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At least 19 recordsLinked to original sources
PubMed1978

Portal circulations and their relation to counter-current systems.

We have reviewed the distribution of portal circulations throughout the animal body; they are commoner than is generally supposed. Most portal circulations consist of two serial capillary beds connected by one or more larger vessels. We have called these 'convergent' portal circulations: examples are hepatic portal, placental, hypophysial, renal, ovarian and testicular circulations, as are parts of the lymphatic circulation. A second type of portal circulation, which is less common, consists of two serial capillary beds that are not connected by larger vessels. These we have called 'continuous' portal circulations: adrenal and pancreatic circulations are examples of this type. When a countercurrent concentrating mechanism exists in the body it is always part of the primary or secondary bed of a convergent portal circulation, though some convergent portal circulations are not associated with countercurrent mechanisms.

Adrenal Glands↗
PubMed1979

Use of circulating immune complex levels in the serodifferentiation of endocarditic and nonendocarditic septicemias.

Distinguishing endocarditic from nonendocarditic septicemias is prognostically and therapeutically important. One hundred two patients with both valvular and nonvalvular sepsis were studied for the presence and quantitation of circulating immune complexes. Ninety per cent of the patients with infective endocarditis versus 50 per cent of septic patients without infective endocarditis had circulating immune complex levels (p less than 0.005). Mean circulating immune complex levels in patients with infective endocarditis were significantly higher than in those without infective endocarditis, 106 +/- 18.58 microgram/ml versus 31 +/- 7.4 microgram/ml (p less than 0.005). Only three of 52 patients without infective endocarditis had circulating immune complex levels greater than 100 microgram/ml, as opposed to 16 of 50 patients with infective endocarditis (p less than 0.005). Similarly, one of 52 patients without infective endocarditis has circulating immune complex levels greater than 200 microgram/ml, as opposed to eight of 50 patients with infective endocarditis (p less than 0.05). In 92 per cent of the patients without infective endocarditis and 76 per cent of those with infective endocarditis peak circulating immune complex levels developed within 14 days after their entry into the study, often on the initial sampling. In febrile, septicemic patients with clinical symdromes nonclassic for endocarditis, measurements of serial circulating immune complex levels may be of adjunctive diagnosis importance. If circulating immune complex levels are undetectable, endocarditis would appear less likely; alternatively, levels above 100 to 200 microgram/ml would suggest a valvular rather than nonvalvular septic focus.

Antigen-Antibody Complex↗
PubMed2026

Translational Gap in Biomarker Discovery: Tumor Surface Markers Rarely Mirror Circulating Levels.

BACKGROUND: Tumor-associated cell surface proteins are frequently proposed as circulating biomarkers for colorectal cancer (CRC) based on their high tumor expression. However, many candidates identified through tissue-based analyses fail to translate into clinically useful biomarkers. We investigated the translational gap between tissue-level expression and circulating detectability in CRC, focusing on molecular subtypes defined by caudal-type homeobox 2 (CDX2) expression. METHODS: Transcriptomic data from The Cancer Genome Atlas (TCGA) were analyzed to identify cell surface markers differentially expressed between CDX2-Low and CDX2-High CRCs. A clinical cohort of right-sided CRC patients was evaluated using paired tumor tissue and preoperative plasma samples. CDX2 expression was assessed by immunohistochemistry, and circulating concentrations of selected cell surface proteins were quantified using a multiplex ELISA platform. RESULTS: Several tumor-associated cell surface markers exhibited marked CDX2-dependent differences in tissue expression. However, for most markers, circulating plasma levels did not mirror tissue-level patterns. CEACAM1 was the sole marker demonstrating concordant CDX2-dependent differences in both tumor tissue and plasma, with significantly lower levels in CDX2-Low CRCs. In contrast, CEACAM5 showed a dissociation between tissue expression and circulating levels, despite analytical validation against serum carcinoembryonic antigen (CEA). CONCLUSIONS: Our findings demonstrate that tumor overexpression of cell surface markers does not necessarily translate into detectable circulating biomarkers. This translational disconnect underscores limitations of biomarker selection strategies based solely on tissue expression and highlights the importance of integrating systemic biology into biomarker development. While some tumor-associated proteins may lack utility as circulating biomarkers, they may still represent viable therapeutic targets in CRC.

CDX2↗
PubMed1976

Specific extraction of antigen in vivo by extracorporeal circulation over antibody immobilized in collodion-charcoal.

A novel extracorporeal immunoadsorbent is described in which anti-bovine serum albumin (anti-BSA) was entrapped in collodion membranes adherent to activated charcoal particles. This immunoadsorbent was capable of specifically removing circulating BSA in vitro and in vivo in an extracorporeal system in dogs. In preparation of the immunoadsorbent, up to 81.2% of added anti-BSA was retained on collodion-charcoal. In vitro circulation studies demonstrated that anti-BSA collodion-charcoal removed 812% more 125I-BSA than control colloidon-charcoal. For in vivo studies, an extracorporeal circulation system was established and arterial blood was passaged through a continuous flow celltrifuge wherein plasma which was separated from formed elements of the blood was circulated over anti-BSA and control rabbit gamma-globulin collodion-charcoal. 125I-BSA was passively infused into mongrel dogs, and plasma was then circulated over extracorpeal immunoadsorbents for 2 hr. Results showed up to 896% greater uptake of circulating 125I-BSA on the charcoal containing immobilized anti-BSA compared to control charcoal. There was no evidence of release of anti-BSA from the immunoadsorbent since 125I-anti-BSA cpm on the charcoal before and after the experiments were unchanged. In addition, there were no significant alterations in hematocrit, leukocyte counts, serum sodium, potassium, calcium, magnesium, or creatinine levels before and after in vivo procedures. These data suggest that this immunoadsorbent consisting of anti-BSA immobilized in collodion membranes adherent to charcoal particles may specifically withdraw circulating antigens in vivo with minimal release of entrapped antibodies and no significant alteration in the host hematologic and biochemical status.

Animals↗
PubMed1979

Developmental patterns of the testicular response to experimental modifications of circulating androgen levels in the fetal rabbit.

The circulating level of free androgens in fetal and newborn rabbits was reduced by active immunization of mothers against testosterone (T) or was increased by injecting dihydrotestosterone (DHT) into the mothers. After immunization, about 100% of the circulating T and DHT in fetuses was bound. After maternal injection of DHT, the circulating level of this hormone in fetuses was increased 2- to 120-fold. The effects of these treatments were evaluated by determining testicular levels of T, a physiological index of circulating gonadotropin. From 20--23 days of gestation, testicular T content was modified neither by circulating antibodies nor by an increase of blood DHT. The same overloads of circulating DHT, which were ineffective between 20--23 days, significantly reduced testicular T content between 25--29 days. Testicular T content was significantly increased in newborns from immunized mothers. These results suggest that the appearance of the negative feedback action of circulating androgens takes place relatively late, at 24 or 25 days, after differentiation of the genital tract.

Animals↗
PubMed1975

High degree of conversion of angiotensin I to angiotensin II in the mesenteric circulation of the isolated perfused terminal ileum of the cat.

Conversion of AI to AII has been studied in the mesenteric circulation of the isolated perfused cat terminal ileum. Infusion of AI through the mesenteric circulation induced a significantly potentiated response when the venous return was superfused over the rat colon and the rabbit aortic strip. Addition of converting-enzyme inhibitor, SQ 20881 to the perfusion medium competitively prevented the potentiation of AI on the assay organs without altering its direct effects. The percent conversion of AI to AII was found to be 68 in the mesenteric circulation. In contrast, infusion of AII through the mesenteric circulation has lost about 40% of its biological activity as measured on the same assay organs. SQ 20881 abolished the inactivation of AII in the mesenteric circulation. It is concluded that the mesenteric circulation of the isolated perfused cat terminal ileum is one of the major conversion areas of AI to AII. SQ 20881 prevented the conversion of AI to AII as well as abolishing the inhibition of AII passing through the mesenteric circulation.

Angiotensin II↗
PubMed1979

UCLA conference. Circulating immune complexes: their immunochemistry, detection, and importance.

The size and molecular composition of circulating immune complexes depend on various factors, including the concentrations and valences of antigens and antibodies and the antigen-antibody ratio. The composition and biological properties of circulating immune complexes, in turn, influence their fate in vivo as well as the likelihood of their detection by various assays. Several assays clearly detect circulating immune complexes, but no single assay has yet been shown to be the most sensitive and the most specific for the entire spectrum of circulating immune complexes. Assays correlate poorly with each other, but this may be desirable if we are to determine which circulating immune complexes have diagnostic, prognostic, or pathogenic importance. Circulating immune complexes are found in numerous rheumatologic disorders and infectious diseases. Their presence in the circulation statistically correlates with disease activity; however, the assays currently used have limited value for diagnosing or aiding in therapeutic decisions. Nevertheless, the future holds promise for such uses.

Antigen-Antibody Complex↗
PubMed2026

Genetically Predicted Gene Expression and Circulating Metabolites Associated with Cervical High-Grade Squamous Intraepithelial Lesion: A Mendelian Randomization Study.

BACKGROUND: High-grade squamous intraepithelial lesion (HSIL) is a precancerous condition of the cervix. Identifying risk factors associated with HSIL and understanding their potential mechanisms may inform prevention strategies. This study aimed to investigate the associations of genetically predicted gene expression and circulating metabolites with HSIL risk using Mendelian randomization (MR). METHODS: We performed two-sample MR analysis to evaluate the associations of genetically predicted gene expression (eQTLGen consortium, N=31,684) and circulating metabolites (genome-wide association study [GWAS], N=8,299) with HSIL risk (FinnGen R12, N=293,218; 8,291 cases). Mediation analysis was conducted to explore whether metabolites might mediate the associations between genes and HSIL. Sensitivity analyses, including Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO), leave-one-out, and colocalization, were performed to assess the robustness of the findings. All GWAS data used in this study were derived from European-ancestry populations. RESULTS: Eleven genes showed significant associations with HSIL after false discovery rate (FDR) correction (q<0.05), including VWA7, PAX8, GUSBP1, IKZF3, PAX8-AS1, NFKBIL1 (interpret with caution due to an influential single nucleotide polymorphism [SNP]), ERBB2, COL11A2, SKIV2L, TCF19, and PGAP3. Eleven circulating metabolites were also significantly associated with HSIL. Mediation analysis suggested that two phospholipid metabolites (GCST90200685 and GCST90200692) might mediate a small proportion of the total protective association of COL11A2 with HSIL (1.46% and 1.45%, respectively), indicating that the protective association of COL11A2 is largely independent of these circulating metabolites. Colocalization analysis showed strong evidence of shared causal variants for eight genes (PP.H4>0.98), while COL11A2 showed weak evidence of colocalization (PP.H4=1.58&#xd7;10-15). Functional enrichment analysis indicated that COL11A2-related genes were enriched in extracellular matrix (ECM)-receptor interaction and PI3K-Akt signaling pathways. CONCLUSION: This MR study identified 11 genes and 11 circulating metabolites associated with HSIL risk. Among these, COL11A2 showed a protective association that appeared to be largely independent of circulating phospholipid metabolites, suggesting potential local mechanisms. These findings provide genetic and metabolic clues for future studies on HSIL etiology.

COL11A2↗
PubMed1975

Adrenergic mechanisms in the cephalic and cerebral circulations of the subhuman primate.

Effects of circulating adrenergic amines on the cerebral circulation remain contraversial. Common carotid (CCF) and internal carotid (ICF) arterial flows were determined electromagnetically in eight lightly anesthetized baboons to evaluate alterations in the cephalic and cerebral vascular beds, respectively. Epinephrine (E), norepinephrine (NE), phenylephrine (PE), and isoproterenol (I) were injected randomly in doses of 10-3, 10-2, 10-1, and 1 mug (base) per kilogram into each carotid artery. Measurements were repeated in four animals after alpha-adrenergic blockade with phenoxybenzamine and in another four animals after beta-adrenergic blockade with propranolol. Baseline CCF was 75 plus or minus 10 (S.E.M.) ml. per minute and ICF was 58 plus or minus 8 ml. per minute. Significant (p smaller than 0.05) CCF changes without arterial pressure alterations occurred with 10-1 mug per kilogram doses. Alpha blockade significantly (p smaller than 0.05) attenuated the effects of E, NE, and PE on CCF while beta blockade significantly (p smaller than 0.05) attenuated the effect of I on CCF. ICF did not change significantly (p greater than 0.05) after injection of any of the vasoactive amines, unless associated with pressure changes at the highest dose. Our data suggest the presence of alpha- and beta-adrenergic receptor sites within the cephalic circulation resulting in significant flow responses to intra-arterial adrenergic amines. The absence of responses in the cerebral circulation suggests that circulating catecholamines do not significantly influence or regulate the cerebral vasculature. In addition the data suggest that use of adrenergic agonists to alter the hemodynamics of the cerebral circulation is limited.

Adrenergic Agonists↗
PubMed1977

Influence of dietary vitamin D3 on the circulating concentration of its active metabolites in the chick and rat.

Plasma concentrations of 25-hydroxyvitamin D3 (25-OHD3) and 1 alpha,25-dihydroxyvitamin D3 (1 alpha, 25-(OH)2D3) in growing chicks and weanling rats were measured by a new radioreceptor assay to determine the effects of varying dietary levels of vitamin D3. The plasma concentration of 25-OHD3 fell from 14.1 ng/ml in 1-day-old chicks to undetectable levels after 3 weeks on a rachitogenic diet. Circulating 1 alpha,25-(OH)2D3 hormone also decreased from 8.9 ng/100 ml to undetectable levels at 3 weeks in these chicks. Chicks receiving an optimal supplement of vitamin D3 (1.4 IU/g diet) for three to four weeks had plasma 25-OHD3 and 1 alpha,25-(OH)2D3 levels of 21-35 ng/ml and 5.1-7.5 ng/100 ml, respectively. Nutritional supplementation with a 50-fold excess of vitamin D3 (70 IU/g diet) elicited a substantial increase in plasma 25-OHD3 to 87-130 ng/ml, while plasma 1 alpha,25-(OH)2D3 was not increased. Increasing dietary calcium from 1.4 to 2.8% did not alter the circulating level of vitamin D3 metabolites in chicks fed 1.4 IU of vitamin D3/g diet. Direct measurement of the renal 25-OHD3-1 alpha-hydroxylase in vitro, showed that lowering dietary calcium or exclusion of vitamin D3 stimulated the biosynthesis of 1 alpha,25-(OH)2D3, but raising calcium did not alter the enzyme activity. It is concluded that the circulating concentration of the 1 alpha,25-(OH)2D3 hormone in the chick is unaffected by abnormally high intakes of vitamin D3 or calcium, but the renal production of the hormone increases during vitamin D3 or calcium deprivation. Additional studies in rats fed a diet supplemented with either 2 or 1000 IU of vitamin D3/g verify that the circulating concentration of 25-OHD3 is markedly increased when the dietary intake of vitamin D3 is elevated. Moreover, 1 alpha,25(OH)2D3 is not increased under these conditions, but actually falls significantly when the dietary level of vitamin D3 is raised from 2 to 1000 IU/g. These studies in both the chick and rat indicate that dietary vitamin D3 excess enhances circulating 25-OHD3, probably because the vitamin D3-25-hydroxylase enzyme is not strigently controlled. The fact that the circulating 1 alpha,25-(OH)2D3 is not concomitantly increased may reflect either decreased synthesis or increased utilization of the 1 alpha,25-(OH)2D3 sterol.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
PubMed2026

Circulating IGF2BP3 enables risk stratification and predicts treatment response in Ewing sarcoma.

Ewing sarcoma (EWS), the second most common pediatric bone tumor, presents with a markedly heterogeneous clinical spectrum and optimal risk stratification is therefore crucial for improving treatment outcomes. The RNA-binding protein IGF2BP3 is a critical oncogenic driver of EWS malignancy. This study evaluates the clinical utility of circulating IGF2BP3 as a biomarker to predict treatment response and risk of disease progression in patients with EWS. Plasma samples from 60 patients with EWS diagnosed and treated at the IRCCS Rizzoli Orthopedic Institute (Bologna, Italy) were collected at diagnosis before treatment initiation and/or after induction chemotherapy. For 51 of these patients, blood was collected at diagnosis, prior to any treatments. For 25 patients, blood samples were available at diagnosis and before surgical intervention, allowing longitudinal analysis in the same patient. For 9 patients, blood was collected only after preoperative chemotherapy, before surgical intervention. Circulating IGF2BP3 levels were quantified using a highly specific and sensitive ELISA assay. Plasma samples from healthy donors served as controls. IGF2BP3 plasma levels were correlated with IGF2BP3 tumor tissue expression, established clinical risk factors, and cumulative incidence of relapse using univariable and multivariable analyses. Plasma IGF2BP3 levels were significantly elevated in patients with EWS compared with healthy controls, with a subset of patients (22/51, 43.2%) exhibiting clinically relevant concentrations. Circulating IGF2BP3 levels reflected tumor expression of the molecule and provided additional prognostic information beyond standard clinicopathologic features. The prognostic impact of circulating IGF2BP3 was primarily observed in patients with localized disease, in whom elevated levels were identified as a significant adverse prognostic factor for disease-specific survival (hazard ratio, 10.63; 95% CI, 1.27-88.62; P = 0.029). Longitudinal monitoring demonstrated that persistence of IGF2BP3 in plasma after induction chemotherapy was a strong predictor of poor clinical outcomes. Circulating IGF2BP3 represents a valuable biomarker for early risk stratification in EWS, particularly in patients with localized disease. Although this is single-marker assay, the expression of the molecule may impact on the fate of many mRNAs. We present an accurate, simple, cost-effective and easy clinical applicable tool to support risk-adapted therapeutic interventions. The limited number of employed patients warrants the need of larger cohorts for validation.

Humans↗