Addressing path dependencies in decision-making processes for operationalizing compound climate-risk management.

The need for a compound risk governance system and management practice is argued in this paper. We find that, historically, risk management strategies have been developed for single hazards and are often subject to path dependency. It is thus difficult to adapt them to a situation that has compound risks. The lack of attention to compound risks in current risk management practices often leads to potential side effects-positive or negative-on other risks and can also result in related management strategies being overlooked. This can ultimately cause barriers to larger transformational adaptation efforts and lead to the intensification of existing societal inequalities or to the creation of new ones. To alert policy- and decision-makers to the need to move toward compound-risk management strategies, we argue that risk management must explicitly highlight various elements of path dependencies, the positive and negative side effects of single-hazard risk management, the appearance of new social inequalities, and the intensification of existing ones.

How path dependency manifests in flood risk management: observations from four decades in the Ennstal and Aist catchments in Austria.

Path dependency occurs when a contingent event predetermines what further steps can be taken and self-reinforcing mechanisms lock-in any further development on a sub-optimal trajectory. Path dependency is a prominent concept in the adaptation pathways literature, but insufficiently defined and operationalised. The present paper empirically tracks all constitutive elements of path dependency for four decades of flood risk management (FRM) in two alpine mountain regions in Austria, the Ennstal and Aist river catchments, using a mixed-methods approach. FRM governance has a critical role whether decisions lead to path dependency. Lock-in manifests not just in technical structures, but also in inertia of incumbent actor coalitions and management paradigms. Sub-optimality is hard to assess for lack of clearly defined protection targets; however, it appears in the ways that structural measures are implemented-too little, too late or with negative impacts on nature conservation. Past floods do not qualify as contingent events, as they have not fundamentally changed FRM practice. By contrast, technological and institutional shifts over longer periods, such as digital hazard maps and EU directives, have gradually reoriented FRM strategies. Institution-based self-reinforcing mechanisms are more prevalent than technology-based self-reinforcing mechanisms. Established actor coalitions combined with institutional density illustrate how those in charge uphold a path to defend their position, power and resources. Our recommendations for how to overcome path dependency in FRM governance are: encourage niche experiments, link FRM more closely with climate change adaptation, revise the national policy framework towards polycentric governance approaches and improve professional training.

Outcome of necrotizing fasciitis and Fournier's gangrene with and without hyperbaric oxygen therapy: a retrospective analysis over 10 years.

BACKGROUND: Necrotizing soft tissue infections (NSTI) require immediate radical debridement, broad-spectrum antibiotics and intensive care. Hyperbaric oxygen therapy (HBOT) may be performed adjunctively, but unequivocal evidence for its benefits is still lacking. METHODS: We performed a retrospective single-center study including 192 patients with necrotizing fasciitis or Fournier's gangrene to assess in-hospital mortality and outcome dependent on patient, disease and treatment characteristics with or without HBOT. RESULTS: The in-hospital mortality rate was 27.6%. Factors associated with increased mortality according to multivariate analysis were higher age, affection of multiple or problem localizations (odds ratio (OR) = 2.88, P = 0.003), ineligibility for HBOT despite clinical indication (OR = 8.59, P = 0.005), pathogens in blood cultures (OR = 3.36, P = 0.002), complications (OR = 10.35, P < 0.001) and sepsis/organ dysfunction (OR = 19.58, P < 0.001). Factors associated with better survival included vacuum-assisted wound closure (OR = 0.17, P < 0.001), larger number of debridements (OR = 0.83, P < 0.001) and defect closure with mesh graft (OR = 0.06, P < 0.001) or flap (OR = 0.09, P = 0.024). When participants were stratified into subgroups without requirement of HBOT (n = 98), treated with HBOT (n = 83) and ineligible for HBOT due to contraindications (n = 11), the first two groups had similar survival rates (75.5% vs. 73.5%) and comparable outcome, although patients with HBOT suffered from more severe NSTI, reflected by more frequent affection of multiple localizations (P < 0.001), sepsis at admission (P < 0.001) and intensive care treatment (P < 0.001), more debridements (P < 0.001) and a larger number of antibiotics (P = 0.001). In the subgroup ineligible for HBOT, survival was significantly worse (36.4%, P = 0.022). CONCLUSION: These results point to a benefit from HBOT for treatment of NSTI in critically ill patients.

Gestational diabetes mellitus modulates cholesterol homeostasis in human fetoplacental endothelium.

Gestational diabetes mellitus (GDM) is associated with excessive oxidative stress which may affect placental vascular function. Cholesterol homeostasis is crucial for maintaining fetoplacental endothelial function. We aimed to investigate whether and how GDM affects cholesterol metabolism in human fetoplacental endothelial cells (HPEC). HPEC were isolated from fetal term placental arterial vessels of GDM or control subjects. Cellular reactive oxygen species (ROS) were detected by H2DCFDA fluorescent dye. Oxysterols were quantified by gas chromatography-mass spectrometry analysis. Genes and proteins involved in cholesterol homeostasis were detected by real-time PCR and immunoblotting, respectively. Cholesterol efflux was determined from [3H]-cholesterol labeled HPEC and [14C]-acetate was used as cholesterol precursor to measure cholesterol biosynthesis and esterification. We detected enhanced formation of ROS and of specific, ROS-derived oxysterols in HPEC isolated from GDM versus control pregnancies. ROS-generated oxysterols were simultaneously elevated in cord blood of GDM neonates. Liver-X receptor activation in control HPEC by synthetic agonist TO901319, 7-ketocholesterol, or 7ß-hydroxycholesterol upregulated ATP-binding cassette transporters (ABC)A1 and ABCG1 expression, accompanied by increased cellular cholesterol efflux. Upregulation of ABCA1 and ABCG1 and increased cholesterol release to apoA-I and HDL3 (78 ±â€¯17%, 40 ±â€¯9%, respectively) were also observed in GDM versus control HPEC. The LXR antagonist GGPP reversed ABCA1 and ABCG1 upregulation and reduced the increased cholesterol efflux in GDM HPEC. Similar total cellular cholesterol levels were detected in control and GDM HPEC, while GDM enhanced cholesterol biosynthesis along with upregulated 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) and sterol O-acyltransferase 1 (SOAT1) mRNA and protein levels. Our results suggest that in GDM cellular cholesterol homeostasis in the fetoplacental endothelium is modulated via LXR activation and helps to maintain its proper functionality.

Maternal Gestational Diabetes Mellitus increases placental and foetal lipoprotein-associated Phospholipase A2 which might exert protective functions against oxidative stress.

Increased Lipoprotein associated phospholipase A2 (LpPLA2) has been associated with inflammatory pathologies, including Type 2 Diabetes. Studies on LpPLA2 and Gestational Diabetes Mellitus (GDM) are rare, and have focused mostly on maternal outcome. In the present study, we investigated whether LpPLA2 activity on foetal lipoproteins is altered by maternal GDM and/or obesity (a major risk factor for GDM), thereby contributing to changes in lipoprotein functionality. We identified HDL as the major carrier of LpPLA2 activity in the foetus, which is in contrast to adults. We observed marked expression of LpPLA2 in placental macrophages (Hofbauer cells; HBCs) and found that LpPLA2 activity in these cells was increased by insulin, leptin, and pro-inflammatory cytokines. These regulators were also increased in plasma of children born from GDM pregnancies. Our results suggest that insulin, leptin, and pro-inflammatory cytokines are positive regulators of LpPLA2 activity in the foeto-placental unit. Of particular interest, functional assays using a specific LpPLA2 inhibitor suggest that high-density lipoprotein (HDL)-associated LpPLA2 exerts anti-oxidative, athero-protective functions on placental endothelium and foetus. Our results therefore raise the possibility that foetal HDL-associated LpPLA2 might act as an anti-inflammatory enzyme improving vascular barrier function.

Human Placental Hofbauer Cells Maintain an Anti-inflammatory M2 Phenotype despite the Presence of Gestational Diabetes Mellitus.

BACKGROUND: Hofbauer cells (HBCs) are macrophages of the feto-placental unit. Despite the general view that these cells have an anti-inflammatory M2 phenotype, recent studies have claimed that pregnancy pathologies-e.g., gestational diabetes mellitus (GDM)-cause a switch from an M2 to an M1 pro-inflammatory phenotype in HBCs. The pilot-study presented here challenges this claim, showing that HBCs maintain anti-inflammatory properties in spite of the hyperglycemic, low-grade inflammatory environment of GDM. METHODS: HBCs were isolated from placentae of healthy women (N = 5) and women with GDM (N = 6) diagnosed in the second trimester. FACS was used to measure surface markers associated with either M1 or M2 phenotype on the cells. In addition, placental tissue sections were subjected to immune histochemical imaging to assess the phenotype within the tissue context. Supernatant from control and GDM HBCs was collected at defined time points and used in a multiplex ELISA-on-beads approach to assess secretion of cytokines, chemokines, and growth factors. The effect of HBC cell culture supernatant on placental endothelial activation was investigated. RESULTS: FACS and immune staining showed that, indeed, M2 markers, such as CD206 and CD209, are increased in HBCs isolated from GDM placentae. Also, the M1 marker CD86 was increased, but only by trend. Secretion of numerous cytokines, chemokines and growth factors was not changed; pro-inflammatory interleukin (IL)-1ß and IL-6 release form GDM HBC was increased but not significant. Exposure to GDM HBC supernatant did not induce cell adhesion molecules (VCAM-1, selectins, vascular endothelial-cadherin) in placental endothelial cells compared to supernatant from control HBCs, an induction of intracellular adhesion molecule 1 was observed however. CONCLUSION: Our study-although performed in a small set of patients-shows that placental macrophages maintain their anti-inflammatory, tissue remodeling M2 phenotype even in pregnancies affected by gestational diabetes. This consistent phenotype might be important for propagation of maternal tolerance toward the fetus and for protection of the fetus from a low-grade inflammatory environment.

De novo HNF-1 beta gene mutation in familial hypoplastic glomerulocystic kidney disease.

Mutations in the gene encoding the transcription factor hepatocyte nuclear factor (HNF)-1 beta are associated with maturity-onset diabetes of the young (type V), non-diabetic renal disease, and occasionally genital malformations in females. Recently, familial hypoplastic glomerulocystic kidney disease (GCKD) has been added to the clinical spectrum of HNF-1 beta gene mutations. Familial hypoplastic GCKD is a rare, dominantly inherited disorder characterized by small kidneys containing glomerular cysts, abnormal pelvicalyceal anatomy, and chronic renal failure. A family with hypoplastic GCKD occurring in the father and the daughter was screened for mutations in the HNF-1 beta gene. The sequence of exon 4 of the HNF-1 beta gene revealed a C insertion at codon 334 resulting in a frameshift mutation (P334fsinsC) in two family members. The P334fsinsC allele co-segregated with hypoplastic GCKD in the family. Oral glucose tolerance testing was normal in the 11-year-old girl. In her 38-year-old father, impaired glucose tolerance was detected. These studies provide further evidence that familial hypoplastic GCKD is associated with HNF-1 beta gene mutations. HNF-1 beta gene mutation screening may prove useful in patients with small cystic kidneys and chronic renal failure, in whom a definite renal diagnosis could otherwise only be established by renal biopsy.