Role of human neutrophil peptides in lung inflammation associated with alpha1-antitrypsin deficiency

Individuals with alpha(1)-antitrypsin (alpha(1)-AT) deficiency are at risk for early-onset destructive lung disease as a result of insufficient lower respiratory tract alpha(1)-AT and an increased burden of neutrophil products such as elastase. Human neutrophil peptides (HNP), the most abundant protein component of neutrophil azurophilic granules, represent another potential inflammatory component in lung disease characterized by increased numbers of activated or deteriorating neutrophils. The purpose of this study was to determine the role of HNP in lower respiratory tract inflammation and destruction occuring in alpha(1)-AT deficiency. alpha(1)-AT-deficient individuals (n = 33) and healthy control subjects (n = 21) were evaluated by bronchoalveolar lavage. HNP concentrations were significantly higher in alpha(1)-AT-deficient individuals (1,976 +/- 692 vs. 29 +/- 12 nM, P < 0.0001), and levels correlated with markers of neutrophil-mediated lung inflammation. In vitro, HNP produced a dose-dependent cytotoxic effect on alveolar macrophages and stimulated production of the potent neutrophil chemoattractants leukotriene B(4) and interleukin-8 by alveolar macrophages, with a 6- to 10-fold increase in chemoattractant production over negative control cultures (P < 0.05). A synergistic effect was noted between HNP and neutrophil elastase with regard to leukotriene B(4) production. Importantly, the proinflammatory effects of HNP were blocked by alpha(1)-AT. HNP likely play an important role in amplifying and maintaining neutrophil-mediated inflammation in the lungs.     

Inhibition of retinoic acid metabolising enzymes by 2-(4-aminophenylmethyl)-6-hydroxy-3,4-dihydronaphthalen-1(2H)-one and related compounds

In a search for inhibitors of all-trans retinoic acid (RA)-metabolising enzymes as potential agents for the treatment of skin conditions and cancer we have examined 2-(4-aminophenylmethyl)-6-hydroxy-3,4-dihydronaphthalen-1(2H)-one (5). Compound (5) is a moderate inhibitor of RA-metabolising enzymes in mammalian cadaverous tissue microsomes and homogenates as well as RA-induced enzymes in cultured human genital fibroblasts and HaCat cells. Overall (5) was more potent than or equipotent with ketoconazole, a standard inhibitor, in the cadaverous systems but less active towards the RA-induced cell culture systems. Examination of the data suggests that RA-induction generates metabolising enzymes not present in the cadaverous systems, which are more susceptible to inhibition by ketoconazole than (5).     

Zonal changes in the three-dimensional morphology of the chondron under compression: the relationship among cellular, pericellular, and extracellular deformation in articular cartilage

The pericellular matrix (PCM) is a narrow region of tissue that completely surrounds chondrocytes in articular cartilage. Previous theoretical models of the "chondron" (the PCM with enclosed cells) suggest that the structure and properties of the PCM may significantly influence the mechanical environment of the chondrocyte. The objective of this study was to quantify changes in the three-dimensional (3D) morphology of the chondron in situ at different magnitudes of compression applied to the cartilage extracellular matrix. Fluorescence immunolabeling for type-VI collagen was used to identify the boundaries of the cell and PCM, and confocal microscopy was used to form 3D images of chondrons from superficial, middle, and deep zone cartilage in explants compressed to 0%, 10%, 30%, and 50% surface-to-surface strain. Lagrangian tissue strain, determined locally using texture correlation, was highly inhomogeneous and revealed depth-dependent compressive stiffness and Poisson's ratio of the extracellular matrix. Compression significantly decreased cell and chondron height and volume, depending on the zone and magnitude of compression. In the superficial zone, cellular-level strains were always lower than tissue-level strains. In the middle and deep zones, however, tissue strains below 25% were amplified at the cellular level, while tissue strains above 25% were decreased at the cellular level. These findings are consistent with previous theoretical models of the chondron, suggesting that the PCM can serve as either a protective layer for the chondrocyte or a transducer that amplifies strain, such that cellular-level strains are more homogenous throughout the tissue depth despite large inhomogeneities in local ECM strains.     

Hyper-osmotic stress induces volume change and calcium transients in chondrocytes by transmembrane, phospholipid, and G-protein pathways

Mechanical compression of cartilage is associated with a rise in the interstitial osmotic pressure, which can alter cell volume and activate volume recovery pathways. One of the early events implicated in regulatory volume changes and mechanotransduction is an increase of intracellular calcium ion ([Ca²⁺]_i). In this study, we tested the hypothesis that osmotic stress initiates intracellular Ca²⁺ signaling in chondrocytes. Using laser scanning microscopy and digital image processing, [Ca²⁺]_i and cell volume were monitored in chondrocytes exposed to hyper-osmotic solutions. Control experiments showed that exposure to hyper-osmotic solution caused significant decreases in cell volume as well as transient increases in [Ca²⁺]_i. The initial peak in [Ca²⁺]_i was generally followed by decaying oscillations. Pretreatment with gadolinium, a non-specific blocker of mechanosensitive ion channels, inhibited this [Ca²⁺]_i increase. Calcium-free media eliminated [Ca²⁺]_i increases in all cases. Pretreatment with U73122, thapsigargin, or heparin (blockers of the inositol phosphate pathway), or pertussis toxin (a blocker of G-proteins) significantly decreased the percentage of cells responding to osmotic stress and nearly abolished all oscillations. Cell volume decreased with hyper-osmotic stress and recovered towards baseline levels throughout the duration of the control experiments. The peak volume change with 550 mOsm osmotic stress, as well as the percent recovery of cell volume, was dependent on [Ca²⁺]_i. These findings indicate that osmotic stress causes significant volume change in chondrocytes and may activate an intracellular second messenger signal by inducing transient increases in [Ca²⁺]_i.     

Development and validation of a correction equation for Corvis tonometry

Primary objective: This study uses numerical analysis and validation against clinical data to develop a method to correct intraocular pressure (IOP) measurements obtained using the Corvis Tonometer for the effects of central corneal thickness (CCT), and age. Materials and Methods: Finite element analysis was conducted to simulate the effect of tonometric air pressure on the intact eye globe. The analyses considered eyes with wide variations in IOP (10–30 mm Hg), CCT (445–645 microns), R (7.2–8.4 mm), shape factor, P (0.6–1) and age (30–90 years). In each case, corneal deformation was predicted and used to estimate the IOP measurement by Corvis (CVS-IOP). Analysis of the results led to an algorithm relating estimates of true IOP as a function of CVS-IOP, CCT and age. All other parameters had negligible effect on CVS-IOP and have therefore been omitted from the algorithm. Predictions of corrected CVS-IOP, as obtained by applying the algorithm to a clinical data-set involving 634 eyes, were assessed for their association with the cornea stiffness parameters; CCT and age. Results: Analysis of CVS-IOP measurements within the 634-large clinical data-set showed strong correlation with CCT (3.06 mm Hg/100 microns, r² = 0.204) and weaker correlation with age (0.24 mm Hg/decade, r² = 0.009). Applying the algorithm to IOP measurements resulted in IOP estimations that became less correlated with both CCT (0.04 mm Hg/100 microns, r² = 0.005) and age (0.09 mm Hg/decade, r² = 0.002). Conclusions: The IOP correction process developed in this study was successful in reducing reliance of IOP measurements on both corneal thickness and age in a healthy European population.     

Role of Paraventricular Nucleus in Regulation of Feeding Behaviour and the Design of Intranuclear Neuronal Pathway Communications

Food consumption and body weight regulations are done in the hypothalamus. Indeed, hypothalamus is the brain’s main area in controlling food intake.     

Immunological biomarkers of tolerance in human kidney transplantation: An updated literature review

The half-life of transplanted kidneys is <10 years. Acute or chronic rejections have a negative impact on transplant outcome. Therefore, achieving to allograft tolerance for improving long-term transplant outcome is a desirable goal of transplantation field. In contrast, there are evidence that distinct immunological characteristics lead to tolerance in some transplant recipients. In contrast, the main reason for allograft loss is immunological responses. Various immune cells including T cells, B cells, dendritic cells, macrophages, natural killer, and myeloid-derived suppressor cells damage graft tissue and, thereby, graft loss happens. Therefore, being armed with the comprehensive knowledge about either preimmunological or postimmunological characteristics of renal transplant patients may help us to achieve an operational tolerance. In the present study, we are going to review and discuss immunological characteristics of renal transplant recipients with rejection and compare them with tolerant subjects.     

Stop the dicing in hematopoiesis: What have we learned?

MicroRNAs (miRNAs) belong to an abundant class of highly conserved small (22nt) non-coding RNAs. MiRNA profiling studies indicate that their expression is highly cell type-dependent. DICER1 is an essential RNase III endoribonuclease for miRNA processing. Hematopoietic cell type- and developmental stage-specific Dicer1 deletion models show that miRNAs are essential regulators of cellular survival, differentiation and function. For instance, miRNA deficiency in hematopoietic stem cells and progenitors of different origins results in decreased cell survival, dramatic developmental aberrations or dysfunctions in mice. We recently found that homozygous Dicer1 deletion in myeloid-committed progenitors results in an aberrant expression of stem cell genes and induces a regained self-renewal capacity. Moreover, Dicer1 deletion causes a block in macrophage development and myeloid dysplasia, a cellular condition that may be considered as a preleukemic state. However, Dicer1-null cells do not develop leukemia in mice, indicating that depletion of miRNAs is not enough for tumorigenesis. Surprisingly, we found that heterozygous Dicer1 deletion in myeloid-committed progenitors, but not Dicer1 knockout, collaborates with p53 deletion in leukemic progression and results in various types of leukemia. Our data indicate that Dicer1 is a haploinsufficient tumorsuppressor in hematopoietic neoplasms, which is consistent with the observed downregulation of miRNA expression in human leukemia samples. Here, we review the various hematopoietic specific Dicer1 deletion mouse models and the phenotypes observed within the different hematopoietic lineages and cell developmental stages. Finally, we discuss the role for DICER1 in mouse and human malignant hematopoiesis.     

Contrasting timing of parturition of chital Axis axis and gaur Bos gaurus in tropical South India – the role of body mass and seasonal forage quality

Seasonal variation in forage availability and quality is understood to affect the annual timing of parturition in large herbivores. In India–where seasonal monsoonal rains define variation in forage availability and quality–chital Axis axis exhibit stronger seasonality in parturition than the larger gaur Bos gaurus. We hypothesized that this difference can be explained by forage requirements determined by body mass. We developed a model to simulate changes in leaf biomass and nitrogen content based on plant available moisture and nutrients, and calibrated our model with field data. Our results show that the minimum forage nitrogen content required by lactating gaur was available throughout the year, but that required by lactating chital was available for less than 40% of the year, i.e. during the early wet season, which coincides with the annual peak period of chital births. The three to four month spread of chital births, which begins in the dry season, implies that the period of highest quality is also important for females to replenish maternal reserves for future reproduction and help maximize the growth rate of neonates. This spread also indicates low synchrony of chital births and suggests that predator swamping was less important in influencing their timing of parturition. As monsoonal rain exhibits annual temporal variation, we analyzed our model under different rainfall patterns while keeping the total annual rainfall constant. We found that the difference between the durations of how long forage quality is available to satisfy the minimum requirements of lactating gaur and lactating chital is similar for all simulated patterns. This insensitivity to variable rainfall patterns lends support to our hypothesis that forage requirements determined by body mass is one plausible explanation for the variation in parturition strategies among large herbivores species.