Collapse of telomere homeostasis in hematopoietic cells caused by heterozygous mutations in telomerase genes

Telomerase activity is readily detectable in extracts from human hematopoietic stem and progenitor cells, but appears unable to maintain telomere length with proliferation in vitro and with age in vivo. We performed a detailed study of the telomere length by flow FISH analysis in leukocytes from 835 healthy individuals and 60 individuals with reduced telomerase activity. Healthy individuals showed a broad range in average telomere length in granulocytes and lymphocytes at any given age. The average telomere length declined with age at a rate that differed between age-specific breakpoints and between cell types. Gender differences between leukocyte telomere lengths were observed for all cell subsets studied; interestingly, this trend could already be detected at birth. Heterozygous carriers for mutations in either the telomerase reverse transcriptase (hTERT) or the telomerase RNA template (hTERC) gene displayed striking and comparable telomere length deficits. Further, non-carrier relatives of such heterozygous individuals had somewhat shorter leukocyte telomere lengths than expected; this difference was most profound for granulocytes. Failure to maintain telomere homeostasis as a result of partial telomerase deficiency is thought to trigger cell senescence or cell death, eventually causing tissue failure syndromes. Our data are consistent with these statements and suggest that the likelihood of similar processes occurring in normal individuals increases with age. Our work highlights the essential role of telomerase in the hematopoietic system and supports the notion that telomerase levels in hematopoietic cells, while limiting and unable to prevent overall telomere shortening, are nevertheless crucial to maintain telomere homeostasis with age.

Effect of chest compressions only during experimental basic life support on alveolar collapse and recruitment

AIM: The importance of ventilatory support during cardiac arrest and basic life support is controversial. This experimental study used dynamic computed tomography (CT) to assess the effects of chest compressions only during cardiopulmonary resuscitation (CCO-CPR) on alveolar recruitment and haemodynamic parameters in porcine model of ventricular fibrillation. MATERIALS AND METHODS: Twelve anaesthetized pigs (26+/-1kg) were randomly assigned to one of the following groups: (1) intermittent positive pressure ventilation (IPPV) both during basic life support and advanced cardiac life support, or (2) CCO during basic life support and IPPV during advanced cardiac life support. Measurements were acquired at baseline prior to cardiac arrest, during basic life support, during advanced life support, and after return of spontaneous circulation (ROSC), as follows: dynamic CT series, arterial and central venous pressures, blood gases, and regional organ blood flow. The ventilated and atelectatic lung area was quantified from dynamic CT images. Differences between groups were analyzed using the Kruskal-Wallis test, and a p<0.05 was considered statistically significant. RESULTS: IPPV was associated with cyclic alveolar recruitment and de-recruitment. Compared with controls, the CCO-CPR group had a significantly larger mean fractional area of atelectasis (p=0.009), and significantly lower PaO(2) (p=0.002) and mean arterial pressure (p=0.023). The increase in mean atelectatic lung area observed during basic life support in the CCO-CPR group remained clinically relevant throughout the subsequent advanced cardiac life support period and following ROSC, and was associated with prolonged impaired haemodynamics. No inter-group differences in myocardial and cerebral blood flow were observed. CONCLUSION: A lack of ventilation during basic life support is associated with excessive atelectasis, arterial hypoxaemia and compromised CPR haemodynamics. Moreover, these detrimental effects remain evident even after restoration of IPPV.

Anesthetic and Airways Management of a Dog with Severe Tracheal Collapse during Intraluminal Stent Placement

This case report describes the anesthetic and airways management of a dog affected by 4th degree tracheal collapse and undergoing endoscope-guided intraluminal stent placement. After premedication with acepromazine and butorphanol, general anesthesia was induced with propofol and maintained with intravenous propofol and butorphanol in constant rate infusion. During intraluminal stent placement, oxygen was supplemented by means of a simple and inexpensive handmade device, namely, a ureteral catheter inserted into the trachea and connected to an oxygen source, which allowed for the maintenance of airways’ patency and adequate patient’s oxygenation, without decreasing visibility in the surgical field or interfering with the procedure. The use of the technique described in the present paper was the main determinant of the successful anesthetic management and may be proposed for similar critical cases in which surgical manipulation of the tracheal lumen, which may potentially result in hypoxia by compromising airways patency, is required.

Experimental Validation of Finite Element Analysis of Human Vertebral Collapse Under Large Compressive Strains

Osteoporosis-related vertebral fractures represent a major health problem in elderly populations. Such fractures can often only be diagnosed after a substantial deformation history of the vertebral body. Therefore, it remains a challenge for clinicians to distinguish between stable and progressive potentially harmful fractures. Accordingly, novel criteria for selection of the appropriate conservative or surgical treatment are urgently needed. Computer tomography-based finite element analysis is an increasingly accepted method to predict the quasi-static vertebral strength and to follow up this small strain property longitudinally in time. A recent development in constitutive modeling allows us to simulate strain localization and densification in trabecular bone under large compressive strains without mesh dependence. The aim of this work was to validate this recently developed constitutive model of trabecular bone for the prediction of strain localization and densification in the human vertebral body subjected to large compressive deformation. A custom-made stepwise loading device mounted in a high resolution peripheral computer tomography system was used to describe the progressive collapse of 13 human vertebrae under axial compression. Continuum finite element analyses of the 13 compression tests were realized and the zones of high volumetric strain were compared with the experiments. A fair qualitative correspondence of the strain localization zone between the experiment and finite element analysis was achieved in 9 out of 13 tests and significant correlations of the volumetric strains were obtained throughout the range of applied axial compression. Interestingly, the stepwise propagating localization zones in trabecular bone converged to the buckling locations in the cortical shell. While the adopted continuum finite element approach still suffers from several limitations, these encouraging preliminary results towardsthe prediction of extended vertebral collapse may help in assessing fracture stability in future work.

Use of nitinol self-expandable stents in 26 dogs with tracheal collapse

A study was designed to describe a novel approach to the treatment of tracheal collapse (TC) in dogs using self-expandable nitinol stents. Medical records were reviewed retrospectively for 26 client owned dogs in which nitinol stents were deployed. The entire length of trachea was supported independently of the extent of TC. Two overlapping stents were used instead of one in cases where one stent was not spanning the entire trachea adequately. The diameter of the cranial radiolucent portion of trachea, just behind the cricoid cartilage, was measured as a specific landmark to select the appropriate size of the stent. Two self-expandable nitinol stents were inserted in 9 of 26 dogs; the trachea in the rest of the cases was supported with only one stent. A follow up tracheoscopy was performed in 10 of 26 cases with recurrent clinical signs. Secondary tracheal stenosis in these cases was caused by stent fracture, granuloma or excessive stent shortening. Additional stents were placed successfully to expand the stenotic lumen. A support of the entire trachea may decrease risk of nitinol fracture at the end of the implant. Long term clinical improvement (25 of 26 dogs, 96 %) is comparable with the results of other studies.

Alveolar derecruitment and collapse induration as crucial mechanisms in lung injury and fibrosis.

Idiopathic pulmonary fibrosis (IPF) and bleomycin-induced pulmonary fibrosis are associated with surfactant system dysfunction, alveolar collapse (derecruitment), and collapse induration (irreversible collapse). These events play undefined roles in the loss of lung function. The purpose of this study was to quantify how surfactant inactivation, alveolar collapse, and collapse induration lead to degradation of lung function. Design-based stereology and invasive pulmonary function tests were performed 1, 3, 7, and 14 days after intratracheal bleomycin-instillation in rats. The number and size of open alveoli was correlated to mechanical properties. Active surfactant subtypes declined by Day 1, associated with a progressive alveolar derecruitment and a decrease in compliance. Alveolar epithelial damage was more pronounced in closed alveoli compared with ventilated alveoli. Collapse induration occurred on Day 7 and Day 14 as indicated by collapsed alveoli overgrown by a hyperplastic alveolar epithelium. This pathophysiology was also observed for the first time in human IPF lung explants. Before the onset of collapse induration, distal airspaces were easily recruited, and lung elastance could be kept low after recruitment by positive end-expiratory pressure (PEEP). At later time points, the recruitable fraction of the lung was reduced by collapse induration, causing elastance to be elevated at high levels of PEEP. Surfactant inactivation leading to alveolar collapse and subsequent collapse induration might be the primary pathway for the loss of alveoli in this animal model. Loss of alveoli is highly correlated with the degradation of lung function. Our ultrastructural observations suggest that collapse induration is important in human IPF.

Local formation of varved sediments in a karstic collapse depression of Lake Banyoles (NE Spain)

Banyoles is the largest and deepest lake of karstic-tectonic origin in the Iberian Peninsula. The lake comprises several circular sub-basins characteri- zed by different oxygenation conditions at their hypolimnions. The multiproxy analysis of a > 5 m long sediment core combined with high resolution seis- mic stratigraphy (3.5 kHz pinger and multi-frequency Chirp surveys), allow a precise reconstruction of the evolution of a karstic depression (named B3) until present times. Local meromictic conditions in this sub-basin have been conducive to deposition and preservation of ca. 85 cm of varved sediments since the late 19th century. The onset of these conditions is likely related to lake waters eutrophication caused by increasing farming activities in the wa- tershed. Increasing clastic input and organic productivity during the second half of the 20th century have also been recorded within the laminated sedi- ments, revealing an intensification of human impact and warmer water tem- peratures.

Large heterogeneities in comet 67P as revealed by active pits from sinkhole collapse

Pits have been observed on many cometary nuclei mapped by spacecraft(1-4). It has been argued that cometary pits are a signature of endogenic activity, rather than impact craters such as those on planetary and asteroid surfaces. Impact experiments(5,6) andmodels(7,8) cannot reproduce the shapes of most of the observed cometary pits, and the predicted collision rates imply that few of the pits are related to impacts(8,9). Alternative mechanisms like explosive activity(10) have been suggested, but the driving process remains unknown. Here we report that pits on comet 67P/Churyumov-Gerasimenko are active, and probably created by a sinkhole process, possibly accompanied by outbursts. We argue that after formation, pits expand slowly in diameter, owing to sublimation-driven retreat of the walls. Therefore, pits characterize how eroded the surface is: a fresh cometary surface will have a ragged structure with many pits, while an evolved surface will look smoother. The size and spatial distribution of pits imply that large heterogeneities exist in the physical, structural or compositional properties of the first few hundred metres below the current nucleus surface.