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The use of vaccinia hyperimmune gamma-globulin in the prophylaxis of smallpox.

This paper records an attempt to assess the prophylactic value of immune gamma-globulin, prepared from the serum of recently vaccinated adults, in the protection of close contacts of smallpox in Madras. The results serve to confirm findings of a previous study made in Madras in 1953, and show that the incidence of smallpox in close contacts given immune gamma-globulin prophylactically was about a quarter of that in the control contacts who received no such passive immunization-a statistically significant difference. Because of the limited supply of immune gamma-globulin, it is likely that its prophylactic use will be restricted to those especially at risk, for example, close unvaccinated family contacts, newborn infants and pregnant women.

Adult↗

Oral contraceptive absorption and sex hormone binding globulins in obese women: effects of jejunoileal bypass.

Plasma levels of two oral contraceptive gestagens were studied during 24 hour oral challenges in seven morbidly obese women after jejunoileal bypass comparing the results to unoperated normal controls. To study binding and transport of the gestagens, sex hormone binding globulin levels were determined in these patients, in normal-weight controls, and in unoperated morbidly obese patients. The unoperated morbidly obese patients had significantly decreased levels of sex hormone binding globulin, compared to normal-weight controls and to the jejunoileal bypass patients, whose levels were similar to the controls. The jejunoileal bypass patients had a reduced capacity to absorb oral contraceptive gestagens, although the plasma levels were of the same magnitude found in normal subjects using lower doses of gestagens. However, the gestagen to sex hormone binding globulin ratio was lower in jejunoileal bypass patients, implying reduced biologic activity and thus reduced contraceptive efficiency of the gestagen. There were no enzymatic or morphologic signs of liver dysfunction. No correlations were found between plasma gestagen levels and number or volume of stools, fecal fat excretion, or intravenous C-cholic acid load. It is concluded that caution must be exercised in prescribing oral contraceptives to jejunoileal bypass patients.

Administration, Oral↗

Alpha-globulins in the surveillance of colorectal cancer.

The alpha1 and alpha2-globulins have been studied at various stages in the evolution of colo-rectal cancer. The alph2 was elevated in some primary tumours and rose in metastatic cancer especially when it involved the liver. Some apparently tumour free patients had an unexplained elevation of alph2-globulins. The macroglobulins were not a major constituent of the raised alpha2-globulins. Haptoglobulin levels were found to be a useful indicator of tumour activity, when their level was raised in metastatic cancer it was usually with an antecedent or coincidental rise of plasma CEA. Primary tumours may cause a high haptoglobin response without an elevation of CEA.

Alpha-Globulins↗

Cancer-associated serum globulin determined in patients with cervical, endometrial and ovarian cancer.

By using polyacrylamide gel electrophoresis, sera were tested on cancer-associated globulin from female patients bearing gynaecological cancers: 45 cervical, 21 endometrial and 38 ovarian. As a control, normal sera were taken from 97 healthy women. Sera were also taken from patients with benign neoplasias: 59 cervical dysplasias, 72 endometrial fibromyomas and 47 ovarian cystadenomas. The cancer-associated globulin was evaluated, as an antibody to a cancer antigen that consists of ceramide-lactoside conjugated to a protein integrated in a tumor cell membrane. This serum globulin can be shown densitometrically as the fourth post-transferrin peak (PTP 4). It was found in 69% cervical cancer patients, 52% of the endometrial cancer patients and 89% of the ovarian cancer patients. False positive results were detected in 11% of the normal sera and 25% of the sera from patients with benign neoplasias.

Electrophoresis, Polyacrylamide Gel↗

Immunoelectrophoretic assay for synovial fluid C3 with correction for synovial fluid globulin.

Synovial fluid C3 was measured by electroimmunoassay. When C3 was expressed as mg/ml, the amounts found in Reiter's disease, psoriatic arthritis, gout, and systemic lupus erythematosus were significantly different from degenerative arthritis. When C3 was corrected for total protein, the levels for rheumatoid arthritis, Reiter's disease, psoriatic arthritis, and systemic lupus were significantly different from degenerative arthritis. When C3 was corrected for synovial fluid globulin, only rheumatoid arthritis and systemic lupus were significantly different from degenerative arthritis. Correction of C3 for globulin increases the difference between rheumatoid arthritis and degenerative arthritis. A proportion of gouty fluids with a relative decrease in C3 is demonstrated. It is argued that correction of C3 for globulin is more meaningful than correction for total protein. While many nonrheumatoid inflammatory effusions demonstrate split products of C3, the majority of fluids from patients with systemic lupus have none.

Arthritis↗

High doses of gamma globulin and methylprednisolone therapy for idiopathic thrombocytopenic purpura in children.

In four children with chronic idiopathic thrombocytopenic purpura (ITP), high doses of gamma globulin or methylprednisolone were effective in increasing platelet counts transiently, yet there was no quantitative relationship between the platelet responses to these two therapies. This finding suggests a qualitative difference in the mechanisms of increasing platelets by the two drugs. High doses of gamma globulin and methylprednisolone showed a synergistic effect on the initial and maximal platelet responses, suggesting an intensification of the effect of gamma globulin by methylprednisolone. This combination therapy should be clinically useful, particularly in the control of acute haemorrhage or in preparations for emergency surgery.

Child↗

A Fos-Jun element in the first intron of an alpha 2u-globulin gene.

The hepatic expression of the alpha-2u-globulin gene family is controlled by a variety of hormones including steroids, growth hormone and insulin. The mechanisms by which these hormones affect alpha 2u-globulin expression are only partially understood. Recently we isolated and characterized clone RAP 01, an alpha 2u-globulin gene expressed in the liver. In preliminary experiments we noted that partial hepatectomy, a procedure which results in a sharp rise in the level of the oncoproteins c-Fos and c-Jun, also causes a transient induction of the messenger RNA corresponding to clone RAP 01. Using the DNAseI footprinting technique we were able to show that this clone contains a TPA (phorbol 12-myristate 13-acetate)-responsive element (TRE) in its first intron. This element (denoted as element X) is identical to the consensus AP-1 binding site (TGACTCAG) and is protected by rat liver nuclear extracts as well as by purified c-Jun. Gel retardation experiments show that an oligonucleotide containing the TRE consensus sequence competes for binding of liver nuclear proteins to element X and that antibodies directed against the M2 peptide of the mouse Fos protein or the PEP-2 peptide of Jun prevent the formation of specific complexes with the same element. Moreover, element X functions as a TRE in transfected BWTG3 hepatoma cells treated with TPA. Co-transfection with fos and jun expression vectors mimics the effects of TPA suggesting that AP-1 is in fact the mediator of the observed response. It is concluded that the first intron of RAP 01 contains a functional Fos-Jun element.

Alpha-Globulins↗

Bioavailability of gamma-globulin after subcutaneous infusions in patients with common variable immunodeficiency.

Replacement therapy, using subcutaneous infusions of gamma-globulin, is being applied increasingly for antibody-deficient patients, as this form of treatment has been found to be related to a very low frequency of adverse systemic reactions. However, the uptake of IgG from subcutaneous tissue may be low, owing to degradation locally, especially for the IgG3 molecule. Therefore, the kinetics of IgG and IgG-subclass concentrations in the sera of 23 patients with common variable immunodeficiency was investigated during 18 months of subcutaneous infusions of gamma-globulin (100 mg/kg/week). Seventeen patients were previously treated with intramuscular injections or intravenous infusions. The mean serum IgG level increased twice in the previously treated patients and four times in the previously untreated patients. A steady state was reached after 6 months if the subcutaneous infusions were given weekly and after 1 week if the patients were given daily infusions for 5 consecutive days and, thereafter, weekly infusions. The fractional catabolic rate of IgG (4.1-5.9% per day) was found to be at the lower limit reported for normal controls, if 100% bioavailability of the infused IgG was assumed. The fractional contents of IgG subclasses in the patients' serum IgG resembled the physiological pattern, with the exception of IgG4, which was not present in the gamma-globulin preparations used. Significantly increased levels of IgG1 and -2 were seen in both previously treated and untreated patients during the treatment.

Administration, Cutaneous↗

Aortic valve replacement and splenectomy in a patient with chronic idiopathic thrombocytopenic purpura--preoperative management with high-dose gamma-globulin.

We report the management of a patient with chronic idiopathic thrombocytopenic purpura and severe aortic valvular disease. Preoperative intravenous high-dose gamma-globulin administration was employed, and aortic valve replacement combined with splenectomy were performed during the same operation. The platelet count at admission was 34,000/mm3 and increased to 146,000/mm3 after the gamma-globulin therapy. Platelet transfusion at the end of the cardiopulmonary bypass was considered no longer necessary in the postoperative period, because the platelet count increased quickly after the procedure. The postoperative course was uneventful. We believe that open heart surgery and splenectomy can successfully be performed simultaneously in a patient with chronic idiopathic thrombocytopenic purpura treated with high-dose gamma-globulin therapy.

Aortic Valve Insufficiency↗

Lack of correlation between sex hormone binding globulin and free testosterone in some cases of "idiopathic" hirsutism.

Plasma 3 alpha-androstanediol levels are increased in a high percentage of hirsute women, including those with normal plasma levels of its precursors, repeatedly evaluated during the menstrual cycle. To better ascertain the origin of this form of hirsutism, so called "idiopathic", 17 hirsute women (aged 19.5 +/- 4.8 SD yr), with normal bw, showing an isolated increase in plasma 3 alpha-androstanediol (0.65 +/- 0.18 SD nmol/l) were studied in basal conditions (on day 6, 7, 17, 18 of the menstrual cycle). A hirsute female (aged 14 yr) with congenital adrenal hyperplasia due to 21-hydroxylase deficiency was also included in the protocol. Sex hormone binding globulin was evaluated using a saturation method (dihydrotestosterone- 3H 0.5-25 nM) with and without 200x cold dihydrotestosterone. Maximum number of binding sites and Ka were calculated in all cases with Scatchard analysis. Free testosterone was evaluated by the equilibrium dialysis technique. The results obtained showed a significant increase in Ka values in 10 out of the 17 cases; low plasma levels of sex hormone binding globulin in 13 cases and normal levels in 4 cases; high levels of free testosterone fraction in 5 cases and in the upper limits of the normal range or normal in the remaining 12. These findings demonstrate that some cases of "idiopathic" hirsutism may present an alteration in the binding affinity of the sex hormone binding globulin which may be genetically transmitted, being found to be increased in two sisters and in their brother.

Adolescent↗

Biphasic interaction of gamma-globulin with copper cations.

Interactions of human serum gamma-globulin with copper cations in solution were studied by differential ultraviolet spectrophotometry. Copper in supraphysiological concentrations increases optical density of protein solution, reflecting the effect of gamma-globulin saturation with metal. In physiological and lower concentrations of copper cations we observed hypochromia in the protein absorption spectrum. Conformational changes in g-globulin molecule during interactions with copper by the surface and intramolecular binding sites and possible role of bivalent metal cations in the maintenance of certain conformations of immunoactive serum proteins are discussed.

Cations↗

Reactions between human serum gamma-globulin and zinc cations.

Interactions of human serum gamma-globulin with zinc cations in solution were studied by differential spectrophotometry in UV light. Supraphysiological concentrations of zinc caused an increment in optical density of protein solution reflecting the effect of gamma-globulin saturation with the metal. Zinc concentrations below physiological led to hypochromism in the protein absorption spectrum. Conformation changes in gamma-globulin during interactions with zinc are analyzed for the surface and intramolecular binding sites and are compared with the effects of copper cations.

Cations↗

Polymorphism of Fc gamma RIIa may affect the efficacy of gamma-globulin therapy in Kawasaki disease.

We evaluated whether there is a possible relationship between the effectiveness of gamma-globulin treatment for patients with Kawasaki disease (KD) and the polymorphism of Fcgamma RIIa, IIIb, and IIIa. Genomic DNA was extracted from whole blood collected from 56 patients with KD who received gamma-globulin treatment. The genotypes for Fcgamma RIIIb-NA(1, 2), Fcgamma RIIa-H/R131, and FcgammaRIIIa-F/V158 were determined to investigate the association between these polymorphisms and the development of coronary lesions (CALs). Twenty-three percent of patients with the HH allele for the Fcgamma RIIa polymorphism progressed to CALs, compared with 60% with the HR and RR alleles. HR and RR alleles may be a predictor of the progression of CALs in KD before the initiation of gamma-globulin therapy.

Antigens, CD↗

Effect of dexamethasone treatment on sex steroid-binding protein, corticosteroid-binding globulin, and steroid hormones in cycling rhesus macaques.

We tested the hypothesis that dexamethasone lowers sex steroid-binding protein levels and observed the effect of dexamethasone on corticosteroid-binding globulin and specific steroid hormones in plasma. Four cycling rhesus macaques were studied during three consecutive menstrual cycles (first and third cycles served as controls). In the second cycle, each animal received 0.5 mg of dexamethasone intramuscularly at 8:00 AM and 8:00 PM daily for 21 consecutive days. Blood samples were taken at 1- to 3-day intervals during each cycle. Concentrations of sex steroid-binding protein, corticosteroid-binding globulin, cortisol, testosterone, progesterone, and estradiol were measured in plasma. The percentage and plasma concentration of free testosterone were also determined. Within 2 days of treatment, dexamethasone suppressed cortisol to 5% of baseline values, which returned in the third cycle. All cycles were ovulatory. Dexamethasone significantly lowered plasma levels of all the compounds except progesterone: sex steroid-binding protein, -30%; corticosteroid-binding globulin, -14%; testosterone, -36%; and estradiol, -45%. The percentage of free testosterone was significantly elevated, but free testosterone concentrations were unchanged. Although our data conclusively show that dexamethasone suppresses plasma sex steroid-binding protein levels in the rhesus macaque, it remains to be established whether this suppressive effect leads to an increase in the metabolic clearance rate of testosterone.

Animals↗

Suppression of serum insulin level by diazoxide does not alter serum testosterone or sex hormone-binding globulin levels in healthy, nonobese women.

Suppression of serum insulin levels with diazoxide is associated with a decrease in serum testosterone and an increase in serum sex hormone-binding globulin in obese women with the polycystic ovary syndrome. To determine whether physiologic insulin levels play a regulatory role in the androgen status of nonobese women with normal menses, the androgen status of five nonobese normal women was assessed on two occasions: during a control study and after 10 days of oral diazoxide (100 mg, three times daily) administration. Insulin release in response to 100 gm oral glucose administration decreased from 108.0 +/- 28.2 to 49.3 +/- 5.2 nmol.min/L (p = 0.05) after diazoxide administration. However, despite suppression of insulin release, diazoxide administration did not affect serum total testosterone (diazoxide, 0.73 +/- 0.10; control, 0.69 +/- 0.11 nmol/L; p = NS) or sex hormone-binding globulin (diazoxide, 79.7 +/- 16.6; control, 70.2 +/- 12.6 nmol/L; p = NS) concentrations. These observations suggest that physiologic insulin levels in nonobese healthy women do not regulate testosterone metabolism and that diazoxide does not exert a direct or independent effect on serum testosterone or sex hormone-binding globulin levels.

Administration, Oral↗

Sequential passage of alpha2mu-globulin through the hepatic endoplasmic reticulum and Golgi apparatus during secretion.

Studies on the synthesis and secretion of the sex-dependent urinary protein, alpha2mu-globulin, have been extended by establishing its sequential passage from the rough to the smooth endoplasmic reticulum and Golgi-rich fractions of the liver of adult male rats. After injection of 14C-labeled amino acids, the maximum radioactivity of alpha2mu occurred at 20 min in the rough, 25 min in the smooth microsomes and 30 or 35 min in the Golgi-rich fractions. Radioactive alpha2mu-globulin appeared in the bloodstream and kidneys after a lag of 20--25 min. Results indicate that alpha2mu-globulin follows a secretory pathway similar to that of serum albumin.

Alpha-Globulins↗

Elevation of hormone-binding globulins in acute intermittent porphyria.

Sex hormone-binding globulin (SHBG), thyroxine-binding globulin (TBG) and cortisol-binding globulin (CBG) were measured in plasma of 26 patients with acute intermittent porphyria (AIP). Twelve patients had clinically manifest disease and all had elevated SHBG levels. All but one of 14 patients with latent porphyria had normal SHBG levels. TBG was elevated in 9 of the patients with clinically manifest porphyria and CBG elevated in three. Levels of TBG and CBG were either normal or only slightly elevated in those with latent porphyria. In a prospective study of 30 attacks of AIP in 7 patients, SHBG levels fell between admission and discharge, the fall being significant in the group of 21 attacks treated with haem arginate (p less than 0.001). Our findings suggest that a close correlation exists between elevated SHBG and clinical expression of AIP.

Adolescent↗