses unique management challenges. Experience regarding indications and outcome is scarce, especially in younger children. The primary aim of this study was to investigate outcome after first lung transplantation in children <12 years of age in comparison to adolescents (12-17 years old). METHODS: Records of patients <18 years who underwent first lung transplantation between 01/2005 and 01/2021 were retrospectively reviewed, and compared between children <12 years old and adolescents. Median (IQR) follow-up was 51 (23-91) months. RESULTS: Of the 117 patients underwent first lung transplantation at our institution, of whom 42 (35.8%) patients were <12 years and 75 (64.2%) ≥12 years old. Compared to adolescents, children were more often transplanted for interstitial lung disease (33.3% vs 12%, p = 0.005) and precapillary pulmonary hypertension (28.6% vs 12%, p = 0.025), and required more often intraoperative cardiopulmonary bypass (31% vs 14.7%, p = 0.036) and postoperative ECMO support (47.6% vs 13.3%, p < 0.001). Postoperatively, children required longer ventilation times (78 vs 18 hours, p = 0.009) and longer ICU stay (9.5 vs 3 days, p < 0.001) compared to their older counterparts. Primary graft dysfunction grade 3 at 72 hours (9.5% vs 9.3%, p = 0.999), in-hospital mortality (2.4% vs 6.7%, p = 0.418), graft survival (80% vs 62%, p = 0.479) and freedom from chronic lung allograft dysfunction (76% vs 59%, p = 0.41) at 8-year follow-up did not differ between groups. CONCLUSIONS: Lung transplantation in children under 12 years is challenging due to underlying medical conditions and operative complexity. Nevertheless, outcomes are comparable to those in older children.

The Belgica 121 expedition to the Western Antarctic Peninsula: a detailed biodiversity census.

BACKGROUND: This dataset relates to the biodiversity census carried out during the Belgica 121 (B121) expedition to the Western Antarctic Peninsula from February to March 2019. One of the aims of the campaign was to explore the surroundings of the Gerlache Strait and to carry out a detailed biodiversity census focusing on inter- and subtidal shallow-water areas using both classic descriptive marine ecology methods, as well as state-of-the art techniques (habitat mapping, genetics, trophic ecology). The biodiversity census was carried out onboard a nimble research vessel, RV Australis. This dataset will offer access to the raw data on biodiversity occurrences, obtained using a range of methods described in this data paper. NEW INFORMATION: New raw biodiversity data for a poorly-sampled region (Western Antarctic Peninsula) with a special focus on shallow ecosystems.

Not Frozen in the Ice: Large and Dynamic Rearrangements in the Mitochondrial Genomes of the Antarctic Fish.

The vertebrate mitochondrial genomes generally present a typical gene order. Exceptions are uncommon and important to study the genetic mechanisms of gene order rearrangements and their consequences on phylogenetic output and mitochondrial function. Antarctic notothenioid fish carry some peculiar rearrangements of the mitochondrial gene order. In this first systematic study of 28 species, we analyzed known and undescribed mitochondrial genome rearrangements for a total of eight different gene orders within the notothenioid fish. Our reconstructions suggest that transpositions, duplications, and inversion of multiple genes are the most likely mechanisms of rearrangement in notothenioid mitochondrial genomes. In Trematominae, we documented an extremely rare inversion of a large genomic segment of 5,300 bp that partially affected the gene compositional bias but not the phylogenetic output. The genomic region delimited by nad5 and trnF, close to the area of the Control Region, was identified as the hot spot of variation in Antarctic fish mitochondrial genomes. Analyzing the sequence of several intergenic spacers and mapping the arrangements on a newly generated phylogeny showed that the entire history of the Antarctic notothenioids is characterized by multiple, relatively rapid, events of disruption of the gene order. We hypothesized that a pre-existing genomic flexibility of the ancestor of the Antarctic notothenioids may have generated a precondition for gene order rearrangement, and the pressure of purifying selection could have worked for a rapid restoration of the mitochondrial functionality and compactness after each event of rearrangement.

AAV-mediated AP-1 decoy oligonucleotide expression inhibits aortic elastolysis in a mouse model of Marfan syndrome.

AIMS: Marfan syndrome is one of the most common inherited disorders of connective tissue caused by fibrillin-1 mutations, characterized by enhanced transcription factor AP-1 DNA binding activity and subsequently abnormally increased expression and activity of matrix-metalloproteinases (MMPs). We aimed to establish a novel adeno-associated virus (AAV)-based strategy for long-term expression of an AP-1 neutralizing RNA hairpin (hp) decoy oligonucleotide (dON) in the aorta to prevent aortic elastolysis in a murine model of Marfan syndrome. METHODS AND RESULTS: Using fibrillin-1 hypomorphic mice (mgR/mgR), aortic grafts from young (9 weeks old) donor mgR/mgR mice were transduced ex vivo with AAV vectors and implanted as infrarenal aortic interposition grafts in mgR/mgR mice. Grafts were explanted after 30 days. For in vitro studies, isolated primary aortic smooth muscle cells (SMCs) from mgR/mgR mice were used. Elastica-van-Giesson staining visualized elastolysis, reactive oxygen species (ROS) production was assessed using dihydroethidine staining. RNA F.I.S.H. verified AP-1 hp dON generation in the ex vivo transduced aortic tissue. MMP expression and activity were assessed by western blotting and immunoprecipitation combined with zymography.Transduction resulted in stable therapeutic dON expression in endothelial and SMCs. MMP expression and activity, ROS formation as well as expression of monocyte chemoattractant protein-1 were significantly reduced. Monocyte graft infiltration declined and the integrity of the elastin architecture was maintained. RNAseq analysis confirmed the beneficial effect of AP-1 neutralization on the pro-inflammatory environment in SMCs. CONCLUSION: This novel approach protects from deterioration of aortic stability by sustained delivery of nucleic acids-based therapeutics and further elucidated how to interfere with the mechanism of elastolysis.

Species integrity, introgression, and genetic variation across a coral reef fish hybrid zone.

Hybridization and introgression are evolutionarily significant phenomena breaking down species boundaries. "Hybrid zones" (regions of species overlap and hybridization) enable quantification of hybridization frequency and examination of mechanisms driving and maintaining gene flow. The hybrid anemonefish Amphiprion leucokranos is found where parent species (A. chrysopterus; A. sandaracinos) distributions overlap. Here, we examine geographic variation in hybridization and introgression, and potential impacts on parent species integrity through assessing relative abundance, social group composition, and genetic structure (mtDNA cytochrome b, 21 microsatellite loci) of taxa at three hybrid zone locations: Kimbe Bay (KB) and Kavieng (KA), Papua New Guinea; the Solomon Islands (SO). Relative abundances of and size disparities between parent species apparently drive hybridization frequency, introgression patterns, and genetic composition of taxa. Conspecific groups are most common in KB (65%) where parent species are similarly abundant. Conversely, mixed species groups dominate SO (82%), where A. chrysopterus is more abundant. Hybrids most commonly cohabit with A. sandaracinos in KB (17%), but with A. chrysopterus in KA (22%) and SO (50%). Genetic differentiation (nDNA) analyses indicate that parent species remain distinct, despite ongoing hybridization and hybrids are genetically similar to A. sandaracinos-resulting from persistent backcrossing with this smallest species. This study shows that hybridization outcomes may depend on the social and ecological context in which taxa hybridize, where relative abundance and disparate size of parent species explain the frequency and patterns of hybridization and introgression in the A. leucokranos hybrid zone, reflecting size-based dominance behaviors of anemonefish social groups.

Pregnancy rates after slow-release insemination (SRI) and standard bolus intrauterine insemination (IUI) - A multicentre randomised, controlled trial.

This multicentre, randomised, controlled cross-over trial was designed to investigate the effect of intra-uterine slow-release insemination (SRI) on pregnancy rates in women with confirmed infertility or the need for semen donation who were eligible for standard bolus intra-uterine insemination (IUI). Data for a total of 182 women were analysed after randomisation to receive IUI (n = 96) or SRI (n = 86) first. The primary outcome was serological pregnancy defined by a positive beta human chorionic gonadotropin test, two weeks after insemination. Patients who did not conceive after the first cycle switched to the alternative technique for the second cycle: 44 women switched to IUI and 58 switched to SRI. In total, there were 284 treatment cycles (IUI: n = 140; SRI: n = 144). Pregnancy rates following SRI and IUI were 13.2% and 10.0%, respectively, which was not statistically significant (p = 0.202). A statistically significant difference in pregnancy rates for SRI versus IUI was detected in women aged under 35 years. In this subgroup, the pregnancy rate with SRI was 17% compared to 7% with IUI (relative risk 2.33; p = 0.032) across both cycles. These results support the hypothesis that the pregnancy rate might be improved with SRI compared to standard bolus IUI, especially in women aged under 35 years.

AAV-mediated TIMP-1 overexpression in aortic tissue reduces the severity of allograft vasculopathy in mice.

BACKGROUND: Allograft vasculopathy (AV) is the primary limiting factor for long-term graft survival. An increased activity of matrix metalloproteinases (MMPs) contributes to neointima formation in AV and represents a potential therapeutic target. Adeno-associated virus (AAV)-mediated gene therapy comprises a potentially benign vector model for the long-term expression of MMP antagonists. METHODS: Aortic allografts from DBA/2 mice were incubated with control buffer, AAV-enhanced green fluorescence protein (EGFP), or tissue inhibitor of metalloproteinases 1 (TIMP-1)-loaded AAV (AAV-TIMP-1) and transplanted into the infrarenal aorta of C57BL/6 mice. Cyclosporine A (10 mg/kg body weight) was administered daily. Explantation as well as histomorphometric and immunohistochemical evaluation was performed after 30 days. Matrix metalloproteinase (MMP) activity was visualized by gelatin in situ zymography. RESULTS: Intima-to-media area ratio and neointima formation were significantly reduced in the AAV-TIMP-1 treatment group compared with those in the control group (by 40%; p < 0.001) and the AAV-EGFP group (by 38.2%; p < 0.001). TIMP-1 overexpression positively affected several pathomechanisms for the development of AV both in vitro and in vivo as compared to that in the control groups: endothelium integrity was preserved as shown by zona occludens 1 and occludin staining; MMP9 expression and activity were significantly reduced (p = 0.01); and smooth muscle cell migration was significantly reduced as smooth muscle actin positive cells predominantly remained in the aortic media in the treatment group (p = 0.001). Moreover, macrophage infiltration was markedly reduced by 49% in the AAV-TIMP-1 group (p < 0.001). CONCLUSION: Immediate post-harvesting allograft incubation with AAV-TIMP-1 reduces neointima formation and macrophage infiltration, constituting a possible adjunct therapeutic strategy to preserve graft function after transplantation.

Short and long-term metabolic outcomes in patients with type 1 and type 2 diabetes receiving a simultaneous pancreas kidney allograft.

BACKGROUND: In contrast to insulin-dependent type 1 diabetes mellitus (T1DM), the indication for Simultaneous pancreas-kidney transplantation (SPK) in patients with type 2 diabetes mellitus (T2DM) is still ambiguous and wisely Eurotransplant (ET) only granted transplant-permission in a selected group of patients. However, with regard to improvement of metabolic conditions SPK might still be a considerable treatment option for lean insulin dependent type 2 diabetics suffering from renal disease. METHODS: Medical data (2001-2013) from all consecutive T1DM and T2DM patients who received a SPK or kidney transplant alone (KTA) at the University Hospital of Leipzig were analyzed. Donor, recipients and long-term endocrine, metabolic and graft outcomes were investigated for T1DM and T2DM-SPK recipients (transplanted upon a special request allocation by ET) and T2DM patients who received a KTA during the same period. RESULTS: Eighty nine T1DM and 12 T2DM patients received a SPK and 26 T2DM patients received a KTA. Patient survival at 1 and 5 years was 89.9 and 88.8% for the T1DM group, 91.7 and 83.3% for the T2DM group, and 92.3 and 69.2% for the T2DM KTA group, respectively (p < 0.01). Actuarial pancreas graft survival for SPK recipients at 1 and 5 years was 83.1 and 78.7% for the T1DM group and 91.7 and 83.3% for the T2DM group, respectively (p = 0.71). Kidney allograft survival at 5 years was 79.8% for T1DM, 83.3% for T2DM, and 65.4% for T2DM KTA (p < 0.01). Delayed graft function (DGF) rate was significantly higher in type 2 diabetics received a KTA. Surgical, immunological and infectious complications showed similar results for T1DM and T2DM recipients after SPK transplant and KTA, respectively. With regard to the lipid profile, the mean high-density lipoprotein (HDL)- cholesterol levels were significantly higher in T1DM recipients compared to T2DM patients before transplantation (p = 0.02) and remained significantly during follow up period. CONCLUSION: Our data demonstrate that with regard to metabolic function a selected group of patients with T2DM benefit from SPK transplantation. Consensus guidelines and further studies for SPK transplant indications in T2DM patients are still warranted.

STEP as a Useful Tool to Screen for Diabetes-Specific Health-Related Problems in Community-Based Geriatric Patients- An Exploratory Secondary Analysis of Cross-Sectional Data.

BACKGROUND AND AIMS: Comprehensive geriatric assessments are established tools for the identification of health problems in the elderly. So far, little is known about tailoring and targeting to facilitate their application. As a starting point for a tailored assessment of patients with diabetes, a highly prevalent health condition, we aimed to assess if the Standardized Assessment of Elderly People (STEP) is able to identify relevant differences in self-reported health problems between diabetic and non-diabetic patients. PATIENTS AND METHODS: We performed a secondary analysis of a cross-sectional study including 1007 adults (aged 65 and older) from 28 German general practices, evaluating the feasibility and usefulness of the self-administered STEP version. For this exploratory study we re-analysed the data and compared patients with and without diabetes. RESULTS: Out of 940 patients included in the secondary analysis, 248 (26.4%) had diabetes. Compared to non-diabetic patients, geriatric diabetic patients reported more often problems in activities of daily living, physical problems typically associated with diabetes such as urinary incontinence, visual impairment, mood disturbances, as well as the use of medical or social services. Most of our results were stable after adjusting for age, sex and body mass index. CONCLUSION: We conclude that the self-administered version of the STEP tool may be used to screen for health problems typically associated with diabetes. Our results may guide the development of a tailored STEP-version specifically for diabetic patients. Further research might evaluate the adoption and usefulness of such a tool in every-day general practice.

AAV-Mediated Expression of AP-1-Neutralizing RNA Decoy Oligonucleotides Attenuates Transplant Vasculopathy in Mouse Aortic Allografts.

Transplant vasculopathy (TV), characterized by obstructive lesions in affected vessels, represents one of the long-term complications of cardiac transplantation. Activation of the transcription factor activator protein-1 (AP-1) is implicated in smooth muscle cell (SMC) phenotypic switch from contractile to synthetic function, increasing the migration and proliferation rate of these cells. We hypothesize that adeno-associated virus (AAV)-mediated delivery of an RNA hairpin AP-1 decoy oligonucleotide (dON) might effectively ameliorate TV severity in a mouse aortic allograft model. Aortic allografts from DBA/2 mice ex vivo transduced with modified AAV9-SLR carrying a targeting peptide within the capsid surface were transplanted into the infrarenal aorta of C57BL/6 mice. Cyclosporine A (10 mg/kg BW) was administered daily. AP-1 dONs were intracellularly expressed in the graft tissue as small hairpin RNA proved by fluorescent in situ hybridization. Explantation after 30 days and histomorphometric evaluation revealed that AP-1 dON treatment significantly reduced intima-to-media ratio by 41.5% (p < 0.05) in the grafts. In addition, expression of adhesion molecules, cytokines, as well as numbers of proliferative SMCs, matrix metalloproteinase-9-positive cells, and inflammatory cell infiltration were significantly decreased in treated aortic grafts. Our findings demonstrate the feasibility, efficacy, and specificity of the anti-AP-1 RNA dON approach for the treatment of allograft vasculopathy in an animal model. Moreover, the AAV-based approach in general provides the possibility to achieve a prolonged delivery of nucleic-acids-based therapeutics in to the blood vessel wall.

Immunological Alterations due to Hemodialysis Might Interfere with Early Complications in Renal Transplantation.

BACKGROUND: Chronic or intercurrent alterations of the immune system in patients with end-stage renal disease (CKD) and intermittent hemodialysis (CKD5D, HD) have been attributed to an acute rejection of renal allograft. METHODS: Leukocyte subsets in flow cytometry, complement activation, and concentrations of TGFß, sCD30 (ELISA), and interleukins (CBA) of fifteen patients eligible for renal transplantation were analyzed before, during, and after a regular HD. RESULTS: Before HD, the median proportion of CD8+ effector cells, CD8+ CCR5+ effector cells, and HLA-DR+ regulatory T cells as well as the median concentration of soluble CD30 increased and naive CD8+ T cells decreased. During HD, there was a significant decrease in CD4- CD8- T cells (p < 0.001) and an increase in CD25+ T cells (p = 0.026), sCD30 (p < 0.001), HLA-DR+ regulatory T cells (p = 0.005), and regulatory T cells (p = 0.003). TGFß and sCD30 increased significantly over time. The activity of the classical complement pathway started to slightly increase after the first hour of HD and lasted until fifteen minutes after finishing dialysis. The decrease in the functional activity of the alternative pathway was only transient and was followed by a significant increase within 15 minutes after finishing the treatment. CONCLUSION: HD might interact with the allograft outcome by influencing T cell subsets and activation of the complement system in a biphasic course.