Suppression of cell proliferation and programmed cell death by dexamethasone during postnatal lung development

Prematurely born babies are often treated with glucocorticoids. We studied the consequences of an early postnatal and short dexamethasone treatment (0.1-0.01 microg/g, days 1-4) on lung development in rats, focusing on its influence on peaks of cell proliferation around day 4 and of programmed cell death at days 19-21. By morphological criteria, we observed a dexamethasone-induced premature maturation of the septa (day 4), followed by a transient septal immatureness and delayed alveolarization leading to complete rescue of the structural changes. The numbers of proliferating (anti-Ki67) and dying cells (TdT-mediated dUTP nick end labeling) were determined and compared with controls. In dexamethasone-treated animals, both the peak of cell proliferation and the peak of programmed cell death were reduced to baseline, whereas the expression of tissue transglutaminase (transglutaminase-C), another marker for postnatal lung maturation, was not significantly altered. We hypothesize that a short neonatal course of dexamethasone leads to severe but transient structural changes of the lung parenchyma and influences the balance between cell proliferation and cell death even in later stages of lung maturation.

Programmed cell death contributes to postnatal lung development

The rat lung undergoes the phase of maturation of the alveolar septa and of the parenchymal microvascular network mainly during the third postnatal week. Speculating that programmed cell death may contribute to the thinning of the alveolar septa, we searched for the presence of DNA fragmentation in rat lungs between postnatal days 6 and 36 using the TUNEL procedure. The number of positive nuclei was compared at different days. We observed an 8-fold increase of programmed cell death toward the end of the third week as compared to the days before and after this time point. The precise timing of the appearance of the peak depended on the size of the litter. Double-labeling for DNA fragmentation (TUNEL) and for type I and type II epithelial cells (antibodies E11 and MNF-116), as well as morphologic studies at electron microscopic level, revealed that during the peak of programmed cell death mainly fibroblasts and type II epithelial cells were dying. While both dying cell types were TUNEL-positive, nuclear fragments and apoptotic bodies were exclusively observed in the dying fibroblasts. We conclude that programmed cell death is involved in the structural maturation of the lung by reducing the number of fibroblasts and type II epithelial cells in the third postnatal week. We observed that the dying fibroblasts are cleared by neighboring fibroblasts in a later stage of apoptosis, and we hypothesize that type II epithelial cells are cleared by alveolar macrophages in early stages of the programmed cell death process.

Border tax adjustments: Can energy and carbon taxes be adjusted at the border?

Will die Schweiz mit unilateralen energie- und klimapolitischen Massnahmen ambitionierte Ziele verfolgen, dann erfahren energieintensive Sektoren Nachteile im internationalen Wett- bewerb. Produktionsverlagerungen und „carbon leakage“ sind die Folgen, was nicht im Sinne der Schweizer Wirtschaft und der globalen Klimaziele ist. Mit Grenzausgleichsmassnahmen (BAM) kann die Schweiz ihre energieintensiven Betriebe nicht vor internationalen Wettbe- werbsnachteilen schützen. Weiter kommt hinzu, dass die Einführung von BAM aus rechtli- cher Sicht „riskant“ ist und bei einem Schweizer Alleingang mit hohen Vollzugshürden ge- rechnet werden muss. Für die Schweiz macht eine Einführung von BAM nur im Rahmen ei- ner grösseren Klimakoalition Sinn (bspw. zusammen mit der EU). Alternativen zu BAM sind die einfacher und autonom umsetzbaren Ausnahmeregelungen für energieintensive Betriebe oder Output-based-allocation-Systeme.

CMR imaging predicts death and other adverse events in suspected cardiac sarcoidosis

OBJECTIVES This study aimed to demonstrate that the presence of late gadolinium enhancement (LGE) is a predictor of death and other adverse events in patients with suspected cardiac sarcoidosis. BACKGROUND Cardiac sarcoidosis is the most important cause of patient mortality in systemic sarcoidosis, yielding a 5-year mortality rate between 25% and 66% despite immunosuppressive treatment. Other groups have shown that LGE may hold promise in predicting future adverse events in this patient group. METHODS We included 155 consecutive patients with systemic sarcoidosis who underwent cardiac magnetic resonance (CMR) for workup of suspected cardiac sarcoid involvement. The median follow-up time was 2.6 years. Primary endpoints were death, aborted sudden cardiac death, and appropriate implantable cardioverter-defibrillator (ICD) discharge. Secondary endpoints were ventricular tachycardia (VT) and nonsustained VT. RESULTS LGE was present in 39 patients (25.5%). The presence of LGE yields a Cox hazard ratio (HR) of 31.6 for death, aborted sudden cardiac death, or appropriate ICD discharge, and of 33.9 for any event. This is superior to functional or clinical parameters such as left ventricular (LV) ejection fraction (EF), LV end-diastolic volume, or presentation as heart failure, yielding HRs between 0.99 (per % increase LVEF) and 1.004 (presentation as heart failure), and between 0.94 and 1.2 for potentially lethal or other adverse events, respectively. Except for 1 patient dying from pulmonary infection, no patient without LGE died or experienced any event during follow-up, even if the LV was enlarged and the LVEF severely impaired. CONCLUSIONS Among our population of sarcoid patients with nonspecific symptoms, the presence of myocardial scar indicated by LGE was the best independent predictor of potentially lethal events, as well as other adverse events, yielding a Cox HR of 31.6 and of 33.9, respectively. These data support the necessity for future large, longitudinal follow-up studies to definitely establish LGE as an independent predictor of cardiac death in sarcoidosis, as well as to evaluate the incremental prognostic value of additional parameters.

Feasibility of post mortem cardiac proton density weighted fast field echo imaging in two cases of sudden death

OBJECTIVE The aim of this work is to investigate and compare cardiac proton density (PD) weighted fast field echo (FFE) post-mortem magnetic resonance (PMMR) imaging with standard cardiac PMMR imaging (T1-weighted and T2-weighted turbo spin-echo (TSE)), postmortem CT (PMCT) as well as autopsy. MATERIALS AND METHODS Two human cadavers sequentially underwent cardiac PMCT and PMMR imaging (PD-weighted FFE, T1-weighted and T2-weighted TSE) and autopsy. The cardiac PMMR images were compared to each other as well as to PMCT and autopsy findings. RESULTS For the first case, cardiac PMMR exhibited a focal region of low signal in PD-weighted FFE and T2-weighted TSE images, surrounded by a signal intense rim in the T2-weighted images. T1-weighted TSE and PMCT did not appear to identify any focal abnormality. Macroscopic inspection identified a blood clot; histology confirmed this to be a thrombus with an adhering myocardial infarction. In the second case, a myocardial rupture with heart tamponade was identified in all PMMR images, located at the anterior wall of the left ventricle; PMCT excluded additional ruptures. In PD-weighted FFE and T2-weighted TSE images, it occurred hypo-intense, while resulting in small clustered hyper-intense spots in T1-weighted TSE. Autopsy confirmed the PMMR and PMCT findings. CONCLUSIONS Presented initial results have shown PD-weighted FFE to be a valuable imaging sequence in addition to traditional T2-weighted TSE imaging for blood clots and myocardial haemorrhage with clearer contrast between affected and healthy myocardium.

Sudden death in a case of sickle cell anemia: post-mortem computed tomography and autopsy correlation from a radiologist's perspective

Sickle cell anemia (SCA) is a hemolytic disease characterized by the production of abnormal hemoglobin chains and distorted red blood cell morphology or sickling. "Sickle cell crisis" includes vaso-occlusive crisis, a plastic crisis, sequestration crisis, haemolytic crisis and often culminating in serious complications, organ damage and even sudden death. Post-mortem computed tomography (PMCT) findings of sickle cell disease have never been reported in literature. This case of sudden death from acute hemolytic crisis in SCA where post-mortem computed tomography (PMCT) and autopsy findings complemented each other, both revealing findings invisible to the other and both crucial to the case.

Thermal and Barometric Constraints on the Intrusive and Unroofing History of the Black Mountains: Implications for Timing, Initial Dip, and Kinematics of Detachment Faulting in the Death-Valley Region, California

Unroofing of the Black Mountains, Death Valley, California, has resulted in the exposure of 1.7 Ga crystalline basement, late Precambrian amphibolite facies metasedimentary rocks, and a Tertiary magmatic complex. The Ar-40/Ar-39 cooling ages, obtained from samples collected across the entire length of the range (>55 km), combined with geobarometric results from synextensional intrusions, provide time-depth constraints on the Miocene intrusive history and extensional unroofing of the Black Mountains. Data from the southeastern Black Mountains and adjacent Greenwater Range suggest unroofing from shallow depths between 9 and 10 Ma. To the northwest in the crystalline core of the range, biotite plateau ages from approximately 13 to 6.8 Ma from rocks making up the Death Valley turtlebacks indicate a midcrustal residence (with temperatures >300-degrees-C) prior to extensional unroofing. Biotite Ar-40/Ar-39 ages from both Precambrian basement and Tertiary plutons reveal a diachronous cooling pattern of decreasing ages toward the northwest, subparallel to the regional extension direction. Diachronous cooling was accompanied by dike intrusion which also decreases in age toward the northwest. The cooling age pattern and geobarometric constraints in crystalline rocks of the Black Mountains suggest denudation of 10-15 km along a northwest directed detachment system, consistent with regional reconstructions of Tertiary extension and with unroofing of a northwest deepening crustal section. Mica cooling ages that deviate from the northwest younging trend are consistent with northwestward transport of rocks initially at shallower crustal levels onto deeper levels along splays of the detachment. The well-known Amargosa chaos and perhaps the Badwater turtleback are examples of this "splaying" process. Considering the current distance of the structurally deepest samples away from moderately to steeply east tilted Tertiary strata in the southeastern Black Mountains, these data indicate an average initial dip of the detachment system of the order of 20-degrees, similar to that determined for detachment faults in west central Arizona and southeastern California. Beginning with an initially listric geometry, a pattern of footwall unroofing accompanied by dike intrusion progress northwestward. This pattern may be explained by a model where migration of footwall flexures occur below a scoop-shaped banging wall block. One consequence of this model is that gently dipping ductile fabrics developed in the middle crust steepen in the upper crust during unloading. This process resolves the low initial dips obtained here with mapping which suggests transport of the upper plate on moderately to steeply dipping surfaces in the middle and upper crust.

Heart transplantation with donation after circulatory determination of death.

The constant shortage of available organs is a major obstacle and limiting factor in heart transplantation; the discrepancy between the number of donors and potential recipients leads to waiting-list mortality of 10-12% per year in Europe and the USA. If adopted for heart transplantation, donation after circulatory determination of death (DCDD) would be expected to improve the availability of organs substantially for both adults and children. With DCDD, however, hearts to be transplanted undergo a period of warm ischaemia before procurement, which is of particular concern because tissue damage occurs rapidly and might be sufficient to preclude transplantation. Nonetheless, the heart is able to withstand limited periods of warm ischaemia, which could provide a window of opportunity for DCDD. Development of clinical approaches specifically for DCDD is critical for the exploitation of these organs, because current practices for donor heart procurement, evaluation, and storage have been optimized for conventional donation after brain death, without consideration of warm ischaemia before organ procurement. Establishment of clinical protocols and ethical and legal frameworks for DCDD of other organs is underway. This Review provides a timely evaluation of the potential for DCDD in heart transplantation.

Still frame from the hour of death: Acute intracerebral hemorrhage on post-mortem computed tomography in a decomposed corpse

We report a case of an acute hypertensive, intracerebral hemorrhage on post-mortem computed tomography (PMCT) in a decomposed corpse. In clinical radiology, the appearance of blood on cross-sectional imaging is used to estimate the age of intracranial hemorrhage. The findings from this case indicate that characteristics of intracerebral blood on PMCT provide a still frame of the hemorrhage, as it was at the time of death. This observation suggests that the appearance of blood on PMCT may be used to estimate the age of an intracerebral hemorrhage but not to estimate the post-mortem interval.

XIAP Restricts TNF- and RIP3-Dependent Cell Death and Inflammasome Activation

X-linked inhibitor of apoptosis protein (XIAP) has been identified as a potent regulator of innate immune responses, and loss-of-function mutations in XIAP cause the development of the X-linked lymphoproliferative syndrome type 2 (XLP-2) in humans. Using gene-targeted mice, we show that loss of XIAP or deletion of its RING domain lead to excessive cell death and IL-1β secretion from dendritic cells triggered by diverse Toll-like receptor stimuli. Aberrant IL-1β secretion is TNF dependent and requires RIP3 but is independent of cIAP1/cIAP2. The observed cell death also requires TNF and RIP3 but proceeds independently of caspase-1/caspase-11 or caspase-8 function. Loss of XIAP results in aberrantly elevated ubiquitylation of RIP1 outside of TNFR complex I. Virally infected Xiap−/− mice present with symptoms reminiscent of XLP-2. Our data show that XIAP controls RIP3-dependent cell death and IL-1β secretion in response to TNF, which might contribute to hyperinflammation in patients with XLP-2.