Increased Radioiodine Uptake of Thyroid Cell Cultures after External Irradiation

BACKGROUND: Radioiodine uptake (RIU) is one of the main prognostic factors for curative results of radioiodine therapy in patients with differentiated thyroid cancer. Some days after application of (131)I, the uptake of a subsequent administration of radioiodine was found to be reduced. In contrast, early after irradiation with high-energy photons glucose and amino acid uptake were observed to be increased. Effects of external irradiation on RIU of thyrocytes using high-energy photons have not been investigated so far. MATERIAL AND METHODS: Two different cell lines (FRTL-5 and ML-1 cells) derived from thyroid tissue were studied in vitro. Cell lines were either incubated with (131)I only (controls) or additionally irradiated with single doses of 6 or 10 Gy of high-energy photons using a linear accelerator. Cell number and RIU were determined 24-96 h after (131)I application. RIU measurements were repeated after application of sodium perchlorate in excess to investigate specificity of the uptake. Statistical analyses were performed using non-parametric tests. RESULTS: Incubation with radioiodine as well as irradiation with high-energy photons slowed down proliferation in investigated cell lines significantly. Irradiation with solely (131)I resulted in stable or slightly decreased iodide uptake. Compared to those cells, the RIU increased significantly in externally irradiated cells, i. e., additional irradiation with 10 Gy resulted in an almost threefold increase of RIU in FRTL-5 after 72 h. The increase of RIU after irradiation was dose-dependent in both cell lines and could be blocked by perchlorate excess. CONCLUSION: It could be demonstrated that external irradiation increases RIU in thyroid cell cultures early after irradiation. The increase was dose-dependent and specific, as it could be blocked by perchlorate. This effect appears to be similar to the increase of other actively transported substances after irradiation with high-energy photons. Therefore, the results of this study may contribute to the knowledge of a generalized irradiation-induced mechanism which causes the activation of different cellular transporters. The clinical impact of these findings on combined therapy concepts has to be investigated in further experiments.     

Pre- and intraoperative methods of controlling cerebral circulation in giant aneurysm surgery

The surgical treatment of giant aneurysms usually requires temporary clipping of the aneurysmatic vessel. In planning the surgical approach and in applying temporary clips, the surgeon must consider collateral circulations. The functional integrity of the collateral vessels frequently decides the patient's outcome.In 8 patients with internal carotid artery giant aneurysm, measurements of blood flow velocities in the ipsilateral middle cerebral artery were performed preoperatively with transcranial Doppler ultrasound (TCD) during manual occlusion of the carotid artery at the neck. Three different perfusion patterns were established, and each collateral capacity was rated as insufficient, temporarily sufficient, or long-term unproblematic. Surgical strategies were conceived. In one patient with giant aneurysm of the middle cerebral artery the temporary occlusion test was not carried out preoperatively.Intraoperatively, collateral circulation was controlled using microvascular Doppler sonography (MVD). In 8 cases cortical blood flow (CoBF) was monitored by thermal diffusion flow probe and/or laser Doppler. In some cases, the complex pathological anatomy required a change in surgical strategy and a new MVD determination of collateral capacity. Despite these precautions 2 patients suffered ischemia of the basal ganglia and the white matter.     

Formation of volatile carcinogenic N-nitroso compounds from drugs under simulated human gastric conditions

41 commercial drugs approved for peroral application in the GDR, whose active agents contain N,N-dialkylamino groups in their chemical structures, have been investigated under simulated conditions of the human stomach. With the drugs containing aminophenazone, amitriptyline, doxycycline and oxytetracycline as active agents N-nitrosodimethylamine is formed as a result of nitrosation reactions. With the drugs containing clomiphene++, disulfiram, probenecid and a diethylamine-containing liquid hypnoticum, there occurred N-nitrosodiethylamine. In no case N-nitrosodi-n-propylamine or N-nitrosopiperidine were detectable. The isolated active agents amitriptyline, clomiphene++ and probenecid themselves proved not to be nitrosatable. The positive findings with these drugs were caused by not yet identified nitrosatable contaminants of these drugs. The quantitative determination of volatile N-nitroso compounds was done upon steam distillation by means of gas chromatograph and chemiluminescence detector.     

Assessment of the strength of minicapsulorhexes

PURPOSE: To evaluate the effect of age, size, position, and species on the strength of minicapsulorhexes. SETTING: Surgical Suite and Laser Laboratory, Ophthalmic Biophysics Center, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida, USA. METHODS: Capsulorhexes 0.7 to 2.3 mm in diameter were made centrally or peripherally in 35 eye-bank eyes and 32 rabbit eyes. A custom-made instrument stretched the capsulorhexes until rupture. Load and stretch at rupture were recorded. RESULTS: Maximum load and stretch were 26.3 mN +/- 20.3 (SD) and 50% +/- 18% for central and 50.8 +/- 20.5 mN and 69% +/- 17% for peripheral capsulorhexes in eye-bank eyes and 19.8 +/- 15.2 mN and 38% +/- 13% for central and 13.5 +/- 9.5 mN and 30% +/- 7% for peripheral capsulorhexes in rabbit eyes. Peripheral capsulorhexes were stronger and more elastic than central capsulorhexes in eye-bank eyes, and maximum load and stretch increased statistically with the capsulorhexis diameter. CONCLUSIONS: Peripheral minicapsulorhexes were more resistant to rupture than central capsulorhexes in eye-bank eyes, probably because of increased lens capsule thickness at the periphery. An increase in capsulorhexis diameter increased the resistance to rupture.     

Goitrous congenital hypothyroidism and hearing impairment associated with mutations in the TPO and SLC26A4/PDS genes

CONTEXT: Pendred syndrome (PS) and thyroid peroxidase (TPO) deficiency are autosomal-recessive disorders that result in thyroid dyshormonogenesis. They share congenital hypothyroidism, goiter, and an iodide organification defect as common features. Whereas the hallmark of PS is sensorineural deafness, other forms of congenital hypothyroidism may also lead to hearing impairment. Therefore, a definite diagnosis may be difficult and require molecular genetic analyses. CASE REPORT: The propositus presented at birth with primary hypothyroidism and goiter. He also had congenital bilateral moderate hearing loss, and PS was suspected. METHODS: We sequenced the SLC26A4/PDS and TPO genes in the propositus and tested familial segregation of mutations in all available family members who were phenotypically normal. The functional consequences of the identified pendrin mutation (p.R776C) were studied in vitro. RESULTS: Sequencing of the SLC26A4/PDS gene revealed a single monoallelic missense mutation in the propositus (p.R776C). This mutation, which was inherited from his unaffected mother, has previously been identified in an individual with deafness and an enlarged vestibular aqueduct. Sequencing of the TPO gene revealed compound heterozygosity for a novel nonsense mutation (p.Q235X) and a known missense mutation (p.Y453D). The mutant pendrin (p.R776C) retained its ability to transport iodide in vitro. CONCLUSIONS: These results show that the propositus carries three sequence variants in two genes: a monoallelic SLC26A4/PDS sequence variant and compound heterozygous TPO mutations. Our study illustrates that if only a single heterozygous SLC26A4/PDS mutation is found in a patient with goiter and deafness, other genetic explanations should be considered.     

The D-dopachrome tautomerase (DDT) gene product is a cytokine and functional homolog of macrophage migration inhibitory factor (MIF)

Macrophage migration inhibitory factor (MIF) is a pivotal regulator of the immune response. Neutralization or genetic deletion of MIF does not completely abrogate activation responses, however, and deletion of the MIF receptor, CD74, produces a more pronounced phenotype than MIF deficiency. We hypothesized that these observations may be explained by a second MIF-like ligand, and we considered a probable candidate to be the protein encoded by the homologous, D-dopachrome tautomerase (D-DT) gene. We show that recombinant D-DT protein binds CD74 with high affinity, leading to activation of ERK1/2 MAP kinase and downstream proinflammatory pathways. Circulating D-DT levels correlate with disease severity in sepsis or malignancy, and the specific immunoneutralization of D-DT protects mice from lethal endotoxemia by reducing the expression of downstream effector cytokines. These data indicate that D-DT is a MIF-like cytokine with an overlapping spectrum of activities that are important for our understanding of MIF-dependent physiology and pathology.