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.     

Ocular findings in patients with autosomal dominant retinitis pigmentosa and Cys110Phe, Arg135Gly, and GIn344stop mutations of rhodopsin

This report describes ocular findings obtained in four patients from three families with autosomal dominant retinitis pigmentosa (adRP) due to missense mutations in the rhodopsin gene. Phenotypes were characterized by standard ophthalmologic examinations, visual fields, electroretinography (ERG), dark adaptation, and two-color dark-adapted threshold perimetry. Two patients aged 38 and 45 years, respectively, from a family with the Cys110Phe mutation showed mild fundus changes without bone spicules as well as small arcuate scotomas in the inferior quadrants of their visual fields but displayed severe functional loss of rods and cones in the ERG. Two-color dark-adapted threshold perimetry revealed a regional type of degeneration. A 48-year-old patient with an Arg135Gly mutation had typical RP with concentrically narrowed visual fields and nondetectable ERG responses. Central visual functions were well preserved for a long time. Two-color dark-adapted threshold perimetry indicated a diffuse type of retinal degeneration. An 18-year-old patient with a GIn344stop mutation has been followed for 13 years. His ERG was clearly reduced at the age of 5 years; since that time, disease progression has been very slow. Currently, there are relatively mild alterations in visual acuity, rod sensitivity, and visual fields. Our findings confirm that there is a large phenotypic variety among patients with adRP and different rhodopsin mutations.This work was presented at the 93rd annual meeting of the Deutsche Ophthalmologische Gesellschaft, Mannheim, 23–26 September 1995     

Diagnosis of dementia in primary care: results of a representative survey in Lower Saxony,Germany

To investigate whether an early diagnosis of dementia is established, whether a differentiation is made between vascular and primary degenerative etiology, and whether treatable causes of dementia are considered in primary care, we performed a survey using three written sample case histories describing slight memory impairment (case 1) or moderate dementia (case 2a: vascular dementia; case 2b: degenerative dementia of Alzheimer type). The combinations 1 and 2a or 1 and 2b were randomly assigned and presented to ambulatory-care physicians (145 general practitioners and primary care internists and 14 neuropsychiatrists in private practice) in Göttingen and rural surroundings by a trained investigator who then performed a standardized interview. The study was representative (response rate 83.2%). For the sample case with slight memory complaints 13.8% of all physicians arrived at a primary diagnosis of depression and 44.0% considered depression for differential diagnosis. Senile dementia of Alzheimer type was considered less often. In the sample cases with moderate dementia according to established scientific criteria, there was a striking under-diagnosis of dementia, and in both cases an over-diagnosis of underlying vascular etiology. Treatable causes of dementia, such as possible drug interactions and substance abuse, were considered only by a minority of physicians. In conclusion, memory deficits seem to be regarded mainly as consequences of disturbed cerebral perfusion, and dementia as well as depression and drug adverse effects seem to be under-diagnosed in primary care.     

Holmium and thulium lasers: Comparison of solid state systems with potential applications for laser angioplasty

Three different Mid-infra-red laser systems with potential applications in peripheral and coronary angioplasty have been investigated: Free running Ho-Tm-Cr-YAG, Q-switched Ho-Tm-Cr-YAG and free running Tm-Cr-YAG. In vitro ablation experiments were performed with atherosclerotic plaque, using both single quartz fibres and multifibre ring catheters. Despite high ablation rates, the free running Ho-Tm-Cr-YAG laser caused thermal and acoustic damage to the tissue with carbonization effects, charring of the crater edges and severe vacuole formation. Using Q-switched Ho-Tm-Cr-YAG irradiation, thermal and acoustic side-effects were reduced, but the energy available from the system was too low to reach the ablation threshold with ring catheters. A free running Tm-Cr-YAG laser also showed limited tissue damage but its output energy was in excess of 1 J, allowing, therefore, effective catheter ablation.     

Mn-DPDP–enhanced MR imaging of malignant liver lesions: Efficacy and safety in 20 patients

Twenty patients with malignant liver lesions underwent magnetic resonance (MR) imaging with manganese (II) DPDP [N,N′-dipyridoxylethylenediamine-N,N′-diacetate 5,5′-bis(phosphate)] to evaluate the safety and efficacy of the contrast agent. In two groups of 10 patients each, 5 μmol/kg Mn-DPDP was administered intravenously (3 mL/min) at a concentration of either 50 or 10 μmol/mL. T1- and T2-weighted images were obtained with a 1.5-T imager. Six patients reported a total of eight instances of side effects (flush, feeling of warmth, metallic taste) of which seven occured at the 50 μmol/mL concentration. A significant decrease in alkaline phosphatase levels 2 hours after injection was recorded. On T1-weighted images, the 10 μmol/mL formulation yielded significantly greater increases in contrast-to-noise ratio (79.8%–137.5%) than the 50 μmol/mL formulation (46.2%–86.6%). In a blinded reader study of 10 patients with one to five lesions each, no lesion was missed on Mn-DPDP–enhanced T1-weighted images; however, four false-positive foci were identified. The authors conclude that slow administration of 5 μmol/kg Mn-DPDP at a concentration of 10 μmol/mL is safe and efficient enough to proceed to further clinical trials.     

OLITA: an alternative in the treatment of therapy-resistant chronic alcoholics

The Outpatient Long-term Intensive Therapy for Alcoholics (OLITA) is a four-step program of care for severely affected chronic alcoholics which, after inpatient detoxification, extends over a total of 2 years. High-frequency short-term individual therapeutic contacts, initially daily, are followed by a slow tapering of individual contact frequency and resolve in a group session once weekly towards the end of the second abstinent year. Further elements of OLITA are: (a) induction of alcohol intolerance by the application of aldehyde dehydrogenase inhibitors; (b) introduction of control factors, i.e. controlled intake of deterrent medication and regular urine analysis for alcohol; and (c) allocation of responsibility to the patient with respect to the overall success of the therapeutic concept including his own physical rehabilitation. Thus far, 30 male alcoholic patients from two recruitment periods have been treated for 6–26 months with a success rate of 60% abstinent patients. In conclusion, OLITA, based on the gradual tapering of high-frequency therapeutic contacts, thus far unique among outpatient programs for alcoholics, represents a promising advance in the treatment of therapy-resistant chronic alcoholics.     

Citalopram counteracts depressive-like symptoms evoked by chronic social stress in rats

Recently, we have described a new model of chronic social stress in rats, based on the resident-intruder paradigm. In this model, rats show behavioural changes that may be considered correlates of depressive symptoms, such as anhedonia and motivational deficits. The present study was designed for pharmacological validation of this model. Animals were socially stressed for 5 weeks and, in parallel, after the first week of stress, they were subjected to chronic (4 weeks) treatment with the antidepressant drug citalopram. The drug was administered via drinking water (30 mg/kg). The optimal dose of citalopram was determined in a pilot study. After 4 weeks of treatment, plasma levels of citalopram and its metabolite were found to be within the human therapeutic range. The effects of social stress and citalopram treatment were assessed by behavioural tests. Chronically stressed rats showed reduced locomotor and exploratory activity, reduced sucrose preference and increased immobility time in the forced swimming test. Chronic oral administration of citalopram abolished those effects and normalized behaviours related to motivation and reward sensitivity. These observations provide evidence for the predictive validity of the chronic social stress paradigm as a model of depressive symptoms in rats.     

The atypical antipsychotics olanzapine and quetiapine, but not haloperidol, reduce ACTH and cortisol secretion in healthy subjects

Rationale Increased activity of the hypothalamic–pituitary–adrenal (HPA) axis is an important aspect of the pathophysiology of major depression and schizophrenia. Despite the usefulness of atypical antipsychotics in the treatment of depression and their positive influence on cognitive functioning possibly related to their impact on cortisol, little is known about their effect on HPA axis function. Objective Therefore, this double-blind, placebo-controlled, randomized cross-over study investigated the influence of the atypical antipsychotics quetiapine and olanzapine in comparison with haloperidol and placebo on plasma adrenocorticotropic hormone (ACTH), cortisol, and prolactin levels. Eleven healthy male volunteers were studied during four sessions one week apart, orally receiving placebo, quetiapine (50 mg), olanzapine (5 mg), or haloperidol (3 mg). Blood samples were taken at hourly intervals from 0900 until 1700 hours. For ACTH, cortisol, and prolactin a significant effect of treatment condition (p≤0.005; p≤0.035; p≤0.0001, respectively) for area under the curve (AUC) was found. In comparison to placebo, quetiapine and olanzapine significantly reduced ACTH (p≤0.002; p≤0.05, respectively) and cortisol (p≤0.005; p≤0.03, respectively). No effect of haloperidol on AUC of ACTH or cortisol levels was observed. In comparison with placebo, haloperidol (p≤0.0001) and olanzapine (p≤0.0001) elevated AUC of prolactin plasma levels, whereas no significant effect was observed for quetiapine as a main effect of treatment condition. The atypical antipsychotics’ strong influence on HPA-function with pronounced ACTH and cortisol lowering is possibly related to the atypicals’ blockade of serotonergic receptors, but blockade of adrenergic or histaminergic receptors may play a role as well. The observed HPA-axis down-regulation may be clinically important for the atypicals’ effects on depressive symptomatology and cognitive functioning.     

Influence of polyclonal anti-thymocyte globulins upon ischemia-reperfusion injury in a non-human primate model

BACKGROUND: Polyclonal anti-thymocyte globulins (ATGs) are used to induce immunosuppression and to treat acute rejection after transplantation. ATGs induce apoptosis and in peripheral T-lymphocytes having the potential to inhibit leukocyte adhesion. We analysed the influence of three different ATGs upon the microvasculature and the different cell-subpopulations after ischemia/reperfusion (IRI). MATERIALS AND METHODS: Extremities of cynomolgus monkeys were surgically isolated and flushed with Ringer's lactate at 4 degrees C. After 60 min of ischemia the limbs were reperfused with matching human blood. ATGs were added to the blood 30 min prior to the reperfusion. Four groups were generated: Tecelac-ATG group, Fresenius(S)-ATG group, Thymoglobulin-ATG group and a control group. Blood analyses were performed in blood samples taken after the beginning of the reperfusion. Biopsies from muscular tissue were obtained after the experiments. RESULTS: The number of circulating leukocytes was lower in the ATG-groups than in control. Morpho-cytological analyses showed depletion of peripheral lymphocytes. Histological examination showed less tissue damage, reduced presence of fibrin and adherent thrombocytes in the ATG-treated groups. Leukocyte infiltration, both in muscle and vascular structures, was significantly diminished in the ATG-groups in comparison to control. DISCUSSION: Our results show that ATGs have a favourable impact on early mechanisms of IRI. ATGs showed a reduction of the number of adherent leukocytes and muscle infiltrates suggesting that preoperative therapy with ATGs may have an advantageous effect on primary non-function and on chronic rejection as well as a positive influence upon IRI.     

Differences of pancreatic expression of 7B2 between C57BL/6J and C3H/HeJ mice and genetic polymorphisms at its locus (Sgne1)

C57BL/6 (B6) mice develop glucose intolerance with age, whereas C3H/He (C3H) mice do not. In this study, we examined whether this differential glucose homeostasis was associated with differences of proteolytic activation of pancreatic prohormones. Radioimmunoassays showed comparable levels of fasting plasma insulin between the two strains but a significantly lower glucagon level in B6 mice. Pulse-chase analysis of glucagon biosynthesis in isolated pancreatic islets revealed that proglucagon was less efficiently processed in B6 mice. Because proprotein convertase (PC)2 and its 7B2 helper protein are required for this processing, we quantified islet mRNA levels by RT-PCR and protein levels by immunoblotting. The levels of proPC2 mRNA were similar between the two strains, but B6 protein extracts contained less of the mature PC2. In contrast, 7B2 mRNA and protein levels were both significantly lower in B6 pancreas. Sequencing of the 7B2 gene promoter and cDNA in the two strains revealed seven single nucleotide polymorphisms and one dinucleotide insertion/deletion in the cDNA as well as a single nucleotide polymorphism and two insertions/deletions in the promoter. Differential expression of 7B2 may contribute to the difference between B6 and C3H mice not only in glucagon production and secretion but also in glucose tolerance.