"Iatrogenicity cascade": doing harm by treating harm?

An electronic survey on substance-induced epileptic crisis was conducted in order to investigate whether doctors, who recognise their own prescription errors, increase their therapeutic aggressiveness, resulting in a so-called "iatrogenicity cascade". Two pairs of clinical vignettes were constructed, in which a patient suffers from iatrogenic (original version) or non-iatrogenic (control version) epileptic crisis. Vignettes were randomised and sent to doctors at the University Hospital of Lausanne, Switzerland, at an interval of 3 weeks. The results of the present survey in the surveyed population of doctors suggest that inappropriate prescription does not increase therapeutic aggressiveness.

City of Cascade, June 30, 2002

City Audit Report

Cascade Municipal Utilities, June 30, 2002

City Audit Report

Volutrauma activates the clotting cascade in the newborn but not adult rat.

Coagulopathy and alveolar fibrin deposition are common in sick neonates and attributed to the primary disease, as opposed to their ventilatory support. Hypothesizing that high tidal volume ventilation activates the extrinsic coagulation pathway, we air ventilated newborn and adult rats at low (10 ml/kg) or high (30 ml/kg) tidal volume and compared them with age-matched nonventilated controls. Blood was collected at the end of the experiment for measurement of clot time, tissue factor, and other coagulation factor content. Similar measurements were obtained from lung lavage material. The newborn clot time (44+/-1) was lower and plasma tissue factor content higher (103.4+/-0.4) than adults (88+/-4 s and 26.6+/-1.4 units; P<0.01). High, but not low, tidal volume ventilation of newborns for as little as 15 min significantly reduced clot time and increased plasma tissue factor content (P<0.01). High volume ventilation increased plasma factor Xa (0.1+/-0.1 to 1.6+/-0.4 nM; P<0.01) and thrombin (1.3+/-0.2 to 2.2+/-0.4 nM; P<0.05) and decreased antithrombin (0.12+/-0.01 to 0.05+/-0.01; P<0.01) in the newborn. Lung lavage material of high volume-ventilated newborns showed increased (P<0.01) factor Xa and thrombin. No changes in these parameters were observed in adult rats that were high volume ventilated for up to 90 min. Compared with adults, newborn rats have a greater propensity for volutrauma-activated intravascular coagulation. These data suggest that mechanical ventilation promotes neonatal thrombosis via lung tissue factor release.

Textural, chemical, and isotopic effects of late-magmatic carbonatitic fluids in the carbonatite-syenite Tamazeght complex, High Atlas Mountains, Morocco

Carbonatites of the Eocene Tamazeght complex, High Atlas Mountains, Morocco, consist of calciocarbonatites (alvikite and sovite dykes) and magnesiocarbonatites (diatreme breccias and dykes rocks). These are associated with ultramafic, shonkinitic, gabbroic to monzonitic and various foid syenitic silicate units. Stable and radiogenic isotope compositions for carbonatites and silicate rocks indicate that they share a common source in the mantle, although for some carbonatitic samples contamination with sedimentary rocks seems important. The observed isotopic heterogeneity is mainly attributed to source characteristics, fractional crystallization (accompanied by various degrees of assimilation), and late- to post-magmatic fluid-rock interaction. During the late fluid-rock interaction, Sr, Mn, and possibly also Fe were mobilized and redistributed to form secondary carbonate minerals in carbonatites. These fluids also penetrated into the adjacent syenitic rocks, causing enrichment in the same elements.

Anachronistic facies from a drowned Lower Triassic carbonate platform: Lower member of the Alwa Formation (Ba'id Exotic), Oman Mountains

- The lower member of the Alwa Formation (Lower Olenekian), found within the Ba'id Exotic in the Oman Mountains (Sultanate of Oman), consists of ammonoid-bearing, pelagic limestones that were deposited on an isolated, drowned carbonate platform on the Neotethyan Gondwana margin. The strata contain a variety of unusual carbonate textures and features, including thrombolites, Frutexites-bearing microbialites that contain synsedimentary cements, matrix-free breccias surrounded by isopachous calcite cement, and fissures and cavities filled with large botryoidal cements. Thrombolites are found throughout the study interval, and occur as 0.5-1.0 m thick lenses or beds that contain laterally laterally-linked stromatactis cavities. The Frutexites-bearing microbialites occur less frequently, and also form lenses or beds, up to 30 cm thick; the microbialites may be laminated, and often developed on hardgrounds. In addition, the Frutexites-bearing microbialites also contain synsedimentary calcite cement crusts and botryoids (typically <1 cm thick) that harbour layers or pockets of what appear to be bacterial sheaths and coccoids, and are indicative of biologically mediated precipitation of the cement bodies. Slumping following lithification led to fracturing of the limestone and the precipitation of large, botryoidal aragonite cements in fissures that cut across the primary fabric. Environmental conditions, specifically palaeoxygenation and the degree of calcium carbonate supersaturation, likely controlled whether the thrombolites (high level of calcium carbonate supersaturation associated with vertical mixing of water masses and dysoxic conditions) or Frutexites-bearing microbialites (low level of calcium carbonate supersaturation associated with anoxic conditions and deposition below a stable chemocline) formed. The results of this study point to continued environmental stress in the region during the Early Triassic that likely contributed to the uneven recovery from the Permian-Triassic mass extinction.

Involvement of the extracellular signal-regulated kinase cascade for cocaine-rewarding properties

A central feature of drugs of abuse is to induce gene expression in discrete brain structures that are critically involved in behavioral responses related to addictive processes. Although extracellular signal-regulated kinase (ERK) has been implicated in several neurobiological processes, including neuronal plasticity, its role in drug addiction remains poorly understood. This study was designed to analyze the activation of ERK by cocaine, its involvement in cocaine-induced early and long-term behavioral effects, as well as in gene expression. We show, by immunocytochemistry, that acute cocaine administration activates ERK throughout the striatum, rapidly but transiently. This activation was blocked when SCH 23390 [a specific dopamine (DA)-D1 antagonist] but not raclopride (a DA-D2 antagonist) was injected before cocaine. Glutamate receptors of NMDA subtypes also participated in ERK activation, as shown after injection of the NMDA receptor antagonist MK 801. The systemic injection of SL327, a selective inhibitor of the ERK kinase MEK, before cocaine, abolished the cocaine-induced ERK activation and decreased cocaine-induced hyperlocomotion, indicating a role of this pathway in events underlying early behavioral responses. Moreover, the rewarding effects of cocaine were abolished by SL327 in the place-conditioning paradigm. Because SL327 antagonized cocaine-induced c-fos expression and Elk-1 hyperphosphorylation, we suggest that the ERK intracellular signaling cascade is also involved in the prime burst of gene expression underlying long-term behavioral changes induced by cocaine. Altogether, these results reveal a new mechanism to explain behavioral responses of cocaine related to its addictive properties.

The death domain-containing protein Unc5CL is a novel MyD88-independent activator of the pro-inflammatory IRAK signaling cascade.

The family of death domain (DD)-containing proteins are involved in many cellular processes, including apoptosis, inflammation and development. One of these molecules, the adapter protein MyD88, is a key factor in innate and adaptive immunity that integrates signals from the Toll-like receptor/interleukin (IL)-1 receptor (TLR/IL-1R) superfamily by providing an activation platform for IL-1R-associated kinases (IRAKs). Here we show that the DD-containing protein Unc5CL (also known as ZUD) is involved in a novel MyD88-independent mode of IRAK signaling that culminates in the activation of the transcription factor nuclear factor kappa B (NF-κB) and c-Jun N-terminal kinase. Unc5CL required IRAK1, IRAK4 and TNF receptor-associated factor 6 but not MyD88 for its ability to activate these pathways. Interestingly, the protein is constitutively autoproteolytically processed, and is anchored by its N-terminus specifically to the apical face of mucosal epithelial cells. Transcriptional profiling identified mainly chemokines, including IL-8, CXCL1 and CCL20 as Unc5CL target genes. Its prominent expression in mucosal tissues, as well as its ability to induce a pro-inflammatory program in cells, suggests that Unc5CL is a factor in epithelial inflammation and immunity as well as a candidate gene involved in mucosal diseases such as inflammatory bowel disease.

Viability and Management of an Endangered Capercaillie (Tetrao urogallus) Metapopulation in the Jura Mountains, Western Switzerland

The populations of Capercaillie (Tetrao urogallus), the largest European grouse, have seriously declined during the last century over most of their distribution in western and central Europe. In the Jura mountains, the relict population is now isolated and critically endangered (about 500 breeding adults). We developed a simulation software (TetrasPool) that accounts for age and spatial structure as well as stochastic processes, to perform a viability analysis and explore management scenarios for this population, capitalizing on a 24 years-long series of field data. Simulations predict a marked decline and a significant extinction risk over the next century, largely due to environmental and demographic stochasticity (average values of life-history parameters would otherwise allow stability). Variances among scenarios mainly stem from uncertainties about the shape and intensity of density dependence. Uncertainty analyses suggest to focus conservation efforts on enhancing, not only adult survival (as often advocated for long-lived species), but also recruitment. The juvenile stage matters when local populations undergo extinctions, because it ensures connectivity and recolonization. Besides limiting human perturbations, a silvicultural strategy aimed at opening forest structure should improve the quality and surface of available patches, independent of their size and localization. Such measures are to be taken urgently, if the population is to be saved.