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PubMed1982

Biocultural risks in longevity: Samoans in California.

Because migration is such a widespread phenomenon, studies of the effects of accompanying life change on the health and well-being of the migrant have special significance in areas like California that support large migrant communities. Previous studies have shown that increased weight and elevated blood pressure may be linked to changes in diet, exercise habits, and the altered sociocultural milieu of the migrant. Among Samoans, a Pacific Island population of Polynesian descent, these changes appear to be particularly prominent in segments of the population that have moved to the environment of Hawaii, which epidemiologic studies have characterized as "intermediate-modern.' Preliminary findings from a survey of weight, height, blood pressure, fasting glucose levels, and mortality records among Samoans living in California indicate that individuals living under more highly urbanized conditions exhibit even more pronounced changes. Adult weight among Samoans in California (San Francisco) greatly exceeds that of their counterparts in Hawaii and Samoa. Elevated blood pressures are also seen, though the extent to which this is associated with excessive weight gain is unclear. The number of individuals with high (greater than or equal to 160 mg/dl) fasting plasma glucose levels would be consistent with a population in which the prevalence of diabetes is many times higher than in the U.S. population. Although mortality patterns are difficult to determine for this population, available records suggest an excess mortality from cardiovascular diseases of all types among adult Samoans under age 50. Further investigations will attempt to link biobehavioral changes in the migrants' lifestyle to these observed patterns of risk.

Adult↗
PubMed2005

Congenital oculomotor nerve synkinesis associated with fetal retinoid syndrome.

INTRODUCTION: Isotretinoin (RA), used for the treatment of cystic acne, is a powerful teratogen, causing craniofacial dysmorphisms and neural tube defects. We present two patients with RA embryopathy and oculomotor nerve synkinesis. METHODS: Retrospective review of patient records. RESULTS: Two patients presented with third nerve synkinesis and fetal RA exposure. Both had marked elevation of the upper eyelids on adduction such that the lid fissures alternately opened and closed on gaze from side to side. Both patients showed typical dysmorphisms of RA embryopathy. The first patient had complete agenesis of the cerebellar vermix and died at 2 years. The second patient had restricted extraocular muscles in one eye and was exotropic and hypotropic. DISCUSSION: Both patients demonstrated simultaneous innervation of the medial rectus and levator palpebrae muscles causing coincident lid elevation in adduction. This evidence of oculomotor nerve synkinesis is consistent with animal studies showing abnormalities in the formation of cranial nerve ganglia following fetal RA exposure. CONCLUSION: RA is a powerful teratogen. These patients provide additional clinical evidence of its influence on neural migration during early development.

Acne Vulgaris↗
PubMed1998

Involvement of interleukin-1beta in zinc deficiency-induced intestinal damage and beneficial effect of cyclosporine A.

In a previous study we have shown that zinc deficiency caused several alterations in intestine of rats. Here we report that interleukin-1beta (IL-1beta) is involved in the zinc deficiency-induced mucosal damage and that cyclosporine A (CsA) protects the intestine against both structural and functional alterations by different mechanisms. The zinc deficient (ZD) rats were maintained on a zinc deficient diet for 40 days. They received a daily injection of CsA (12 mg/kg) for the last 10 days. The histological analysis of small intestine revealed that the dramatic alterations induced by zinc deficiency (ulcerations, inflammation, edema, vasodilatation), were not present after CsA treatment. The IL-1beta gene expression, analyzed by PCR, was increased in the three intestinal regions of ZD rats, as compared to C rats. There was a relation between increasing IL-1beta expression and increased severity of damage, and the highest cytokine elevation was in the most damaged region, i.e. the jejunum. After CsA administration the IL-1beta mRNA was similar to control rats. The intestinal cell proliferation, measured as crypt cell production rate and labelling index, as well the cell renewal, measured as cell migration rate and turnover time, were affected by zinc deficiency. After CsA treatment, all these variables were similar to control rats, suggesting that CsA induces a stimulation of intestinal cell proliferation in zinc deficiency. Finally, the decrease in the disaccharidase activities induced by zinc deficiency was abrogated by CsA treatment.

Animals↗
PubMed1997

Increased incidence of psychotic disorders in migrants from the Caribbean to the United Kingdom.

BACKGROUND: Several studies have replicated the finding of increased incidence of schizophrenia and related psychoses in first and second generation migrants from the Caribbean. The finding has remained consistent in studies employing different methods, but concern has been expressed about indirect methods of calculating the population at risk. This study aims to overcome these short-comings. METHOD: A further prospective study was undertaken in Nottingham assembling an inception cohort of psychotic patients (N = 168) presenting from a defined catchment area. The 1991 census, which includes codings for self-ascribed ethnic origin, was used to calculate the denominator, employing correction factors for potential under-enumeration. Case-ascertainment was based upon all service contacts and subjects had in-depth assessments including the SCAN. Collateral history was obtained from informants. RESULTS: Subjects born in the Caribbean, or who had one or both parents born in the Caribbean, had a greatly elevated risk (incidence ratios above 7) for all psychotic disorders and for ICD-10 (DCR)-defined F20 Schizophrenia. CONCLUSIONS: The size of the increase and the methodological safeguards employed support the validity of this now highly replicated finding. A personal or family history of migration from the Caribbean is a major risk factor for psychosis; the consistency of this finding justifies a systematic evaluation of potential aetiological factors. Any hypothesis derived from the evidence so far must explain: increased incidence in first and second generation migrants; increased risk for all psychoses (including affective psychoses); and an effect specifically associated with a migration history from the Caribbean to Northern Europe.

Adolescent↗
PubMed2002

Selective alpha4beta7 integrin antagonists and their potential as antiinflammatory agents.

The accumulation of leukocytes in various tissues contributes to the pathogenesis of numerous human autoimmune diseases. The integrin alpha4beta7, expressed on the surface of B and T lymphocytes, plays an essential role in lymphocyte trafficking throughout the gastrointestinal (GI) tract via interaction with its primary ligand, mucosal addressin cell adhesion molecule (MAdCAM). Elevated MAdCAM expression in the intestines and liver has been linked to GI-associated autoimmune disorders, including Crohn's disease, ulcerative colitis, and hepatitis C. Monoclonal antibodies that block the interaction of alpha4beta7 with MAdCAM inhibit lymphocyte homing to murine intestines without effecting migration to peripheral organs; this suggests that alpha4beta7-selective antagonists might be useful as GI specific antiinflammatory agents. Here, we report the discovery of highly potent and selective alpha4beta7 antagonists affinity selected from a random peptide-phage library. Subsequent optimization of initial peptide leads afforded alpha4beta7-selective heptapeptide inhibitors that competitively inhibit binding to MAdCAM in vitro and inhibit lymphocyte homing to murine intestines in vivo. Substitution of a single carboxylate moiety alters selectivity for alpha4beta7 by more than 500-fold to afford a potent and selective alpha4beta1 antagonist. The antagonists described here are the first peptides to demonstrate potency and selectivity for alpha4beta7 compared to other integrins.

Alanine↗
PubMed1988

Factor VIII/von Willebrand factor abnormalities during L-asparaginase treatment in patients with acute lymphoblastic leukemia.

Factor VIII/von Willebrand factor (VIII/vWf) related properties were studied in 10 patients affected by acute lymphoblastic leukemia during L-asparaginase-vincristine-prednisone treatment. These properties remained within the normal range during the period of observation without any difference from the basal values. On the contrary, VIII:C activity was already increased before medication and showed gradual additional elevation during the observation period, reaching a peak 1 week after discontinuation of L-asparaginase administration. Crossed immunoelectrophoresis of vWf, performed weekly in 2 patients during the period of medication, demonstrated a normal pattern before the beginning of treatment, but an apparently faster migrating peak during L-asparaginase therapy, suggesting a qualitative abnormality of vWf. No abnormal bleeding tendency was found in any of the patients.

Adolescent↗
PubMed2003

Participation of heme oxygenase-1 in a model of acute inflammation.

In this study, the role of heme oxygenase-1 (HO-1) in the inflammatory response elicited by zymosan in the mouse air pouch model has been examined. This response is characterized by a time-dependent increase in HO-1 expression in the leukocytes migrating into the exudates. At 24-48 h maximal HO-1 expression was accompanied by reduced cyclooxygenase-2 (COX-2) and nitric oxide synthase-2 (NOS-2) expression as well as low levels of inflammatory mediators. Hemin administration into the air pouch caused an elevation of HO-1 protein and bilirubin levels induced by zymosan with inhibition of COX-2 expression. In mouse peritoneal macrophages from hemin-injected mice, we also observed an increased expression of HO-1 with inhibition of COX-2 expression and prostaglandin E(2) (PGE(2)) levels. Our data suggest an anti-inflammatory role for HO-1 in the response induced by this phagocytic stimulus.

Animals↗
PubMed1989

Isolation, characterization, and quantitative measurement of serum alpha 1-acid glycoprotein in cattle.

Bovine alpha 1-acid glycoprotein (alpha 1AG) was purified from pooled normal bovine sera by successive ammonium sulfate precipitation, ion-exchange chromatographies and gel filtration. Bovine alpha 1AG had a molecular weight of 42,000 +/- 2,000 and a sedimentation coefficient of 3.4S. It contained 26.6% carbohydrate. Gel isoelectric focusing revealed a microheterogeneity with 7 to 8 bands in a pI range of 3.2 to 3.7. It migrated to the alpha 1-globulin region upon immunoelectrophoresis. Single radial immunodiffusion was developed for the quantitative measurement of bovine alpha 1AG in serum. The mean serum value of alpha 1AG in 152 healthy Holstein cattle (1-12 years old) was 283.2 +/- 82.3 micrograms/ml. Elevated values (cut-off value = 450 micrograms/ml) were observed in cattle with traumatic pericarditis (100%), arthritis (100%), mastitis (91%), pneumonia (70%), and mesenteric liponecrosis (43%).

Age Factors↗
PubMed1999

Angiogenic activity of human soluble intercellular adhesion molecule-1.

Serum levels of soluble intercellular adhesion molecule-1 (sICAM-1) are elevated in a number of pathological conditions associated with angiogenesis, including tumor growth. Because the increased levels of sICAM-1 suggested that it may be angiogenic, we tested the ability of sICAM-1 to promote angiogenesis. Human recombinant sICAM-1 stimulates chemokinetic endothelial cell migration, endothelial cell tube formation on Matrigel, and sprouting of aortic rings. sICAM-1 also mediates angiogenesis in the chick chorioallantoic membrane assay. Additionally, we found a Mr 49,000 molecule that binds to sICAM-1 that may be the surface ligand on endothelial cells. The evidence that sICAM-1 has angiogenic activity suggests a possible role linking inflammation and neovascularization. Furthermore, sICAM-1 may enhance tumor growth by promoting angiogenesis and escape from immunosurveillance.

Angiogenesis Inducing Agents↗
PubMed1991

IFN-gamma inhibits inflammatory cell recruitment and the evolution of bacterial cell wall-induced arthritis.

Localization of streptococcal cell wall Ag (SCW) in the synovial tissue of treated rats induces an influx of leukocytes and a cell-mediated immune response leading to arthritis and joint destruction. Systemic administration of the T cell product, IFN-gamma (10(6) U/kg/day), suppresses the recruitment of leukocytes into the synovium and effectively inhibits the inflammation and pathology characteristic of SCW-induced arthritis (articular index 10.4 +/- 0.6 for SCW vs 2.0 +/- 0.7 for SCW with IFN-gamma, p less than 0.005). Monocyte-macrophages from animals treated with IFN-gamma exhibited defective chemotactic responses when tested in vitro and furthermore, monocytes cultured with IFN-gamma (25 to 500 U/ml) in vitro had significantly suppressed chemotactic responses to the complement fragment C5a (p less than 0.005). The decreased ability to migrate to C5a was associated with decreased binding of fluorochrome-conjugated C5a indicative of reduced expression of C5a receptors. Based on these data, IFN-gamma that induces monocyte maturation as reflected by increased Ia expression conversely inhibits C5a receptor expression. Although locally elevated IFN-gamma levels may serve to inhibit recruitment away from an inflammatory site, systemic exposure to IFN-gamma appears to inhibit leukocyte recruitment to the inflammatory site by its ability to induce premature maturation and concomitant inability to respond to certain chemotactic ligands. Inasmuch as monocyte recruitment to the synovium is pivotal in the development of SCW-induced polyarthritis, the ability of IFN-gamma to inhibit this event effectively inhibits the synovial pathology.

Animals↗
PubMed1980

[Immune response in the course of Kaposi's sarcoma].

9 patients with Kaposi's sarcoma, not treated with immunosuppressant drugs, were studied. In the Kaposi's disseminated form an impaired function of T mediated immunity (Leukocytes migration inhibition for PHA and PPD and skin test for DNCB) was found. The number of T lymphocytes (E rosettes) was normal. In the Kaposi's initial form with multiple dermal plaques and nodules, these alterations of cellular immunity were absent. In 4 patients elevated titles of Cytomegalovirus antibodies were found. The occurrence of an impairment of cellular immunity only in the serious and disseminated Kaposi's form is emphasized by the Authors.

Aged↗
PubMed1996

[Antistreptococcal immunity in rheumatism and urban ecological risk factors].

143 rheumatic patients and 40 healthy subjects exposed to different air pollution have been studied. In three representative groups the following parameters were studied: immunocompetent cell function (by leukocyte migration inhibition with streptococcal antigen), humoral response (by antibodies to streptococcus A polysaccharide shown at immunodiffusion), titres of antistreptolysin 0 (ASL0) and antistreptohyaluronidase (ASH). High hypersensitivity of delayed type was registered in patients from clean zones. In those breathing with polluted air there were elevated levels of antibodies to A-polysaccharide. ASL0 and ASH, their high titer in summer evidencing toxic influence of photo-oxidants. Based on the data obtained it is possible to predict the risk of greater rheumatism activity in zone with greater air pollution.

Adult↗
PubMed1997

Effects of concurrently administered copper and mercury on phagocytic cell activity and antibody levels in guinea pigs with experimental ascariasis.

The subchronic effect of copper and mercury on selected immunological parameters in guinea pigs with experimental ascariasis was studied. Cupric sulphate and mercuric chloride administered for 28 days did not suppress the levels of specific circulating antibody in a subsequent Ascaris suum infection. Intoxication of animals significantly inhibited the phagocytic activity of peritoneal macrophages throughout the experiment. Ascaris suum infection elevated macrophage phagocytic activity but values remained significantly lower in comparison with infected non-intoxicated animals. Both the concurrently administered metal compounds changed the phagocytic ability of polymorphonuclear leucocytes in the blood. The intensity of infection assessed by the number of Ascaris larvae migrating in the lungs of animals currently intoxicated with both the metal compounds increased by 28.6%, compared with controls.

Animals↗
PubMed2006

Insights into the use of time-lapse GPR data as observations for inverse multiphase flow simulations of DNAPL migration.

Perchloroethylene (PCE) saturations determined from GPR surveys were used as observations for inversion of multiphase flow simulations of a PCE injection experiment (Borden 9 m cell), allowing for the estimation of optimal bulk intrinsic permeability values. The resulting fit statistics and analysis of residuals (observed minus simulated PCE saturations) were used to improve the conceptual model. These improvements included adjustment of the elevation of a permeability contrast, use of the van Genuchten versus Brooks-Corey capillary pressure-saturation curve, and a weighting scheme to account for greater measurement error with larger saturation values. A limitation in determining PCE saturations through one-dimensional GPR modeling is non-uniqueness when multiple GPR parameters are unknown (i.e., permittivity, depth, and gain function). Site knowledge, fixing the gain function, and multiphase flow simulations assisted in evaluating non-unique conceptual models of PCE saturation, where depth and layering were reinterpreted to provide alternate conceptual models. Remaining bias in the residuals is attributed to the violation of assumptions in the one-dimensional GPR interpretation (which assumes flat, infinite, horizontal layering) resulting from multidimensional influences that were not included in the conceptual model. While the limitations and errors in using GPR data as observations for inverse multiphase flow simulations are frustrating and difficult to quantify, simulation results indicate that the error and bias in the PCE saturation values are small enough to still provide reasonable optimal permeability values. The effort to improve model fit and reduce residual bias decreases simulation error even for an inversion based on biased observations and provides insight into alternate GPR data interpretations. Thus, this effort is warranted and provides information on bias in the observation data when this bias is otherwise difficult to assess.

Computer Simulation↗
PubMed2004

Blockade of macrophage migration inhibitory factor ameliorates experimental autoimmune myocarditis.

Macrophage migration inhibitory factor (MIF) is a cytokine that plays a critical role in the regulation of macrophage effector functions and T-cell activation. However, its role in the pathogenesis of experimental autoimmune myocarditis (EAM) has remained unresolved. In this study, we studied the role of the MIF in EAM. We investigated the expression of MIF in EAM using enzyme-linked immunosorbent assay, Northern blotting, and immunohistochemistry. Moreover, a neutralizing antibody (Ab) to MIF was injected intraperitoneally from day 0 to 20 (experiment 1), or from day 13 to 19 (experiment 2), after the immunization. Disease severity was estimated by the macroscopic and microscopic findings for the heart, heart weight to body weight ratio, and cellular and humoral immune responses on day 21. Enhanced MIF protein and mRNA expression in the heart tissue and an elevated serum MIF concentration were confirmed in EAM. In experiment 1, the anti-MIF Ab treatment markedly inhibited the onset of EAM. Moreover, a significant reduction in disease severity was also achieved even after the delayed anti-MIF Ab treatment in experiment 2. Furthermore, we demonstrated that MIF blockade decreased the expression of VCAM-1, TNF-alpha, and IL-1beta and the migration of T-cells and macrophages in the EAM heart. These results demonstrate an important role of MIF in the pathogenesis of EAM and suggest that MIF blockade may be a promising new strategy for the treatment of myocarditis.

Animals↗
PubMed1989

Increased expression of PDGF-B (c-sis) mRNA in rat lung precedes DNA synthesis and tissue repair during chronic hyperoxia.

Several aspects of tissue response to injury, including cell proliferation, cell migration, and deposition of extracellular matrix, have been attributed to platelet-derived growth factor (PDGF)-like cytokines. Because these responses play key roles in lung injury, PDGF-B (c-sis) gene expression was measured by Northern blot analysis of lung total RNA prepared after oxidant injury was induced by chronic exposure of rats to 85% oxygen for zero, 1, 3, and 7 days. Constitutive but low levels of PDGF-B mRNA (4.0 kb) were observed in the lungs of control animals exposed to 21% oxygen. Steady-state levels of PDGF-B mRNA in lung were elevated 2.5-fold by day 3 of hyperoxia and remained so up to at least day 7. The early increase in PDGF-B mRNA expression after 3 days of hyperoxic exposure preceded several other aspects of the reparative response. DNA synthesis measured by in vivo incorporation of [3H]thymidine into lung DNA was unchanged at day 3 but markedly elevated by day 7. A similar increase in extractable lung RNA implies a quantitative or qualitative change in extractable RNA at this later phase of tissue injury. Subtle changes in actin mRNA expression were also noted late in the course of lung injury. The content of cytoplasmic (beta,gamma) actin mRNA (2.1 kb) in lung was doubled after 7 days of hyperoxia (P less than 0.05). In addition, increased expression of an actin cDNA-hybridizing mRNA, which co-migrates with muscle-specific alpha-actin mRNA (1.7 kb), was detected on day 7, suggesting hyperplasia of smooth muscle and myofibroblasts. These data show that PDGF-B transcripts are constitutively expressed in rat lung tissue. The expression of PDGF-B mRNA increases early in the course of hyperoxic lung injury and precedes an increase in DNA synthesis and other responses that reflect tissue remodeling. These results suggest that the production of PDGF-like cytokines by cells within the lung itself initiates or modulates various aspects of lung injury and repair.

Actins↗
PubMed2005

Metabolic profile of long-distance migratory flight and stopover in a shorebird.

Migrating birds often complete long non-stop flights during which body energy stores exclusively support energetic demands. The metabolic correlates of such long-distance travel in free-living migrants are as yet poorly studied. Bar-tailed godwits, Limosa lapponica taymyrensis, undertake a 4500 km flight to their single spring stopover site and thus provide an excellent model in which to determine the energy fuels associated with endurance travel. To this end, we evaluated plasma concentrations of six key metabolites in arriving godwits caught immediately upon landing near their stopover site. Initial metabolite levels were compared with levels after 5 h of inactive rest to determine how flight per se affects energy metabolism. Birds refuelling on the stopover site were also examined. Arriving godwits displayed elevated plasma free fatty acids, glycerol and butyrate, confirming the importance of lipid fuel in the support of extended migratory activity. Further-more, elevated plasma triglycerides in these birds suggest that fatty acid provisioning is facilitated through hepatic synthesis and release of neutral lipids, as previously hypothesized for small migrants with high mass-specific metabolic rates. Finally, elevations in plasma uric acid suggest that protein breakdown contributes to the support of long-distance movement, to possibly maintain citric acid cycle intermediates, gluconeogenesis and/or water balance.

Africa↗
PubMed1998

Endothelial cell intracellular Ca2+ concentration is increased upon breast tumor cell contact and mediates tumor cell transendothelial migration.

Tumor cell extravasation is a determinant step in the process of hematogenous metastasis. The signal transduction pathways involved in the interactions between tumor cells and the vascular endothelium during transendothelial migration are still undefined. In the present study, we have investigated the influence of human breast adenocarcinoma cells (MCF7) on human umbilical vein endothelial cell (HUVEC) intracellular Ca2+ concentration ([Ca2+]i). We show that the contact between MCF7 cells and a confluent HUVEC monolayer induces an immediate and transient increase in HUVEC [Ca2+]i. This [Ca2+]i rise could not be elicited by tumor cell-conditioned medium, isolated tumor cell membranes, inert beads or normal breast epithelial cells, demonstrating the involvement of specific recognition mechanisms between MCF7 cells and HUVEC. Depletion of HUVEC intracellular Ca2+ stores by the endoplasmic reticulum Ca2+-ATPase inhibitor thapsigargin as well as the selective depletion of inositol 1,4,5-triphosphate (IP3)-sensitive Ca2+ stores by prior activation of HUVEC using histamine resulted in a complete inhibition of tumor cell-induced [Ca2+]i elevation. Similar results were obtained when HUVEC monolayers were treated with the tyrosine kinase inhibitor herbimycin A, suggesting a role for tyrosine kinase-associated cell surface receptors in tumor cell-endothelial cell interactions. The depletion of HUVEC intracellular Ca2+ stores by thapsigargin was also shown to delay MCF7-induced endothelial cell disjunction, to prevent their spreading on the subendothelial extracellular matrix and transendothelial migration in vitro. These results suggest that transient changes in endothelial [Ca2+]i may govern multiple steps of tumor cell extravasation.

Adenocarcinoma↗