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PubMed2005

Controlling for anthropogenically induced atmospheric variation in stable carbon isotope studies.

Increased use of stable isotope analysis to examine food-web dynamics, migration, transfer of nutrients, and behavior will likely result in expansion of stable isotope studies investigating human-induced global changes. Recent elevation of atmospheric CO2 concentration, related primarily to fossil fuel combustion, has reduced atmospheric CO2 delta13C (13C/12C), and this change in isotopic baseline has, in turn, reduced plant and animal tissue delta13C of terrestrial and aquatic organisms. Such depletion in CO2 delta13C and its effects on tissue delta13C may introduce bias into delta13C investigations, and if this variation is not controlled, may confound interpretation of results obtained from tissue samples collected over a temporal span. To control for this source of variation, we used a high-precision record of atmospheric CO2 delta13C from ice cores and direct atmospheric measurements to model modern change in CO2 delta13C. From this model, we estimated a correction factor that controls for atmospheric change; this correction reduces bias associated with changes in atmospheric isotopic baseline and facilitates comparison of tissue delta13C collected over multiple years. To exemplify the importance of accounting for atmospheric CO2 delta13C depletion, we applied the correction to a dataset of collagen delta13C obtained from mountain lion (Puma concolor) bone samples collected in California between 1893 and 1995. Before correction, in three of four ecoregions collagen delta13C decreased significantly concurrent with depletion of atmospheric CO2 delta13C (n > or = 32, P < or = 0.01). Application of the correction to collagen delta13C data removed trends from regions demonstrating significant declines, and measurement error associated with the correction did not add substantial variation to adjusted estimates. Controlling for long-term atmospheric variation and correcting tissue samples for changes in isotopic baseline facilitate analysis of samples that span a large temporal range.

Atmosphere↗
PubMed1993

Polymorphonuclear neutrophil granulocyte chemotactic hyperresponsiveness in a case of canine acromegaly.

Growth hormone (GH) has recently been shown to affect polymorphonuclear neutrophil granulocyte (PMN) function and to be secreted by mononuclear cells, indicating that the hormone may be active in an immunophysiologic network, acting as an endo- or paracrine priming agent. The purpose of the present study was to evaluate the chemotactic responsiveness of canine peripheral PMN in a dog with acromegaly, caused by spontaneous, progesterone-induced hypersecretion of GH and, secondary to this, a seven-fold increase in insulin-like growth factor I (IGF-I). The chemotactic responsiveness towards zymosan-activated serum (ZAS) and leukotriene B4 (LTB4) was evaluated at a time when the dog suffered from acromegaly and again 57 days after corrective surgery (ovariohysterectomy). The experiments showed that PMN from the patient exhibited enhanced chemotactic migration that appeared to be associated with the hypersomatotropic condition as judged from the reversibility of the phenomenon. The glucose intolerance and elevated serum alkaline phosphatase that were observed in the acromegalic dog were also shown to be reversible following surgery.

Acromegaly↗
PubMed2005

Expression levels and functional aspects of the hyaluronan receptor CD44. Effects of insulin, glucose, IGF-I, or growth hormone on human arterial smooth muscle cells.

An increased amount of hyaluronan (HA) in the arterial wall is a feature of the diabetic macroangiopathy. The functional consequences of accumulated HA are mediated through binding to CD44. The regulation of this receptor by diabetic metabolic and hormonal factors is, however unknown. The objective of this study was to examine the influence of glucose, insulin, insulin-like growth factor I (IGF-I), and human growth hormone (hGH) on the formation and function of the HA receptor CD44 in cultures of human aortic smooth muscle cells (SMCs). Migration of nonproliferating SMCs were determined by estimating the area covered by cells 6 days after removal of a barrier. Cellular content of standard CD44 and its isoforms, CD44v3 and CD44v6, and HA-binding capacity were measured using a modified enzyme-linked immunosorbent assay procedure. The analysis is made either with antibodies against CD44 or with HA as a ligand. The migration assay showed that glucose, insulin, and IGF-I were able to stimulate SMC migration (2 P < .01). Anti-CD44 antibody inhibited the stimulated migration at most concentrations. Insulin increased HA binding at 100 to 1000 micro U/mL insulin (2 P < .03). CD44 expression was only elevated at 1000 micro U/mL insulin (2 P < .03), whereas CD44 content decreased at 2 ng/mL hGH and increased at 16 ng/mL hGH (2 P < .01). Glucose and IGF-I reduced the amount of the variant isoform CD44v3 (2 P < .01) but did not change the amount of total CD44. CD44v6 was not present on human arterial SMCs. In conclusion, the present data obtained with human arterial SMCs in vitro support a role of CD44 and its isoform, CD44v3, in the SMC response to the metabolic and hormonal disorders of diabetes.

Aorta↗
PubMed1998

Persistently raised serum acid phosphatase activity in a patient with hypophosphatasia: electrophoretic and molecular weight characterisation as type 5.

Hypophosphatasia is a rare disorder characterised by low levels of serum alkaline phosphatase activity resulting in abnormal phosphorylated metabolites and varying skeletal abnormality. We have followed a patient with adult type hypophosphatasia for over ten years who has also shown a persistently elevated tartrate resistant acid phosphatase activity (TRAP) without any obvious cause. Characterisation of this TRAP by polyacrylamide gel electrophoresis (pH 4.0) showed migration to band 5 position. Molecular weight determination by FPLC and an estimate of the molecular weight by gradient gel electrophoresis gave a molecular weight of 29,000-43,600. This molecular weight makes it unlikely for this to be a IgG/TRAP complex persisting in the circulation. Paranitrophenylphosphate was the preferred substrate. This characterises the enzyme as type 5 acid phosphatase which is of the mononuclear/phagocyte type, possibility of osteoclastic origin, though the tissue source remains unknown.

Acid Phosphatase↗
PubMed2004

Macrophages in mouse type 2 diabetic nephropathy: correlation with diabetic state and progressive renal injury.

BACKGROUND: Macrophage-mediated renal injury has been implicated in progressive forms of glomerulonephritis; however, a role for macrophages in type 2 diabetic nephropathy, the major cause of end-stage renal failure, has not been established. Therefore, we examined whether macrophages may promote the progression of type 2 diabetic nephropathy in db/db mice. METHODS: The incidence of renal injury was examined in db/db mice with varying blood sugar and lipid levels at 8 months of age. The association of renal injury with the accumulation of kidney macrophages was analyzed in normal db/+ and diabetic db/db mice at 2, 4, 6, and 8 months of age. RESULTS: In db/db mice, albuminuria and increased plasma creatinine correlated with elevated blood glucose and hemoglobin A1c (HbA1c) levels but not with obesity or hyperlipidemia. Progressive diabetic nephropathy in db/db mice was associated with increased kidney macrophages. Macrophage accumulation and macrophage activation in db/db mice correlated with hyperglycemia, HbA1c levels, albuminuria, elevated plasma creatinine, glomerular and tubular damage, renal fibrosis, and kidney expression of macrophage chemokines [monocyte chemoattractant protein-1 (MCP-1), osteopontin, migration inhibitory factor (MIF), monocyte-colony-stimulating factor (M-CSF)]. The accrual and activation of glomerular macrophages also correlated with increased glomerular IgG and C3 deposition, which was itself dependent on hyperglycemia. CONCLUSION: Kidney macrophage accumulation is associated with the progression of type 2 diabetic nephropathy in db/db mice. Macrophage accumulation and activation in diabetic db/db kidneys is associated with prolonged hyperglycemia, glomerular immune complex deposition, and increased kidney chemokine production, and raises the possibility of specific therapies for targeting macrophage-mediated injury in diabetic nephropathy.

Animals↗
PubMed2002

Immobilization of radionuclides and heavy metals through anaerobic bio-oxidation of Fe(II).

Adsorption of heavy metals and radionuclides (HMR) onto iron and manganese oxides has long been recognized as an important reaction for the immobilization of these compounds. However, in environments containing elevated concentrations of these HMR the adsorptive capacity of the iron and manganese oxides may well be exceeded, and the HMR can migrate as soluble compounds in aqueous systems. Here we demonstrate the potential of a bioremediative strategy for HMR stabilization in reducing environments based on the recently described anaerobic nitrate-dependent Fe(II) oxidation by Dechlorosoma species. Bio-oxidation of 10 mM Fe(II) and precipitation of Fe(III) oxides by these organisms resulted in rapid adsorption and removal of 55 microM uranium and 81 microM cobalt from solution. The adsorptive capacity of the biogenic Fe(III) oxides was lower than that of abiotically produced Fe(III) oxides (100 microM for both metals), which may have been a result of steric hindrance by the microbial cells on the iron oxide surfaces. The binding capacity of the biogenic oxides for different heavy metals was indirectly correlated to the atomic radius of the bound element. X-ray absorption spectroscopy indicated that the uranium was bound to the biogenically produced Fe(III) oxides as U(VI) and that the U(VI) formed bidentate and tridentate inner-sphere complexes with the Fe(III) oxide surfaces. Dechlorosoma suillum oxidation was specific for Fe(II), and the organism did not enzymatically oxidize U(IV) or Co(II). Small amounts (less than 2.5 microM) of Cr(III) were reoxidized by D. suillum; however, this appeared to be inversely dependent on the initial concentration of the Cr(III). The results of this study demonstrate the potential of this novel approach for stabilization and immobilization of HMR in the environment.

Anaerobiosis↗
PubMed1995

Does cytosolic free Ca2+ signal neutrophil chemotaxis in response to formylated chemotactic peptide?

Cytosolic free Ca2+ concentration was measured and imaged in human neutrophils moving towards a source of formylated peptide in a micropipette held close to the cells. Under these conditions, neutrophils changed shape and displayed chemotaxis without significant or persistent global or localised elevations in cytosolic free Ca2+. A rear-to-front persistent Ca2+ gradient of less than 0.5 nM/micron was present in the migrating neutrophils, until they reached the zone of higher peptide concentration, when an abrupt rise in cytosolic free Ca2+ concentration was triggered and chemotaxis stopped. Small localised rises in cytosolic free Ca2+, which were occasionally observed during neutrophil manoeuvring, were attributed to the effect of local deformation of the neutrophil membrane, since deformation of the membrane with a blunt micropipette caused similar Ca2+ changes. These data suggest that neutrophil chemotaxis towards a source of formylated peptide occurs without significant changes in Ca2+ signalling.

Calcium↗
PubMed2005

Altered expression of IGFs and IGF-binding proteins during intrauterine growth restriction in guinea pigs.

The IGF system is one of the most important endocrine and paracrine growth factor systems that regulate fetal and placental growth. We hypothesized that intrauterine growth restriction (IUGR) in guinea pigs is mediated by the altered expression of IGFs and/or IGF binding protein (BP) mRNAs in tissues and is related to growth of specific tissues. IUGR was induced by unilateral uterine artery ligation on day 30 of gestation, and fetal plasma, amniotic fluid and tissue samples were collected at 55-57 days (term about 68 days) from paired IUGR and control fetuses (n=6). Western ligand blotting and immunoblotting were used to compare IGFBP levels in plasma and amniotic fluid. Total RNA was extracted from placenta and fetal tissues, and the relative abundance of IGF-II and IGFBP-1-6 mRNA was determined by Northern blotting, using species-specific probes where available. IUGR fetuses had decreased (P<0.01, by Student's t-test) placental weight and body weight with an increase in the brain:liver weight ratio. The principal IGFBPs in fetal plasma migrated at 40-35, 30 and 25 kDa and were identified as IGFBP-3, -2 and -4 respectively. IUGR was associated with elevated plasma IGFBP-2 and IGFBP-4 and reduced IGFBP-3 levels. IGFBPs were detected at low levels in amniotic fluid of control fetuses but at higher levels in IUGR fetuses. In IUGR placentae, there was a small increase in IGFBP-4 mRNA (P<0.05). IGFBP-2 mRNA increased (P<0.001) in liver of IUGR fetuses. IGF-II and IGFBP mRNA expression did not change in fetal muscle. The results are consistent with reduced IGF action, directly or through inhibition by IGFBPs, particularly by circulating and tissue IGFBP-2, as a potential causal factor in decreased growth of the placenta and certain fetal tissues.

Amnion↗
PubMed1997

Host defensive, immunological, and microbiological observations of an early-onset periodontitis patient with virus-associated hemophagocytic syndrome.

Virus-associated hemophagocytic syndrome (VAHS) is a disorder characterized by benign generalized histiocytic proliferation and marked hemophagocytosis associated with systemic viral infection. An immunodeficiency which includes an extremely decreased leukocyte and platelet count together with abnormalities in the CD4/CD8 ratio are the most common features of VAHS. Here we report an early-onset periodontitis (EOP) patient with VAHS from the standpoint of host-parasite interaction to understand the effect of this systemic disorder which might possibly influence susceptibility to periodontal disease. The patient is a 16-year-old Japanese male clinically diagnosed as having generalized EOP with slight gingival inflammation and moderate bone loss. This patient manifested VAHS at 3 years of age, and then had an unusual 4 recurrences (at 5, 7, 11, and 14 years old). Laboratory tests conducted include: 1) complete blood analyses: 2) peripheral neutrophil functions (chemotaxis, phagocytosis, superoxide production, and adherence); 3) peripheral lymphocyte subpopulations and functions, T-cell proliferative activity and productivity of cytokines (interleukin-2 [IL-2], interferon gamma [IFN-gamma], and tumor necrosis factor alpha [TNF-alpha]); 4) serum cytokine levels (IL-1 beta, IL-2, soluble IL-2 receptor [sIL-2R], IL-4, IL-6, IFN-gamma, and TNF-alpha; 5) serum immunoglobulin G (IgG) antibody titers against periodontopathic bacteria; 6) serological human leukocyte antigen (HLA) typing; and 7) determination of bacterial flora of the periodontal pockets. The results indicated that the patient's neutrophil chemotaxis and random migration were below the normal range. In lymphocyte examinations, T-cell proliferative activity, IL-2, and IFN-gamma productivity were elevated. Serum IFN-gamma level was also significantly higher than normal range. No specific periodontopathic bacteria were predominant in the periodontal pockets, however, the serum IgG titer against Porphyromonas gingivalis was elevated throughout the examination period. It is suggested that VAHS might be a possible risk factor for periodontal disease, and hence may serve as a model in understanding the role of host defense mechanisms in the establishment of inflammatory periodontal disease.

Adolescent↗
PubMed2005

Expression of osteopontin and HGF/met in adult soft tissue tumors.

There is a need for molecular markers that predict biological behavior of adult soft tissue tumors. Elevated levels of osteopontin (OPN) a transformation-linked protein, have been associated with poor survival in many cancers. OPN induces cell migration in cancer cells, in part through activation of the hepatocyte growth factor (HGF) receptor (Met) and its signaling pathway. Met expression has been associated with a poor prognosis in some sarcomas. In a series of 15 patients with adult soft tissue tumors, we found that mRNA levels of OPN (p=0.015), Met (p=0.03) and HGF (p<0.001) were significantly higher in tumor tissues relative to paired normal tissues. By immunohistochemistry, in tumor tissue from 33 patients, we demonstrated that increased expression of OPN, but not Met protein, was associated with higher stage (p=0.025) and grade (p=0.005). We found that increased expression of OPN, but not Met protein, was associated with decreased overall survival (p=0.008) at five years. This study, which is the first to examine coexpression of these two markers, suggests that OPN may have potential as a prognostic marker in adult soft tissue sarcomas, and further that OPN+/-Met signaling pathways may contribute to their biological behavior.

Adult↗
PubMed2000

Factors affecting sentinel node localization during preoperative breast lymphoscintigraphy.

UNLABELLED: Variable success rates for identifying axillary (AX) sentinel nodes in breast cancer patients using preoperative lymphoscintigraphy have been reported. We evaluated the effects of age, weight, breast size, method of biopsy, interval after biopsy, and imaging view on the success of sentinel node identification and on the kinetics of radiopharmaceutical migration. METHODS: Preoperative breast lymphoscintigraphy was performed in consecutive breast cancer patients from February 1998 to December 1998. The ipsilateral shoulder was elevated on a foam wedge and the arm was abducted and elevated overhead. Imaging using this modified oblique view of the axilla (MOVA) started immediately after peritumoral injection of Millipore-filtered 99mTc-sulfur colloid and continued until AX sentinel nodes were identified. Anterior views were obtained after MOVA. AX, internal mammary (IM), and clavicular (CL) basins were monitored in all patients. MOVA was compared with the anterior view for sentinel node identification. Age, weight, breast size, method of biopsy, interval after biopsy, and primary tumor location were evaluated for their effects on sentinel node localization and transit times from injection to arrival at the sentinel nodes. RESULTS: Seventy-six lymphoscintigrams were obtained for 75 patients. AX sentinel nodes were revealed in 75 (99%) cases. IM or CL sentinel nodes were found in 19 (25%) cases and were not related to tumor location; exclusive IM drainage was present in 1 (1%) case. Identification of AX sentinel nodes was equivalent with MOVA and anterior views in 18 (24%) patients, was better with MOVA in 20 (26%) patients, and was accomplished only with MOVA in 38 (50%) patients. Median transit time was 17.5 min (range, 1 min to 18 h) after injection, and larger breast size was associated with increased transit time. No effect of age, weight, biopsy method, interval from biopsy, or tumor location on transit time was found. CONCLUSION: Use of MOVA can improve identification of AX sentinel nodes. Although AX drainage is the predominant pattern, a tumor in any portion of the breast can drain to IM sentinel nodes. Transit time was influenced by breast size. Overall short arrival times with this technique allow sentinel lymph node dissection to be performed on the same day as lymphoscintigraphy.

Axilla↗
PubMed1987

Phosphorylation of caldesmon77 by protein kinase C in vitro and in intact human platelets.

Caldesmon is a widely distributed calmodulin- and actin-binding protein which occurs in different forms depending on the tissue or cell type under examination. On the basis of molecular weight, caldesmon species can be divided into two classes: caldesmon77 (Mr 70,000-80,000) and caldesmon150 (Mr 140,000-150,000). We have examined the phosphorylation of caldesmon77 by protein kinase C (the Ca2+/phospholipid-dependent enzyme) in vitro and in intact platelets. Caldesmon77, purified from bovine liver, could be phosphorylated by purified rat brain protein kinase C to a level of approximately 1.0 mol of phosphate per mol of caldesmon77 monomer. Two-dimensional tryptic peptide mapping and phosphoamino acid analysis reveals that caldesmon77 is phosphorylated at two major sites exclusively on serine residues. Following treatment of platelets with tumor-promoting phorbol ester, caldesmon77 phosphorylation was elevated 4-fold. Tryptic peptide mapping of phosphorylated platelet caldesmon77 demonstrates that phosphorylation is most significantly enhanced on two peptides which had migration patterns identical with those of the two major phosphopeptides of bovine liver caldesmon77 phosphorylated in vitro. The results of this study indicate that protein kinase C can phosphorylate caldesmon77 in vitro and in intact platelets, suggesting a role for protein kinase C in the regulation of caldesmon77 function or localization.

Animals↗
PubMed1986

Mechanism of polar body formation in the mouse oocyte: an interaction between the chromosomes, the cytoskeleton and the plasma membrane.

The influence of mouse oocyte chromosomes on their immediate environment has been investigated following their dispersal by dissolution of the metaphase spindle with nocodazole. Small clusters of chromosomes become redistributed around the egg cortex in a microfilament-dependent process. Each cluster has the capacity, on removal from nocodazole, to organize a spindle that rotates to yield a polar body. In this process of spindle formation, the chromosome clusters are able both to promote tubulin polymerization in their vicinity and to recruit microtubule-organizing centres (MTOCs) which organize the polymerized tubulin into spindles. In addition each oocyte chromosome cluster, as well as the non-dispersed sperm-derived haploid group of chromosomes, induces a focal accumulation of subcortical actin (corresponding to a filamentous area devoid of organelles) and a loss of surface Concanavalin A binding activity (corresponding to a loss of surface microvilli) in the overlying cortex. This induction ceases with the formation of pronuclei whether or not the pronuclei migrate centrally. Pronuclear formation is sensitive to the action of nocodazole for up to 2-4 h postinsemination, and pronuclear migration is totally sensitive to the drug. If pronuclei are blocked in a peripheral location by nocodazole they are associated with an elevation in Con A binding activity of the overlying membrane which corresponds to an area of the surface rich in blebby microvilli.

Animals↗
PubMed1984

[Pancreatic oncofetal antigen (POA) and carcinoma of the pancreas].

Pancreatic oncofetal antigen (POA) was purified from fetal pancreas and migrated in beta-region electrophoretically. Its molecular weight was 80 X 10(4) daltons. Enzyme immunoassay for serum POA revealed that elevated levels of POA were found in sera of patients with pancreatic cancer. By a serological screening of 440 out-patients with combined assay of tumor markers including POA, 4 cases of pancreatic cancer were found. POA was demonstrated in the ductal cells of fetal pancreas and cancer cells of duct cell type pancreatic adenocarcinoma immunohistochemically. Elevated levels of serum POA of patients with pancreatic cancer was probably derived from cancer tissue. These findings indicate that serum POA assay is clinically useful.

Adenocarcinoma↗
PubMedDate not supplied

BN-50739: a PAF antagonist and limitation of myocardial infarct size.

Anesthetized rats were subjected to coronary artery ligation (CAL) for 72 h and infarct size was measured macroscopically using TTC staining. Systolic blood pressure and ECG were monitored. BN-50739 (5 mg/kg i.p.) decreased the myocardial infarct size in rats. It prevented the loss of R wave, an electrophysiological measure of ischemic injury in this model. In addition, BN-50739 markedly reduced serum malondialdehyde levels elevated as a consequence of CAL. It is speculated that being a PAF antagonist, BN-50739 decreased lipid peroxidation, perhaps by inhibiting migration of PMN cells to the site of ischemic injury through the limited collateral flow available in rat myocardium, and consequently may have reduced the generation of oxygen reactive species. This may be responsible for its beneficial effect in limiting infarct size.

Animals↗
PubMed1997

[Effect of the rotator cuff condition on the results of shoulder arthroplasty].

PURPOSE OF THE STUDY: The purpose of this report was to study the repercussions of rotator cuff condition on unconstrained shoulder arthroplasty results. METHODS: Between 1986 and 1993, 40 unconstrained shoulder prostheses were performed (24 total and 16 hemiarthroplasties). At the time of the operation, rotator cuff condition was reported to be normal in 15 shoulders, atrophic in 10, scarred in 3, torn in 12. Clinical and radiographical results were analyzed and supplemented with a rotator cuff echography. Postoperative follow-up averaged 42.25 months (12 to 97 months). RESULTS: When the rotator cuff was intact at the time of operation, clinical results were the best at the time of review. Constant score, overall mobility, forward elevation, external rotation with the elbow along the side were better for intact than for atrophic, scarred or torn rotator cuffs (p < 0.01). Ruptures repaired by local tissue transfer or trapezo deltoidal flap substitution (3 cases) gave satisfactory results, whereas two dacron cuff prostheses failed. In the non repaired ruptures (7 cases), arthroplasty resulted in 3/4 fair or poor results. At the time of review, the total incidence of postoperative rotator cuff tears was high (12 cases), functional repercussions were variable. Among the 15 rotator cuff tears observed at the time of the review, the long head of the biceps was present and in place in 9 cases and ruptured in 6 cases. In these latter cases, Constant score (p < 0.01), the forward elevation (p < 0.01), external rotation with elbow along side (p < 0.05) and overall mobility (p < 0.05) were worse; moreover, humeral head superior migration was greater (p < 0.01). DISCUSSION: Our study confirms the superiority of clinical results when the cuff was intact at the time of the operation. The repair of rotator cuff tears seems to be justified. When the rupture has not been repaired, clinical results were fair or poor in 5 cases out of 7, the initial rupture spread to the other tendons in 3 cases out of 7. Secondary ruptures were frequent (12 cases). No predictive factor was identified, but an overlapping of the greater tuberosity appears to be detrimental. Among rotator cuff tears present at the time of review, long head of the biceps rupture jeopardized clinical results and was associated with a proximal migration of the humeral head which was significantly more severe than with an intact non displaced long head of the biceps. CONCLUSION: During unconstrained shoulder prosthesis implantation, it is therefore recommend to systematically repair any associated rotator cuff rupture, in order to avoid any greater tuberosity overlap relative to the prosthetic head and to preserve the long head of the biceps tendon which limits upward migration of the humeral head and improves prosthetic kinetics.

Adult↗
PubMed2006

Altered granulopoietic profile and exaggerated acute neutrophilic inflammation in mice with targeted deficiency in the sialyltransferase ST6Gal I.

Elevation of serum sialic acid and the ST6Gal-1 sialyltransferase is part of the hepatic system inflammatory response, but the contribution of ST6Gal-1 has remained unclear. Hepatic ST6Gal-1 elevation is mediated by P1, 1 of 6 promoters regulating the ST6Gal1 gene. We report that the P1-ablated mouse, Siat1DeltaP1, and a globally ST6Gal-1-deficient mouse had significantly increased peritoneal leukocytosis after intraperitoneal challenge with thioglycollate. Exaggerated peritonitis was accompanied by only a modest increase in neutrophil viability, and transferred bone marrow-derived neutrophils from Siat1DeltaP1 mice migrated to the peritonea of recipients with normal efficiency after thioglycollate challenge. Siat1DeltaP1 mice exhibited 3-fold greater neutrophilia by thioglycollate, greater pools of epinephrine-releasable marginated neutrophils, greater sensitivity to G-CSF, elevated bone marrow CFU-G and proliferative-stage myeloid cells, and a more robust recovery from cyclophosphamide-induced myelosuppression. Bone marrow leukocytes from Siat1DeltaP1 are indistinguishable from those of wild-type mice in alpha2,6-sialylation, as revealed by the Sambucus nigra lectin, and in the expression of total ST6Gal-1 mRNA. Together, our study demonstrated a role for ST6Gal-1, possibly from extramedullary sources (eg, produced in liver) in regulating inflammation, circulating neutrophil homeostasis, and replenishing granulocyte numbers.

Acute Disease↗
PubMed1993

Alpha 4/180, a novel form of the integrin alpha 4 subunit.

The integrin alpha 4 beta 1 (VLA-4) is a versatile cell-cell and cell-extracellular matrix adhesion receptor. The alpha 4 subunit can be expressed on the cell surface in two forms: an intact form (alpha 4/150) and a cleaved form (alpha 4/80,70). Here we have characterized a third form of alpha 4, called alpha 4/180. Although alpha 4/180 (M(r) 180, nonreduced) is different in size than alpha 4/150 (M(r) 150, nonreduced), these two forms are clearly related, as they (i) shared the same amino-terminal sequence, (ii) were both recognized in Western blots by an anti-alpha 4 COOH-terminal antiserum, (iii) migrated with the same apparent size and charge when reduced, and (iv) were both immunoprecipitated using anti-VLA-4 reagents. In pulse-chase experiments, precursors to both forms appeared simultaneously and matured at the same rate, indicating that one is most likely not the biosynthetic precursor of the other. Although reduction of alpha 4/180 to yield alpha 4/150 suggested the release of a cysteine-linked 30-kDa fragment, seven different biochemical techniques failed to identify such a fragment. Also, alpha 4/180 was converted to alpha 4/150 by incubation at pH 11, by treatment with EDTA at 56 degrees C, or by heating in the presence of elevated SDS levels. Together our findings suggest that alpha 4/180 and alpha 4/150 represent different conformations of the same alpha 4 polypeptide, with the former having anomalous slower migration in SDS-polyacrylamide gel electrophoresis. This unusual biochemical feature of alpha 4 is not shared by other beta 1-associated integrin alpha subunits and suggests that VLA-4 has unique structural properties.

Alternative Splicing↗