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PubMed2000

Comparison of globulin mobilization and cysteine proteinases in embryonic axes and cotyledons during germination and seedling growth of vetch (Vicia sativa L.).

Vicilin and legumin, the storage globulins of mature dry vetch (Vicia sativa L.) seeds, are found in protein bodies which are present not only in the cotyledons, but also in the radicle, axis and shoot (together, for reasons of simplicity, here called axis). When at 24 h after the start of imbibition (hai) the radicle breaks through the seed coat a major part of the globulins in the axis has already been degraded, whereas in the cotyledons globulin breakdown cannot yet be detected. Globulin mobilization starts with the degradation of vicilin. At 48 hai when globulin mobilization in the cotyledons just begins, the axis is already nearly depleted of globulins. Mobilization of storage globulin is probably brought about by a complex of different cysteine proteinases (CPRs). The papain-like CPR2 and CPR4, and the legumain-like VsPB2, together with their mRNAs, are already present in axes and cotyledons of dry seeds. This means that they must have been formed during seed maturation. Additional papain-like CPRs are formed later during germination and seedling growth. CPR4 and VsPB2 together with their corresponding mRNAs become undetectable as germination and seedling growth proceed. VsPB2 and VsPB2-mRNA are substituted by the homologous legumain-like proteinase B and its mRNA. The composition of stored and newly formed CPRs undergoes developmental changes which differ between axes and cotyledons. It is concluded that storage globulin mobilization in germinating vetch seeds is started by stored CPRs, whereas the mobilization of the bulk of globulin is predominantly mediated by CPRs which are formed de novo.

Cotyledon↗
PubMed1976

Effects of sex hormones on the level of the messenger RNA for the rat hepatic protein alpha 2u globulin.

Alpha 2u Globulin is a protein synthesized in the liver, secreted into the serum, and excreted in the urine of mature male rats. The effects of androgens and estrogens on the level of the messenger RNA coding for the male rat hepatic protein have been investigated. Castrated male rats have reduced levels of alpha 2u globulin in serum and liver cytosol, as measured by a radial immunodiffusion assay. The livers from these castrated males were found to contain similarly reduced levels of the mRNA coding for alpha 2u globulin, as measured in an mRNA-dependent wheat germ cell-free translational system. Administration of dihydrotestosterone to castrated males resulted in increased levels of alpha 2u globulin in liver and serum and this increase in the level of the protein following androgen administration was accompanied by a parallel increase in the functional level of alpha 2u globulin mRNA. Administration of estradiol-17 beta to intact male rats gradually diminishes the levels of alpha 2u globulin in liver and serum. The livers from these estrogen-treated males were found to contain alpha 2u globulin mRNA at similarly reduced levels. The time course of the disappearance of the alpha 2u globulin mRNA following estrogen treatment parallels the disappearance of the protein in liver cytosol and serum. These results indicate that sex steroids affect the synthesis of the hepatic protein alpha 2u globulin by acting pretranslationally, possibly at the level of transcription. Although the liver had not been considered a primary target tissue for sex hormones, these results indicate that sex steroids can affect certain hepatic functions in a manner consistent with the accepted model for the action of steroid hormones on their target tissues.

Alpha-Globulins↗
PubMed1982

Modifications in alpha 2u globulin gene structure, transcription, and mRNA translation in hepatomas.

alpha 2u globulin synthesis ceases when a liver cell becomes malignant. We have compared the structure and transcription of the alpha 2u globulin genes in Morris hepatomas 5123D and 7793 with that of normal hepatic genes using alpha 2u globulin cDNA as a hybridization probe. No alpha 2u globulin mRNA was detected in hepatoma 7793 by cell-free translation, Northern blot, or R0t analysis. In hepatoma 5123D, however, a small number of alpha 2u globulin RNA sequences were detected by Northern blot and R0t analysis, but this RNA was not detectably translationally active either in vivo or in an in vitro cell-free translational system. No structural differences between normal liver and the hepatoma alpha 2u globulin genes were observed by Southern blot analysis of genomic DNA digested with restriction endonucleases Pst I, Bam HI, or Ava I. However, a general demethylation of cytosine residues in the alpha 2u globulin genes of hepatomas has been found using the restriction enzyme Hha I and the isoschizomeric pair of restriction enzymes Msp I and Hpa II. Therefore, loss of the alpha 2u globulin phenotype in these hepatomas is accompanied by extensive demethylation of DNA sequences within and/or immediately flanking the alpha 2u globulin genes.

Alpha-Globulins↗
PubMed1981

Rat alpha 2u globulin is encoded by a multigene family.

The hormonally responsive rat liver protein designated alpha 2u globulin is encoded by a multigene family. Southern blot hybridization analysis, and solution hybridization using a cloned alpha 2u globulin cDNA, indicate the presence of 18-20 alpha 2u globulin genes per haploid genome. In situ hybridization to rat metaphase chromosomes, using 125I-labeled alpha 2u globulin cDNA, indicates that most, and perhaps all, of the alpha 2u globulin genes are clustered on chromosome 5. Several alpha 2u globulin genes have been isolated from a rat library cloned in lambda phage. At least six of these clones appear to contain the entire alpha 2u globulin mRNA coding region. These genes are contained on different-sized restriction fragments, and are surrounded by distinct flanking sequences. Two of the six clones containing the alpha 2u globulin genes were found to have diverged greatly from the other four in the DNA sequence corresponding to the 3' untranslated region of mRNA. The implications for the hormonal control of alpha 2u globulin synthesis are discussed.

Alpha-Globulins↗
PubMed1983

Interacting role of thyroxine and growth hormone in the hepatic synthesis of alpha 2u-globulin and its messenger RNA.

Hypophysectomy completely abolishes and thyroidectomy results in a 90% reduction in the hepatic content of alpha 2u-globulin and its mRNA in the male rat. Thyroid hormone is also known to be required for the synthesis and secretion of pituitary growth hormone. In the hypothyroid rat either thyroxine or growth hormone was found to increase the activity and number of sequences of the mRNA for alpha 2u-globulin (measured by translational assay and hybridizational analysis with a cloned cDNA probe) to the euthyroid level. Treatment of hypophysectomized rats with a hormone combination containing growth hormone but not thyroxine increased the hepatic level of the mRNA for alpha 2u-globulin to that of normal animals. From these results we conclude that thyroxine indirectly influences the hepatic concentration of the mRNA for alpha 2u-globulin through its effect on pituitary growth hormone. Although administration of growth hormone to hypothyroid animals raised the hepatic concentration of alpha 2u-globulin mRNA to the euthyroid level, synthesis of alpha 2u-globulin remained low (50% of the normal). Complete recovery of alpha 2u-globulin synthesis required thyroxine. Therefore, in addition to an indirect effect on the hepatic level of alpha 2u-globulin mRNA, thyroxine also directly influences the synthesis of this protein. This direct effect of thyroxine on alpha 2u-globulin synthesis seems to be exerted at a step distal to the formation of mature mRNA.

Alpha-Globulins↗
PubMed1984

Differential regulation of alpha 2u globulin gene expression in liver, lachrymal gland, and salivary gland.

The alpha 2u globulins, products of a highly homologous multigene family, are synthesized in the liver and submaxillary salivary glands of the rat. Although their precise function has not been ascertained, they are of interest because of the complex developmental and hormonal regulation of their tissue levels. We now report that alpha 2u globulin is synthesized in a third tissue of the rat, the extraorbital lachrymal gland. Immunocytochemical studies indicate that the distribution of alpha 2u globulin is more homogeneous in the lachrymal gland than in the liver or submaxillary gland. In situ hybridization to alpha 2u globulin RNA reveals specific signal only over the acinar cells of the lachrymal gland. Several different isoelectric forms of alpha 2u globulin are encoded by lachrymal gland mRNA. The major lachrymal and salivary gland isoforms are indistinguishable from one another, but more acidic than the hepatic isoforms. In addition, analysis of double-stranded cDNAs with a diagnostic restriction-enzyme pair detects no differences between the alpha 2u globulin mRNAs of lachrymal and salivary gland, but clearly distinguishes these from their hepatic counterparts. In spite of the similarity between the lachrymal and salivary gland alpha 2u globulin gene products, we find that the hormonal and developmental regulation of alpha 2u globulin expression differs markedly in these two tissues. In the liver, where a different subset of alpha 2u globulin genes is expressed, a third regulatory phenotype is observed.

Alpha-Globulins↗
PubMed1978

gamma-Globulin level and dietary protein intake during the first year of life.

To investigate the possible causes of relatively low blood gamma-globulin levels (less than or equal to 0.5 gm/dl) during the first year of life, 287 patients less than 1 year of age who were suffering from mild diseases were studied retrospectively. They were divided into two groups, those with a gamma-globulin level less than 0.5 gm/dl and those with a gamma-globulin level greater than 0.5 gm/dl. By reconstructing the diets given, it was found that they had been receiving isocaloric diets that differed only in protein supply: patients with lower gamma-globulin levels received 2.9 gm/kg/day of protein and patients with higher gamma-globulin levels received 4.0 gm/kg/day. Fifty-five healthy subjects were studied prospectively during the first year of life on two isocaloric diets that differed only in their protein content: the first one supplied 2.5 gm/kg/day of protein and the second supplied 4.0 gm/kg/day. At approximately 5, 7, and 10 months of age, hemoglobin, total protein, albumin, globulins, immunoglobulins, and other common blood parameters were measured. Patients on the lower protein diet had a gamma-globulin concentration of less than or equal to 0.5 gm/dl and those on the higher protein diet had a gamma-globulin concentration of greater than or equal to 0.8 gm/dl. Immunoglobulin levels, particularly IgG, were lower in patients on the lower protein diet. The subjects with lower protein intake and lower levels of gamma-globulin and immunoglobulins showed significantly higher morbidity.

Blood Protein Electrophoresis↗
PubMed2001

Gc-globulin is an acute phase reactant and an indicator of muscle injury after spinal surgery.

OBJECTIVES AND DESIGN: Actin is the dominating protein in mammalian cells, including muscle cells, and is released into the circulation after tissue injury. Gc-globulin, one of the proteins in the Extracellular Actin Scavenger System (EASS) is responsible for the clearance of actin from the circulation. Clinical studies show that plasma levels of Gc-globulin are reduced in situations with tissue death, and that the degree of reduction correlates with development of organ dysfunction and survival. The purpose of the present study was to describe the serial changes in Gc-globulin after a standardized surgical procedure resulting in major muscle injury, comparing changes in Gc-globulin with changes in other acute phase proteins. MATERIAL AND METHODS: Twelve patients who underwent posterolateral lumbar fusion from L4 or L5 to sacrum were included in the study. Peripheral venous blood samples were obtained before surgery and on day 1, 3, 5, 12, 21, and 28 after surgery. Serum samples were analyzed for total Gc-globulin (Gc(total)), percentage of Gc-globulin complexed with actin (GC(complexed)), albumin, orosomucoid, haptoglobin, transferrin and creatin phosphokinase (CK). RESULTS: Gc(total) decreased to 87% of pre-operative values on day one. Thereafter the levels increased to a maximum of 135% of pre-operative values on day five, approaching baseline values towards the end of the observation period. Compared to this, changes in GC(complexed) displayed a mirror-like time-course, with levels of Gc(total) and GC(complexed) being significantly inversely correlated on day one (P < 0.05). Levels of albumin remained below pre-operative values the first three weeks post-operatively, reaching baseline at the end of the observation period (P < 0.05). CONCLUSION: The initial changes in Gc-globulin can be explained by increased release of actin from injured muscle tissue. Subsequently Gc-globulin displays characteristics of a so-called positive acute phase reactant, supporting previous in vitro studies, and clinical studies after minor surgery. In spite of genetic linkage and structural homology Gc-globulin and albumin are regulated differently after surgical trauma.

Actins↗
PubMed1987

Immunoregulatory effects of intravenous immune serum globulin therapy in common variable hypogammaglobulinemia.

Because of evidence of immunoregulatory effects of short-term administration of pooled donor gamma globulins, the effects of intravenous immune serum globulin were studied in nine adult patients with common variable hypogammaglobulinemia over a two-year period. Baseline assessment prior to immune serum globulin replacement included evaluation of B cell function, suppressor cell activity, and T cell subsets. These analyses were subsequently performed during the course of a first-year treatment period of intravenous immune serum globulin at doses of 100 to 200 mg/kg per month and a second-year trial at doses of 300 to 400 mg/kg per month. Five patients were re-evaluated following discontinuation of the intravenous immune serum globulin therapy for four months between the first and second treatment periods. During both treatment periods with intravenous immune serum globulin, suppressor cell activity increased markedly compared with baseline, and declined following discontinuation of drug therapy in the five patients. Suppressor cell activity was reversed by either irradiation of the T cell fraction or removal of the T8-positive cell fraction by flow cytometry. There was a reduction in the absolute number of total lymphocytes, the T3-positive cells (total T cells), and the T4-positive cells (helper cells) following intravenous immune serum globulin therapy; however, the percentages of the T cell subsets did not change significantly. Following immune serum globulin therapy, the number of T8-positive cells was not significantly changed but the T4:T8 ratio decreased from 2.1 at baseline to 1.5 after therapy (p greater than 0.05). These data demonstrate that long-term intravenous immune serum globulin administration modulates the immune system by increasing suppressor T cell functional activity but is not accompanied by changes in the number of T8-positive cells in the peripheral blood.

Adult↗
PubMed1989

Modulation of Fc receptor clearance and antiplatelet antibodies as a consequence of intravenous immune globulin infusion in patients with immune thrombocytopenic purpura.

In 1981 Paul Imbach first reported the usefulness of intravenous immune globulin infusions in the treatment of children with immune thrombocytopenic purpura. Other studies have shown that intravenous immune globulin was associated with the fastest platelet increase of any therapy, confirming the initial observation in children and adults. We and other investigators have used intravenous immune globulin as a maintenance therapy and speculated that repeated single infusions might have a curative value, in addition to an acute effect. The best-defined mechanism of intravenous immune globulin in this model autoimmune disease is Fc receptor blockade. This was first demonstrated by a slowing of antibody-coated, chromium-labeled red blood cell survival. Subsequent confirmation has come from the use of intravenous anti-D and a monoclonal anti-FcRIII that has been used in patients refractory to treatment. In vitro studies have demonstrated alteration in Fc receptor expression on circulating cells, and this mechanism is presumed to be related intimately to the acute platelet increase seen after intravenous immune globulin. Studies with the latest platelet antibody methodology do not support interference with binding of antiplatelet antibodies as an important mechanism, but there are in vitro data to support this hypothesis. Another leading hypothesis is that intravenous immune globulin decreases the production of autoantibodies. Clinically, this has been suspected in immune thrombocytopenic purpura in which there are apparent improvements in patients with chronic disease, but no controlled studies have been performed to verify this. In acquired hemophilia and von Willebrand's disease, however, it seems quite clear that there is direct neutralization of autoanti-factor VIII antibodies by intravenous immune globulin by a presumed Fab-mediated anti-idiotype mechanism. This hypothesis has appeal and has been postulated on the basis of in vitro studies, as well as looking directly at the B cell. Another study supporting this mechanism showed that intravenous immune globulin preparations with altered Fc portions still mediate some platelet increase, even if not as much as intact IgG molecules. It remains unclear whether any effects that are the result of a lower level of autoantibody could be mediated through T cells or macrophages, rather than having direct action on the B cell. In any event, these findings strongly support the hypothesis that decreased levels of autoantibody lead to intermediate (weeks) and long-term (months to years) responses after intravenous immune globulin treatment.

Autoantibodies↗
PubMed1989

Modulation of in vitro synthesis of immunoglobulin and the induction of suppressor activity by therapy with intravenous immune globulin.

Intravenous immune globulin has become an important modality of replacement therapy for children and adults with hypogammaglobulinemia or agammaglobulinemia. It is also evident that intravenous immune globulin is effective in patients with a variety of automimmune disorders. The present study was undertaken to evaluate the effects of intravenous immune globulin replacement therapy in patients with common variable hypogammaglobulinemia. We measured pokeweed mitogen-induced immunoglobulin synthesis of patients' peripheral blood mononuclear cells cocultured in equal numbers with normal subjects' lymphocytes to assess suppressor cell activity. The mean suppressor cell activity in coculture experiments at baseline of nine patients in the study was -16%. Suppressor activity was demonstrated in two of nine patients at baseline who received intravenous immune globulin therapy before initiation of the study. After intravenous immune globulin therapy at a low dose (100 to 200 mg/kg/mo), suppressor cell activity was demonstrated in all nine patients, which ranged from -63% to -100%. In five patients intravenous immune globulin therapy was discontinued for 4 months. There was a return to baseline levels, with suppressor activity ranging from -20% to -50%. On reinstitution of high-dose intravenous immune globulin therapy (300 to 400 mg/kg/mo), all patients except one again demonstrated increased suppressor cell activity. Cell separation and recombination cell culture experiments were performed. All patients had an intrinsic B cell defect before the initiation of therapy so that the effects of intravenous immune globulin therapy on B cell function could not be assessed. Combining normal B cells with the patient's T cell-enriched fraction showed marked suppression of pokeweed mitogen-induced immune globulin synthesis. This suppression was reversible by irradiation of the T cell fraction. Removal of CD8-positive T cells by cell sorting resulted in normal immunoglobulin synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Agammaglobulinemia↗
PubMed1987

Use of cytomegalovirus immune globulin to prevent cytomegalovirus disease in renal-transplant recipients.

We undertook a prospective randomized trial to examine whether an intravenous cytomegalovirus (CMV) immune globulin would prevent primary CMV disease in renal-transplant recipients. Fifty-nine CMV-seronegative patients who received kidneys from donors who had antibodies against CMV were assigned to receive either intravenous CMV immune globulin or no treatment. The immune globulin was administered in multiple doses over the first four months after transplantation. The incidence of virologically confirmed CMV-associated syndromes was reduced from 60 percent in controls to 21 percent in recipients of CMV immune globulin (P less than 0.01). Fungal or parasitic superinfections were not seen in globulin recipients but occurred in 20 percent of controls (P = 0.05). Only 4 percent of globulin recipients had marked leukopenia (reflecting serious CMV disease), as compared with 37 percent of the controls (P less than 0.01). There was a concomitant but not statistically significant reduction in the incidence of CMV pneumonia (17 percent of controls as compared with 4 percent of globulin recipients). A significant reduction in serious CMV-associated disease was observed even when patients were stratified according to therapy for transplant rejection (P = 0.04). We observed no effect of immune globulin on rates of viral isolation or seroconversion, suggesting that treated patients often harbored the virus but that clinically evident disease was much less likely to develop in them. We conclude that CMV immune globulin provides effective prophylaxis in renal-transplant recipients at risk for primary CMV disease.

Adult↗
PubMed1991

Intravenous immune globulin for the prevention of bacterial infections in children with symptomatic human immunodeficiency virus infection.

BACKGROUND: Serious recurrent bacterial infections are a major cause of morbidity and mortality in children infected with the human immunodeficiency virus (HIV). Because intravenous immune globulin has been shown to prevent bacterial infection in patients with primary immunodeficiency and in uncontrolled studies of HIV-infected children, we undertook a multicenter study of its safety and efficacy in children with symptomatic HIV infection. METHODS: In a double-blind trial, 372 HIV-infected children (mean age, 40 months) with clinical or immunologic evidence of HIV disease were randomly assigned to receive either intravenous immune globulin (400 mg per kilogram of body weight) or placebo (0.1 percent albumin) every 28 days. The children were stratified into two groups according to CD4+ lymphocyte count at entry into the study and the clinical classification of the Centers for Disease Control. The median length of follow-up was 17 months. RESULTS: For children in either group with CD4+ counts greater than or equal to 0.2 x 10(9) per liter (greater than or equal to 200 per cubic millimeter) at entry, treatment with intravenous immune globulin significantly increased the time free from serious infection; estimated infection-free rates after 24 months were 67 percent for children receiving immune globulin as compared with 48 percent for those receiving placebo (P = 0.01). In addition, immune globulin was associated with an overall reduction in the number of both serious and minor bacterial infections (relative risk, 0.68; P = 0.01) and in the number of hospitalizations for acute care (relative risk, 0.65; P = 0.03). No such benefits were seen for children with CD4+ counts below 0.2 x 10(9) per liter at entry. For group 1 overall, there was a trend toward a difference in serious bacterial infection between immune globulin and placebo (24-month infection-free survival, 31 percent for intravenous immune globulin vs. 25 percent for placebo; P = 0.10). For group 2, the estimates of survival without serious infection were 73 percent with intravenous immune globulin as compared with 53 percent with placebo (P = 0.04). There was no effect of treatment on mortality for any group or CD4+ count at entry. Adverse reactions, noted for less than 1 percent of infusions, were minor. CONCLUSIONS: In symptomatic HIV-infected children the prophylactic use of intravenous immune globulin, is safe, and it significantly increases the time free from serious bacterial infections for those entering treatment with CD4+ lymphocyte counts greater than or equal to 0.2 x 10(9) per liter.

Acquired Immunodeficiency Syndrome↗
PubMed2003

Plasma concentration of Gc-globulin is associated with organ dysfunction and sepsis after injury.

OBJECTIVE: Clinical and experimental studies suggest that the proteins of the extracellular actin scavenger system have a role in the pathophysiological processes taking place in critically ill and injured patients. Circulating levels of Gc-globulin and gelsolin are reduced shortly after severe trauma, and admission levels of Gc-globulin are associated with survival. Herein, we sought to measure the association between admission levels of Gc-globulin and postinjury organ dysfunction and infection. We also wanted to describe the serial changes in Gc-globulin in these severely injured patients. DESIGN: Prospective cohort. SETTING: Intensive care unit at a county hospital that serves as a level one trauma center. PATIENTS: Ninety-eight consecutive trauma victims admitted to the intensive care unit for >24 hrs during a 4-month period. MEASUREMENTS AND MAIN RESULTS: Circulating levels of Gc-globulin were measured by using immunonephelometry. All patients were evaluated daily to obtain the necessary data for assessment of organ dysfunction and sepsis. The median Gc-globulin concentration at admission was 127 mg/L in patients who developed severe multiple organ dysfunction compared with 184 mg/L in patients who did not (p =.001). The admission level of Gc-globulin was comparable to known risk factors such as age and injury severity score, regarding development of organ dysfunction. Plasma concentrations of Gc-globulin remained significantly lower in patients who developed respiratory failure and sepsis, compared with patients who did not develop these complications (p =.02 and p=.015, respectively). CONCLUSIONS: Admission plasma concentration of Gc-globulin is lower in patients who develop organ dysfunction and sepsis after traumatic injury. These data, combined with the work of others, support the hypothesis that actin release and depletion of the extracellular actin scavenger system proteins are associated with, and may contribute in part to, the complications of sepsis and organ dysfunction, particularly respiratory failure and thrombocytopenia.

Adult↗
PubMed1988

Gc-globulin (vitamin D-binding protein) enhances the neutrophil chemotactic activity of C5a and C5a des Arg.

Several serum proteins have been shown to be important in modulating leukocyte chemotaxis and inflammation. We investigated the possibility that the multifunctional serum protein Gc-globulin (vitamin D-binding protein) may also enhance the neutrophil chemotactic activity of complement-derived peptides. Purified Gc-globulin by itself did not induce chemotaxis of human neutrophils. However, as little as 0.01 nM Gc-globulin greatly enhanced the neutrophil chemotactic activity of C5a and its derivative, C5a des Arg over a wide concentration range. The effect was most pronounced at nonchemotactic doses of C5a (0.01 nM) and C5a des Arg (1 nM). Gc-globulin was unable to augment the neutrophil chemotactic activity of FMLP and leukotriene B4. This enhancing activity was not due to a nonspecific effect of anionic proteins since other purified serum proteins, of similar size and charge as Gc-globulin (alpha 1 acid glycoprotein, alpha 2 HS glycoprotein, alpha 2 histidine-rich glycoprotein), could not increase the chemotactic activity of C5a des Arg. Serum depleted of Gc-globulin by immunoaffinity chromatography totally lacked chemotactic enhancing activity for C5a des Arg. Gc-globulin-depleted serum activated with zymosan also had significantly less chemotactic activity than control- (sham-depleted) activated serum. Finally, radioiodinated C5a or C5a des Arg formed a 1:1 complex with purified Gc-globulin when analyzed by gel filtration chromatography. These results indicate that Gc-globulin is the major chemotactic enhancing factor in serum and may function as an up-regulator of the chemotactic activity of C5-derived peptides.

Anaphylatoxins↗
PubMed2001

Familial corticosteroid-binding globulin deficiency due to a novel null mutation: association with fatigue and relative hypotension.

Corticosteroid-binding globulin is a 383-amino acid glycoprotein that serves a hormone transport role and may have functions related to the stress response and inflammation. We describe a 39-member Italian-Australian family with a novel complete loss of function (null) mutation of the corticosteroid-binding globulin gene. A second, previously described, mutation (Lyon) segregated independently in the same kindred. The novel exon 2 mutation led to a premature termination codon corresponding to residue -12 of the procorticosteroid-binding globulin molecule (c.121G-->A). Among 32 family members there were 3 null homozygotes, 19 null heterozygotes, 2 compound heterozygotes, 3 Lyon heterozygotes, and 5 individuals without corticosteroid-binding globulin mutations. Plasma immunoreactive corticosteroid-binding globulin was undetectable in null homozygotes, and mean corticosteroid-binding globulin levels were reduced by approximately 50% at 18.7 +/- 1.3 microg/ml (reference range, 30-52 microg/ml) in null heterozygotes. Morning total plasma cortisol levels were less than 1.8 microg/dl in homozygotes and were positively correlated to the plasma corticosteroid-binding globulin level in heterozygotes. Homozygotes and heterozygote null mutation subjects had a high prevalence of hypotension and fatigue. Among 19 adults with the null mutation, the systolic blood pressure z-score was 12.1 +/- 3.5; 11 of 19 subjects (54%) had a systolic blood pressure below the third percentile. The mean diastolic blood pressure z-score was 18.1 +/- 3.4; 8 of 19 subjects (42%) had a diastolic blood pressure z-score below 10. Idiopathic chronic fatigue was present in 12 of 14 adult null heterozygote subjects (86%) and in 2 of 3 null homozygotes. Five cases met the Centers for Disease Control criteria for chronic fatigue syndrome. Fatigue questionnaires revealed scores of 25.1 +/- 2.5 in 18 adults with the mutation vs. 4.2 +/- 1.5 in 23 healthy controls (P < 0.0001). Compound heterozygosity for both mutations resulted in plasma cortisol levels comparable to those in null homozygotes. Abnormal corticosteroid-binding globulin concentrations or binding affinity may lead to the misdiagnosis of isolated ACTH deficiency. The mechanism of the association between fatigue and relative hypotension is not established by these studies. As idiopathic fatigue disorders are associated with relatively low plasma cortisol, abnormalities of corticosteroid-binding globulin may be pathogenic.

Adrenocorticotropic Hormone↗
PubMed1990

Effect of adrenalectomy at different pregnancy stages on maternal and fetal serum corticosteroid binding globulin and corticosterone in the rat.

The response of pregnant rat corticosteroid binding globulin to maternal adrenalectomy was studied as a function of the stage of pregnancy. Non-pregnant or pregnant rats were deprived of their adrenal glands during 4 days. In non-pregnant animals, adrenalectomy led to undetectable corticosterone levels and to the doubling of corticosteroid binding globulin. In pregnant rats adrenalectomized at 12 days and studied at 16 days, the serum corticosterone was likewise undetectable and the corticosteroid binding globulin was doubled as compared with pregnant rats of the corresponding age. In contrast, adrenalectomy from day 14 to 18 or from day 16 to 20 did not deplete the maternal serum corticosterone and the corticosteroid binding globulin remained unchanged. Under these conditions neither fetal corticosteroid binding globulin nor fetal corticosterone were modified. However, when the pregnant rats adrenalectomized from day 16 to 20 also received an injection of 30 mg of metyrapone on days 19 and 20 in order to inhibit fetal adrenal secretion, the maternal response was again a depletion of serum corticosterone together with an increase in corticosteroid binding globulin. Under these conditions, the fetus also reacted by a fall of corticosterone and a rise of corticosteroid binding globulin. Our results suggest that the maternal response of corticosteroid binding globulin to adrenalectomy depends on the pregnancy stage inasmuch as it may be influenced by a supply of corticosterone from the fetus during late pregnancy. Moreover, they show that in this late period, fetal corticosteroid binding globulin is regulated independently.

Adrenal Glands↗
PubMed1995

Serial measurements of serum Gc-globulin in acetaminophen intoxication.

OBJECTIVES: To describe serum Gc-globulin and the extent to which it complexes with monomeric actin in the initial phase of acetaminophen (Paracetamol) intoxication and to relate this to the severity of liver necrosis and the clinical course. PATIENTS AND METHODS: Serial measurements of Gc-globulin and the proportion of Gc-globulin complexed to G-actin (complex ratio) were made on admission and every 3 h thereafter in eighteen consecutive patients with acetaminophen intoxication. Eight patients developed hepatic encephalopathy (HE) and two died. RESULTS: On admission, all patients had significantly reduced serum Gc-globulin levels compared with normal individuals (P < 0.0001); patients with HE had significantly lower values than patients without HE (P < 0.001). Gc-globulin levels in the two patients who died did not differ from those in patients who survived hepatic encephalopathy. Fourty-four of 52 serum samples with Gc-globulin levels below 120 mg/l were from patients with encephalopathy (all eight of these patients provided at least three samples). The complex ratio on admission did not differ significantly between patients with and those without HE and fluctuated considerably during the observation period. The peak complex ratio was, however, higher in patients with HE than in patients without HE (P < 0.01), and three of four patients with peak complex ratios above 75% had HE. In addition, the mean complex ratio was greater in the two patients who died than in those who survived HE (P < 0.05). CONCLUSION: Gc-globulin levels were decreased in individuals suffering from acetaminophen intoxication; this decrease correlated with the most severe sign of liver dysfunction, HE. Serum Gc-globulin levels below 120 mg/l and peak complex ratios above 75% may be critical values. However, as a result of considerable fluctuations in the complex ratio, serial measurements are needed to evaluate the Gc-globulin complexing capacity.

Acetaminophen↗