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Reversal of gallium arsenide-induced suppression of the antibody-forming cell response by vehicle supernatants. I. Pharmacokinetics after in vitro and in vivo exposure.

Exposure of splenocytes in vivo or in vitro to gallium arsenide (GaAs) dose-dependently suppresses the ability of these cells to produce antibody after in vitro immunization with sheep red blood cells. In addition, it has been demonstrated that GaAs exerts immunosuppressive effects early (36 hr) in the generation of a primary antibody-forming cell (AFC) response. The objective of this study was to determine if the GaAs-induced suppression was produced as a result of a GaAs-induced alteration in the secretion of soluble mediators. Supernatants from in vivo and in vitro vehicle (VH)-exposed splenocyte cultures time-dependently reversed GaAs-induced suppression of the in vitro-generated primary AFC response produced by both in vitro (50 microM) and in vivo (200 mg/kg) exposure to GaAs. Supernatants from in vitro GaAs-exposed cells suppressed the VH response 40, 89 and 93% at 24, 36 and 48 hr, respectively. Using the arsenic-binding compound meso-2,3-dimercaptosuccinic acid (100 microM), it was determined that the suppression of the VH response by supernatants from in vitro GaAs-exposed cultures was confounded by the presence of free arsenic in the in vitro GaAs-exposed culture supernatant. In contrast, suppression of in vivo VH-exposed AFC responses by supernatants from in vivo GaAs-exposed cells was not seen. The time-dependent reversal of immunosuppression produced by in vivo or in vitro exposure to GaAs, by supernatants from in vivo and in vitro VH-exposed cells mimics the reported kinetics of suppression by addition of GaAs to antibody cultures.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Gallium-67-citrate and bone scintigraphy in disseminated North American blastomycosis.

We present a patient with North American blastomycosis involving lung and bone. Chest radiographs and CT scan showed a mass in the lung. Bone scintigraphy detected a photon-deficient area in the sternum and 67Ga SPECT showed uptake in the right upper lung and in the sternum. A diagnostic thoracotomy and needle biopsy from the sternal lesion revealed granulomatous infection due to Blastomyces dermatitidis. After 3 mo of antifungal therapy, the follow-up 67Ga study showed no evidence of the original lesions but demonstrated a new, asymptomatic, unsuspected lesion in the left infraspinatous muscle. This case illustrates that North American blastomycosis should be included in the differential diagnosis in cases of atypical pulmonary disease with bone involvement, even in geographic regions that are not considered endemic for this microorganism. Gallium-67 and bone scintigraphy may be useful in determining the extent of dissemination, in detecting occult lesions and in the follow-up of response to therapy.

Adult↗

The gallium melting-point standard: its role in manufacture and quality control of electronic thermometers for the clinical laboratory.

I discuss the traceability of calibration of electronic thermometers to thermometric constants of nature or to the National Bureau of Standards, form a manufacturer's basic standards through the manufacturing process to the user's laboratory. Useful electrical temperature sensors, their advantages, and means for resolving their disadvantages are described. I summarize our development of a cell for realizing the melting phase equilibrium of pure gallium (at 29.770 degrees C) as a thermometer calibration fixed point, and enumerate its advantages in the routine calibration verification of electrical thermometers in the clinical chemistry laboratory.

Chemistry, Clinical↗

Reversal of gallium arsenide-induced suppression of the antibody-forming cell response by vehicle supernatants. II. Nature and identification of reversing factors.

Previous studies have demonstrated that several immunological events which are T cell mediated are significantly suppressed by a single exposure to gallium arsenide (GaAs). In addition, in the in vitro-generated antibody-forming cell (AFC) response supernatants from vehicle (VH) cultures were able to time-dependently reverse suppression induced by either in vivo (200 mg/kg) or in vitro (50 microM) exposure to GaAs. The present studies were designed to determine the nature and identification of the reversing factors present in VH supernatants. VH supernatants (25-100%) were able to dose-dependently reverse suppression of the AFC response (from 45% suppression to 48% enhancement of the VH response) induced by GaAs exposure (200 mg/kg). Concentration of 24-hr VH supernatants and treatment with proteinases revealed that the reversing factors were protein in nature with a molecular weight between 5,000 and 50,000 Da. This molecular weight range encompasses many of the lymphokines known to be necessary for the generation of an immune response. In antibody cultures exposed either in vivo or in vitro to VH or GaAs, HT-2 bioassay and antigen capture enzyme-linked immunosorbent assays demonstrated that GaAs exposure alters production of interleukin (IL)-2, IL-4, IL-5 and IL-6. Interestingly, the alterations in lymphokine production differed between the exposure regimes. Direct addition of IL-2 to antibody cultures resulted in a dose-dependent (6.25-50 ng/ml) reversal of GaAs-induced suppression (in vivo exposure) and was also dependent on the concentration of GaAs (50-200 mg/kg). IL-4 suppressed the VH AFC response and failed to reverse GaAs suppression.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Arsenic in the sera of gallium arsenide-exposed mice inhibits bacterial growth and increases host resistance.

The objective of the present investigations was to evaluate whether the presence of gallium arsenide (GaAs) in the sera of exposed mice was sufficient to retard bacterial growth. Host resistance studies demonstrated that exposure of GaAs (50-200 mg/kg) produced an increased resistance to Streptococcus pneumoniae and Listeria monocytogenes (50-100 mg/kg GaAs) when microbial challenge occurred 24 hr after exposure. In contrast, exposed mice exhibited a profound and dose-related decrease in resistance to the B16F10 melanoma. Serial dilutions of GaAs (0.039-5 mg/ml) were added to BHI broth and cultures were innoculated with either S. pneumoniae or L. monocytogenes. GaAs slowed the growth of both organisms with a minimal inhibitory concentration (MIC) of 0.625 mg/ml. Sera from mice euthanized at various time intervals after exposure to vehicle (0.05% Tween 80 in saline) or GaAs (200 mg/kg) was also capable of retarding the growth of both organisms with the maximal inhibition noted for euthanization 24 hr after exposure. However, sera from GaAs-exposed mice (24 hr after exposure) was incapable of slowing the growth of the B16F10 melanoma. Addition of the arsenic-binding compound meso-2,3-dimercaptosuccinic acid (100 microM) to sera from mice exposed to GaAs followed by innoculation with L. monocytogenes resulted in growth of this organism, which was comparable to growth observed in vehicle cultures.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Effects of gallium chloride on changes in action potentials and contraction in guinea pig ventricular muscle.

The electrophysiological effects of gallium chloride (Ga ) and its activity on arrhythmias induced by digitalis were investigated in guinea pig papillary muscle. KCl microelectrodes were used to record transmembrane electrical activity from Purkinje cells from the papillary muscle of guinea pig hearts during superfusion and electrical stimulation in vitro at 37 degrees C. Myocardial contractility was continuously monitored. Ga was superfused alone in cumulative concentrations(4.5 . 10(-5) to 3.6 . 10(-4) M). Arrhythmias were induced by a superfusion of Digitoxin (7.5 . 10 (-7) M). A superfusion of Ga (4.5 . 10(-5), 9 . 10(-5), 1.8 . 10(-4) M and 3.6 . 10(-4) M) was started 20 min later and maintained for 70 min. Ga alone produced a dose dependent reduction of action potential duration and contractility. Ga potentiated the decrease in the amplitude and duration of the action potential induced by Digitoxin. The incidence of arrhythmias was immediately reduced by two concentrations of Ga (4.5 . 10(-5) and 9 . 10(-5) M) in the digitalized papillary muscles. It is concluded that Ga inhibits calcium movements and has negative inotropic and antidysrhythmic effects.

Action Potentials↗

[Prolonged fever in painless subacute thyroiditis--diagnosis by gallium scan].

Patients with subacute, granulomatous thyroiditis usually present with a typical clinical picture of fever, anterior neck pain and an exquisitely tender thyroid. Abnormal thyroid function tests and suppressed radio-iodine uptake strongly support the diagnosis. Occasionally the disease may simulate systemic or malignant disease when it presents atypically, without signs or symptoms directly related to the thyroid, We report a 43-year-old man who presented with fever of unknown origin. A diagnosis of silent thyroiditis was made from evidence of biochemical thyrotoxicosis, intense gallium-67 citrate thyroidal localization, and an excellent response to aspirin.

Adult↗

Gallium-67-citrate scintigraphy of high-grade T-cell non-Hodgkin's lymphoma.

Scintigraphy with 67Ga-citrate indicated the transition of an orbital pseudotumor into a lymphoma by a distinct increase in 67Ga avidity. The patient initially presented with a pseudotumor in the right orbit that was verified by CT and MRI. It was caused by a chronic reactive lymphocytic inflammation extending from the lacrimal gland. At that time, scintigraphy was negative. Six and a half weeks later, the tumor had not responded to therapy and scintigraphy then showed a striking increase in gallium avidity. Consequently the tumor was excised and histology ultimately revealed a high-grade non-Hodgkin's T-cell lymphoma.

Adult↗

Gallium arsenide selectively suppresses antigen processing by splenic macrophages for CD4+ T cell activation.

Gallium arsenide (GaAs) is an intermetallic compound used in the electronics industry as a semiconductor. Acute exposure of animals to GaAs suppresses various immune functions. We investigated the effects of GaAs on immunocompetency with emphasis on macrophages. Mice were given 12.5 to 200 mg/kg GaAs i.p., and immune parameters were examined 1 or 5 days later. Chemically exposed mice did not display alteration in spienic cellular composition. Despite this, primary in vitro humoral response to sheep red blood cells by GaAs-exposed mice was inhibited in a dose-dependent manner. The ability of 5-day vehicle- or 200 mg/kg GaAs-exposed splenic macrophages to induce interleukin-2 production by antigen-specific CD4+ helper T cell hybridomas stimulated with soluble protein antigens was assessed. GaAs-exposed macrophages were less competent in eliciting T cell responses to pigeon cytochrome c and pork insulin than vehicle-exposed cells. However, GaAs-exposed macrophages activated hen egg lysozyme- and chicken ovalbumin-specific T cells as efficiently as vehicle control cells. Also, suppressed processing of cytochrome c was not observed after a 1-day exposure. Chemical exposure did not alter the expression of major histocompatibility complex class II molecules on the macrophages or their activation of T cells by peptides, which do not require processing. Therefore, GaAs causes a time- and antigen-dependent defect in antigen processing that is essential for CD4+ T cell stimulation by splenic macrophages.

Animals↗

Changes in results of Gallium-67-citrate scanning after interferon therapy for chronic hepatitis C.

UNLABELLED: Gallium-67 scanning is useful for early diagnosis and grading of interstitial lung disease. In a study of the side effects of interferon (IFN) on the lungs of patients with chronic hepatitis C, we performed 67Ga scanning before and after IFN therapy. METHODS: The 66 subjects who underwent at least one scanning, before IFN therapy, were 8 patients with chronic persistent hepatitis (CPH), 21 with chronic aggressive hepatitis 2A (CAH-2A), 25 with chronic aggressive hepatitis 2B (CAH-2B) and 12 with cirrhosis. All had underlying hepatitis C viral infection. Of those patients, 20 were examined again within 1 mo after IFN therapy. Patients received an intravenous injection of 340 MBq 67Ga-citrate and were imaged 72 hr later. ROIs were established for anterior views of the lungs (Lu), liver (Li) and soft tissue of the upper arm as background (B). The counts per unit size of each region of interest were used in calculation of the ratios Lu/B and Li/B. RESULTS: The medians of Lu/B were 2.46 in CPH, 2.56 in CAH-2A, 2.50 in CAH-2B and 2.47 in cirrhosis. These differences were not statistically significant. The medians of Li/B were 6.42 in CPH, 6.14 in CAH-2A, 5.11 in CAH-2B and 4.03 in cirrhosis. The differences between the median Li/B of cirrhotic patients and the medians for patients with CPH, CAH-2A and CAH-2B were significant. After therapy, Lu/B was higher than before in 16 of the 20 patients and lower in the four other patients; the overall rise was significant (Wilcoxon rank-sum test). Li/B was higher than before in 11 of the 20 patients and lower in the nine other patients. CONCLUSION: IFN caused uptake of the radionuclide to increase in most patients. This method showed changes in the accumulation of 67Ga-citrate that could have been missed if the results had been inspected by eye. IFN can cause interstitial lung disease, but unlike other drugs with this side effect, the onset seems to be gradual enough to be detected quantitatively by 67Ga scanning.

Adult↗

Comparison of gallium scan, computed tomography, and magnetic resonance in patients with mediastinal Hodgkin's disease.

BACKGROUND: In patients with Hodgkin's disease, the use of gallium-67 scintigraphy (Ga-67) compared to conventional staging and restaging techniques is still controversial. In particular, in a combined modality treatment with chemotherapy and radiotherapy given in sequence, its role in detecting active disease after chemotherapy may be useful in planning the subsequent radiotherapeutic strategy. PATIENTS AND METHODS: From March 1990 to September 1994, 125 patients with previously untreated histologically proven Hodgkin's disease were enrolled in two different prospective trials according to clinical stage. Staging procedures included Ga-67, chest-abdominal computed tomography (CT), and/or magnetic resonance (MR). All three tests were performed in 53 patients at staging and in 47 at restaging. Results of Ga-67 at staging were compared to conventional procedures or pathological findings. Results of Ga-67, CT scan, and MR at restaging were compared to disease outcome during the follow-up. Finally a cost/benefit ratio for each test was determined. RESULTS: At staging, Ga-67 showed lower sensitivity than CT and MR (90 vs. 96 and 100%, respectively) because of the number of false-negative images. Nevertheless, by using both CT and Ga-67 scan, the sensitivity is equal to that observed with MR (100%). At restaging, Ga-67 is superior to CT scan and equivalent to MR in detecting true negative patients (specificity: 98% vs. 45% vs. 92%). CONCLUSIONS: As a single technique, Ga-67 scan cannot substitute for CT scan or MR in staging patients with Hodgkin's disease. Nevertheless, Ga-67 scan has an important role in defining complete remission after treatment and therefore in planning subsequent treatment. Considering the lower costs of CT scan plus Ga-67 ($320) versus MR alone ($810), the two tests may be considered procedures of choice in staging as well as in restaging patients with Hodgkin's disease.

Adult↗

Use of gallium-67 in the assessment of response to antibiotic therapy in malignant otitis externa--a case report.

Malignant Otitis Externa (MOE) can cause considerable morbidity and mortality in affected individuals. The outlook is now much improved with the use of ciprofloxacin, but it is important to ascertain that the infection has been completely eradicated before stopping treatment, as undertreatment may lead to a recurrence which is usually more resistant than the initial infection. Gallium-67 Single Photon Emmision Computerised Tomography (SPECT) is a sensitive and cost effective tool in monitoring the disease activity of MOE, and should be used in the assessment of the response to antibiotic therapy.

Anti-Infective Agents↗

Shear bond strength of amalgam and gallium alloys to dentine.

The purpose of this in vitro investigation was to determine the shear bond strength of admixed (Dispersalloy), irregular (Oralloy) and spherical (Lojic) amalgams, as well as an admixed gallium alloy (Galloy) to superficial, buccal, human dentine surfaces, using the Scotchbond Multi-Purpose Plus system. The bonds were stressed to failure in an Instron testing machine after 48 hours, and the following values (MPa) were obtained: Admixed = 7.74 +/- 0.7; Irregular = 9.47 +/- 1.4; Spherical = 9.82 +/- 2.4; Galloy = 11.03 +/- 2.5. Data were statistically analysed and fracture sites examined in a scanning electron microscope. Galloy demonstrated a statistical significant higher shear bond strength than to the other types of amalgams (p < 0.01).

Dental Alloys↗

Gallium arsenide modulates proteolytic cathepsin activities and antigen processing by macrophages.

Gallium arsenide (GaAs) is a semiconductor utilized in the electronics industry. Chemical exposure of animals causes a local inflammatory reaction, but systemic immunosuppression. Mice were administered i.p. 200 mg/kg GaAs crystals or latex beads, or vehicle. Five days after exposure, splenic macrophages were defective, whereas thioglycolate-elicited peritoneal macrophages (PEC) were more efficient in processing the Ag, pigeon cytochrome c, than vehicle control macrophages. Various aspects of the MHC class II Ag-processing pathway were examined. Both macrophage populations normally presented a peptide fragment to the CD4+ T cells. Surface MHC class II expression on the PEC was up-regulated, but splenic cells had normal MHC class II expression. PEC had elevated levels of glutathione and cysteine, major physiologic reducing thiols. However, the cysteine content of splenic macrophages was diminished. Proteolytic activities of aspartyl cathepsin D, and thiol cathepsins B and L were decreased significantly in splenic macrophages. On the other hand, thiol cathepsin activities were increased selectively in PEC. Latex bead-exposed PEC were not more potent APC, and their thiol cathepsin activities were unchanged, indicating that phagocytosis and nonspecific irritation were not responsible. The phenotype of PEC directly exposed to GaAs mirrored cytokine-activated macrophages, in contrast to splenic macrophages from a distant site. Therefore, GaAs exposure differentially modulated cathepsin activities in splenic macrophages and PEC, which correlated with their Ag-processing efficiency. Perhaps such distinct alterations may contribute to the local inflammation and systemic immunotoxicity caused by chemical exposure.

Adjuvants, Immunologic↗

Gallium-67 scanning for carcinoma of the lung.

Gallium-67 citrate scanning was prospectively evaluated in 55 patients who had lung lesions suspected to be primary carcinoma on chest x-ray films and in whom subsequent histologic diagnosis was obtained. Of 47 patients with histologically proved carcinoma of the lung, 44 (94 per cent) had a positive 67Ga scan. No patient with a positive scan had a benign lesion, so that the positive scan accuracy rate was 100 per cent. All 8 patients with a benign lesion and 3 patients with a malignant lesion had negative scans, for a negative scan accurary rate of 72 per cent for benign lesions. These results give statistical validity for the usefulness of the 67Ga scan in diagnosing carcinoma of the lung (p less than 0.001). Tumor cell type had little effect on the sensitivity of 67Ga scan. The 67Ga scan was equally useful in the evaluation of peripheral and central lesions. There was little difference amount T1, T2, and T3 classified lesions in their ability to take up 67Ga. The 67Ga scan was competitive with mediastinoscopy in assessing mediastinal lymph node metastases and provides a noninvasive method of assessing hilar lymph node metastases. There was a good correlation between the clinical staging of patients with lung cancer based on a chest x-ray film and 67Ga scanning and the staging after surgical treatment based on the histology of the resected specimens.

Gallium Radioisotopes↗

Functional imaging of Hodgkin's disease with FDG-PET and gallium-67.

We report a case of Hodgkin's lymphoma (Stage I B) which was studied using Ga-67-scintigraphy as well as whole body FDG-PET. Ga-67-scintigraphy detected a slightly increased uptake in the paraaortic and pelvic lymph nodes. However, FDG-PET was able to localize a much larger number of affected foci with a high glucose utilization rate in the right and left paraaortal regions, in the middle of the epigastrium, in the right and left parailiacal regions and one focus in the left upper mediastinum. Our experiences give rise to the assumption that FDG-PET ist significantly superior to gallium scintigraphy in Hodgkin's disease. Whole body FDG-PET can result in an upstaging of the patient and has therefore a major impact on the therapeutic management.

Antineoplastic Combined Chemotherapy Protocols↗

Synthesis and crystal structure of IM-6, a new open framework cobalt-gallium phosphate with ten- and twelve-membered pore openings.

A new three-dimensional microporous cobalt-gallium phosphate, named IM-6, has been synthesized under solvothermal conditions with an N-substituted piperazine as organic template. The structure was solved by single-crystal X-ray diffraction (triclinic, P(-)1, a=9.848(20), b=12.470(32), c=12.603(28)A, alpha=63.47(16) degrees, beta=74.56(16) degrees, gamma=76.03(17) degrees). IM-6 exhibits a new framework topology. The inorganic framework is built up of MO(4) (M=Co, Ga) and PO(4) tetrahedra. It displays a two-dimensional interconnected channel system running along the [0(-)11] and [100] directions and delimited by ten- and twelve-membered ring openings, respectively.

Journal Article↗