Cyclic stretching of mesangial cells up-regulates intercellular adhesion molecule-1 and leukocyte adherence: A possible new mechanism for glomerulosclerosis

Intraglomerular hypertension is a primacy causal factor in the progressive glomerulosclerosis that characterizes diabetic nephropathy or severe renal ablation. However, inflammation of the glomerular mesangium also participates in at least the early phase of these diseases. In glomerulonephritis, where inflammation is thought to be the predominant causal factor, intraglomerular hypertension is also often present. Mesangial cells (MCs) are critical in orchestrating key functions of the glomerulus including extracellular matrix metabolism, cytokine production, and interaction with leukocytes. Because MCs are subject to increased stretching when intraglomerular hypertension is present, and in glomerulonephritis MC/leukocyte interactions seem to be mediated primarily via the up-regulation of intercellular adhesion molecule-1 (ICAM-1), we examine the possibility that cyclic stretching is a stimulus for increased MC ICAM-1 activity. We demonstrate that the normal low levels of MC ICAM-1 mRNA and protein are dramatically up-regulated by even short intervals of cyclic stretch. This effect is dose- and time-dependent, and requires little amplitude and a brief period of elongation for significant induction. Stretch-induced MC ICAM-1 also leads to a marked elevation in phagocytic leukocyte adherence. This stimulated adherence is equal or greater than that induced by the inflammatory cytokine tumor necrosis factor-α, whereas an additive effect occurs when both are applied in combination. Our results indicate that stretch-induced ICAM-1 may provide a direct link between hypertension and inflammation in the progression of injury and glomerulosclerosis in diabetes, renal ablation, and other forms of glomerulonephritis. © 2001 American Society for Investigative Pathology

Differential expression of an α-galactosyl-containing trisaccharide on high- and low-malignant murine sarcoma cells: Identification and regulation

Past studies have shown that carbohydrate residues reactive with the Griffonia simplicifolia isolectin B 4 (GS I-B4) are present on the surface of highly-malignant murine sarcoma cells but are lacking or expressed in much lower amounts on the surface of low-malignant cells isolated from the same parent tumors (Am J Pathol 111: 27; J Nat Cancer Inst 71: 1281). In the present study it is shown that an antibody which recognizes the trisaccharide Galα1-3Galβ1-4GlcNAc- is reactive with the highly-malignant cells but is non-reactive with the low-malignant cells. Further studies show that the high-malignant cells not only bind GS I-B 4 but also bind Evonymus europaea lectin (which like GS I-B 4 recognizes terminal galactose in α1-3 linkage) and Erythina crystagalli lectin (which recognizes sub-terminal galactose in the β1-4 linkage – e.g., Galβ1-4GlcNAc). In contrast, the low malignant cells bind Erythina crystagalli lectin as efficiently as the high malignant cells but do not bind (or bind much smaller amounts of) either GS I-B 4 or Evonymus europaea lectin. The present studies also show that there is no significant difference between high- and low-malignant cells in expression of α-galactosidase activity. In contrast, the high-malignant cells express high levels of α-galactosyl transferase activity while this enzyme is virtually undetectable in low-malignant cells. Taken together, these studies indicate that differential expression of a single monosaccharide residue distinguishes high- and low-malignant murine sarcoma cells. These studies also identify a mechanism to account for surface carbohydrate differences between the high- and low-malignant cells.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/42582/1/10585_2004_Article_380463.pd

Experiences, Opportunities and Challenges of Implementing Task Shifting in Underserved Remote Settings: The Case of Kongwa District, Central Tanzania.

Tanzania is experiencing acute shortages of Health Workers (HWs), a situation which has forced health managers, especially in the underserved districts, to hastily cope with health workers' shortages by adopting task shifting. This has however been due to limited options for dealing with the crisis of health personnel. There are on-going discussions in the country on whether to scale up task shifting as one of the strategies for addressing health personnel crisis. However, these discussions are not backed up by rigorous scientific evidence. The aim of this paper is two-fold. Firstly, to describe the current situation of implementing task shifting in the context of acute shortages of health workers and, secondly, to provide a descriptive account of the potential opportunities or benefits and the likely challenges which might ensue as a result of implementing task shifting. We employed in-depth interviews with informants at the district level and supplemented the information with additional interviews with informants at the national level. Interviews focussed on the informants' practical experiences of implementing task shifting in their respective health facilities (district level) and their opinions regarding opportunities and challenges which might be associated with implementation of task shifting practices. At the national level, the main focus was on policy issues related to management of health personnel in the context of implementation of task shifting, in addition to seeking their opinions and perceptions regarding opportunities and challenges of implementing task shifting if formally adopted. Task shifting has been in practice for many years in Tanzania and has been perceived as an inevitable coping mechanism due to limited options for addressing health personnel shortages in the country. Majority of informants had the concern that quality of services is likely to be affected if appropriate policy infrastructures are not in place before formalising tasks shifting. There was also a perception that implementation of task shifting has ensured access to services especially in underserved remote areas. Professional discontent and challenges related to the management of health personnel policies were also perceived as important issues to consider when implementing task shifting practices. Additional resources for additional training and supervisory tasks were also considered important in the implementation of task shifting in order to make it deliver much the same way as it is for conventional modalities of delivering care. Task shifting implementation occurs as an ad hoc coping mechanism to the existing shortages of health workers in many undeserved areas of the country, not just in the study site whose findings are reported in this paper. It is recommended that the most important thing to do now is not to determine whether task shifting is possible or effective but to define the limits of task shifting so as to reach a consensus on where it can have the strongest and most sustainable impact in the delivery of quality health services. Any action towards this end needs to be evidence-based

Astrovirus replication in human intestinal enteroids reveals multi-cellular tropism and an intricate host innate immune landscape.

Human astroviruses (HAstV) are understudied positive-strand RNA viruses that cause gastroenteritis mostly in children and the elderly. Three clades of astroviruses, classic, MLB-type and VA-type have been reported in humans. One limitation towards a better understanding of these viruses has been the lack of a physiologically relevant cell culture model that supports growth of all clades of HAstV. Herein, we demonstrate infection of HAstV strains belonging to all three clades in epithelium-only human intestinal enteroids (HIE) isolated from biopsy-derived intestinal crypts. A detailed investigation of infection of VA1, a member of the non-canonical HAstV-VA/HMO clade, showed robust replication in HIE derived from different patients and from different intestinal regions independent of the cellular differentiation status. Flow cytometry and immunofluorescence analysis revealed that VA1 infects several cell types, including intestinal progenitor cells and mature enterocytes, in HIE cultures. RNA profiling of VA1-infected HIE uncovered that the host response to infection is dominated by interferon (IFN)-mediated innate immune responses. A comparison of the antiviral host response in non-transformed HIE and transformed human colon carcinoma Caco-2 cells highlighted significant differences between these cells, including an increased magnitude of the response in HIE. Additional studies confirmed the sensitivity of VA1 to exogenous IFNs, and indicated that the endogenous IFN response of HIE to curtail the growth of strains from all three clades. Genotypic variation in the permissiveness of different HIE lines to HAstV could be overcome by pharmacologic inhibition of JAK/STAT signaling. Collectively, our data identify HIE as a universal infection model for HAstV and an improved model of the intestinal epithelium to investigate enteric virus-host interactions

CHANDRA/VLA Follow-up of TeV J2032+4131, the Only Unidentified TeV Gamma-ray Source

The HEGRA Cherenkov telescope array group recently reported a steady and extended unidentified TeV gamma-ray source lying at the outskirts of Cygnus OB2. This is the most massive stellar association known in the Galaxy, estimated to contain ~2600 OB type members alone. It has been previously argued that the large scale shocks and turbulence induced by the multiple interacting supersonic winds from the many young stars in such associations may play a role in accelerating Galactic cosmic rays. Indeed, Cyg OB2 also coincides with the non-variable MeV-GeV range unidentified EGRET source, 3EG 2033+4118. We report on the near-simultaneous follow-up observations of the extended TeV source region with the CHANDRA X-ray Observatory and the Very Large Array (VLA) radio telescope obtained in order to explore this possibility. Analysis of the CO, HI, and IRAS 100 micron emissions shows that the TeV source region coincides with an outlying sub-group of powerful OB stars which have evacuated or destroyed much of the ambient atomic, molecular and dust material, and which may be related to the very high-energy emissions. An interesting SNR-like structure is also revealed near the TeV source region in the CO, HI and radio emission maps. Applying a numerical simulation which accurately tracks the radio to gamma-ray emission from primary hadrons as well as primary and secondary e+/-, we find that the broadband spectrum of the TeV source region favors a predominantly nucleonic - rather than electronic - origin of the high-energy flux, though deeper X-ray and radio observations are needed to confirm this. A very reasonable, ~0.1%, conversion efficiency of Cyg OB2's extreme stellar wind mechanical luminosity to nucleonic acceleration to ~PeV (10^15 eV) energies is sufficient to explain the multifrequency emissions.Comment: ApJ accepte

Massive Stars In The W33 Giant Molecular Complex

Rich in H II regions, giant molecular clouds are natural laboratories to study massive stars and sequential star formation. The Galactic star-forming complex W33 is located at = ∼ ◦ l 12.8 and at a distance of 2.4 kpc and has a size of ≈10 pc and a total mass of ≈(0.8−8.0) × 105 M⊙. The integrated radio and IR luminosity of W33—when combined with the direct detection of methanol masers, the protostellar object W33A, and the protocluster embedded within the radio source W33 main—mark the region as a site of vigorous ongoing star formation. In order to assess the long-term star formation history, we performed an infrared spectroscopic search for massive stars, detecting for the first time 14 early-type stars, including one WN6 star and four O4–7 stars. The distribution of spectral types suggests that this population formed during the past ∼2–4 Myr, while the absence of red supergiants precludes extensive star formation at ages 6–30 Myr. This activity appears distributed throughout the region and does not appear to have yielded the dense stellar clusters that characterize other star-forming complexes such as Carina and G305. Instead, we anticipate that W33 will eventually evolve into a loose stellar aggregate, with Cyg OB2 serving as a useful, albeit richer and more massive, comparator. Given recent distance estimates, and despite a remarkably similar stellar population, the rich cluster Cl 1813–178 located on the northwest edge of W33 does not appear to be physically associated with W33

Thrombospondin production and thrombospondin-mediated adhesion in U937 cells

U937 cells have low levels of surface thrombospondin (TSP) under control conditions but express higher levels after treatment for 1 day with 100 nM phorbol myristate acetate (PMA). Increased surface expression is due, in part, to increased biosynthesis. Untreated U937 cells do not adhere to TSP-coated plastic culture dishes but adhere strongly to TSP after stimulation with PMA. Untreated U937 cells also adhere weakly to endothelial cell monolayers while PMA-treated U937 cells attach strongly to monolayers of rat pulmonary artery endothelial cells. Endothelial cell adhesion appears to be mediated, in part, by TSP since antibodies to TSP partially inhibit.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29248/1/0000305.pd

Effects of ATRA combined with citrus and ginger-derived compounds in human SCC xenografts

<p>Abstract</p> <p>Background</p> <p>NF-κB is a survival signaling transcription factor complex involved in the malignant phenotype of many cancers, including squamous cell carcinomas (SCC). The citrus coumarin, auraptene (AUR), and the ethno-medicinal ginger (Alpinia galanga) phenylpropanoid, 1'-acetoxychavicol acetate (ACA), were previously shown to suppress 12-<it>O</it>-tetradecanoylphorbol-13-acetate (TPA) induced mouse skin tumor promotion. The goal of the present study was to determine whether AUR and ACA are effective either alone or in combination with all-<it>trans </it>retinoic acid (ATRA) for suppressing SCC tumor growth.</p> <p>Methods</p> <p>We first determined the effects of orally administered ACA (100 mg/kg bw) and AUR (200 mg/kg bw) on lipopolysaccharide (LPS)-induced NF-κB activation in NF-κB-RE-luc (Oslo) luciferase reporter mice. Dietary administration of AUR and ACA ± ATRA was next evaluated in a xenograft mouse model. Female SCID/bg mice were fed diets containing the experimental compounds, injected with 1 × 10⁶SRB12-p9 cells s.c., palpated and weighed twice a week for 28 days following injection.</p> <p>Results</p> <p>Both ACA and AUR suppressed LPS-induced NF-κB activation in the report mice. In the xenograft model, AUR (1000 ppm) and ACA (500 ppm) modestly suppressed tumor volume. However, in combination with ATRA at 5, 10, and 30 ppm, ACA 500 ppm significantly inhibited tumor volume by 56%, 62%, and 98%, respectively. The effect of ATRA alone was 37%, 33%, and 93% inhibition, respectively. AUR 1000 ppm and ATRA 10 ppm were not very effective when administered alone, but when combined, strongly suppressed tumor volume by 84%.</p> <p>Conclusions</p> <p>Citrus AUR may synergize the tumor suppressive effects of ATRA, while ACA may prolong the inhibitory effects of ATRA. Further studies will be necessary to determine whether these combinations may be useful in the control of human SCC.</p

Spent Culture Medium from Virulent Borrelia burgdorferi Increases Permeability of Individually Perfused Microvessels of Rat Mesentery

Lyme disease is a common vector-borne disease caused by the spirochete Borrelia burgdorferi (Bb), which manifests as systemic and targeted tissue inflammation. Both in vitro and in vivo studies have shown that Bb-induced inflammation is primarily host-mediated, via cytokine or chemokine production that promotes leukocyte adhesion/migration. Whether Bb produces mediators that can directly alter the vascular permeability in vivo has not been investigated. The objective of the present study was to investigate if Bb produces a mediator(s) that can directly activate endothelial cells resulting in increases in permeability in intact microvessels in the absence of blood cells.The effects of cell-free, spent culture medium from virulent (B31-A3) and avirulent (B31-A) B. burgdorferi on microvessel permeability and endothelial calcium concentration, [Ca(2+)](i), were examined in individually perfused rat mesenteric venules. Microvessel permeability was determined by measuring hydraulic conductivity (Lp). Endothelial [Ca(2+)](i), a necessary signal initiating hyperpermeability, was measured in Fura-2 loaded microvessels. B31-A3 spent medium caused a rapid and transient increase in Lp and endothelial [Ca(2+)](i). Within 2-5 min, the mean peak Lp increased to 5.6+/-0.9 times the control, and endothelial [Ca(2+)](i) increased from 113+/-11 nM to a mean peak value of 324+/-35 nM. In contrast, neither endothelial [Ca(2+)](i) nor Lp was altered by B31-A spent medium.A mediator(s) produced by virulent Bb under culture conditions directly activates endothelial cells, resulting in increases in microvessel permeability. Most importantly, the production of this mediator is associated with Bb virulence and is likely produced by one or more of the 8 plasmid(s) missing from strain B31-A