6-Hydroxydopamine lesion in the ventral tegmental area fails to reduce extracellular dopamine in the cerebral cortex.

Dopamine and noradrenaline are both involved in modulation of superior cognitive functions that are mainly dependent on frontal cortex activity. Experimental evidence points to parallel variations in extracellular concentrations of catecholamines in the cerebral cortex, which leads us to hypothesize their corelease from noradrenergic neurons. This study aimed to verify this hypothesis, by means of cerebral microdialysis following destruction of dopaminergic innervation in rats. The unilateral injury of dopaminergic neurons, by 6-hydroxydopamine injection in the ventral tegmental area, dramatically reduced the immunoreactivity for dopamine transporter in the cerebral hemisphere ipsilateral to the lesion. Tissue dopamine content in the ipsilateral nucleus accumbens and medial prefrontal and parietal cortex was also profoundly decreased, whereas noradrenaline was only slightly affected. Despite the lower tissue content in the denervated side, the extracellular dopamine level was not changed in the cortex, although it was markedly decreased in the nucleus accumbens ipsilateral to the lesion. The effect of drugs selective for D(2)-dopaminergic (haloperidol) or alpha(2)-noradrenergic (RS 79948) receptors was verified. Haloperidol failed to modify extracellular dopamine in either cortex but increased it in the nucleus accumbens, such an increase being greatly reduced in the denervated side. On the other hand, RS 79948 increased extracellular dopamine and DOPAC in all areas tested, the increases being of the same degree in both intact and lesioned sides. The results strongly support the hypothesis that the majority of extracellular dopamine in the cortex, unlike that in the nucleus accumbens, originates from noradrenergic terminals.

Nicotinamide increases thyroid radiosensitivity by stimulating nitric oxide synthase expression and the generation of organic peroxides.

Differentiated thyroid cancer and hyperthyroidism are treated with radioiodine. However, when the radioisotope dose exceeds certain limits, the patient must be hospitalized to avoid contact with people that would otherwise be exposed to radiation. It would be desirable to obtain a similar therapeutic effect using lower radioiodine doses. Radiosensitizers can be utilized for this purpose. Nicotinamide (NA) increases thyroid radiosensitivity to 131I in both normal and goitrous glands. NA causes a significant increase in thyroid blood flow, which would increase tissue oxygenation and tissue damage via free radicals. Wistar rats were treated with either nicotinamide (NA), 131I or both. The expression of the three isoforms of nitric oxide synthase (NOS) in the thyroid (Western blot) and the activities of SOD, GPx, catalase and organic peroxides were determined. Treatment with NA or 131I increased the expression of eNOS and the generation of organic peroxides. When administered jointly, they showed a synergistic effect. No changes were observed in the other NOS isoforms or in the activities of catalase, glutathione peroxidase and superoxide dismutase. NA potentiates the effect of 131I by increasing eNOS, which would in turn stimulate NO production, increasing thyroid blood flow and tissue damage via organic peroxides.

Boron neutron capture therapy for undifferentiated thyroid carcinoma: preliminary results with the combined use of BPA and BOPP.

We have shown the selective uptake of borophenylalanine (BPA) by undifferentiated human thyroid cancer (UTC) ARO cells both in vitro and in vivo. Moreover, a 50% histologic cure of mice bearing the tumor was observed when the complete boron neutron capture therapy was applied. More recently we have analyzed the biodistribution of BOPP (tetrakis-carborane carboxylate ester of 2,4-bis-(alpha,beta-dihydroxyethyl)-deutero-porphyrin IX) and showed that when BOPP was injected 5 days before BPA, and the animals were sacrificed 60 min after the i.p. injection of BPA, a significant increase in boron uptake by the tumor was found (38-45 ppm with both compounds vs. 20 ppm with BPA alone). Five days post the i.p BOPP injection and 1h after BPA the ratios were: tumor/blood 3.75; tumor/distal skin 2. Other important ratios were tumor/thyroid 6.65 and tumor/lung 3.8. The present studies were performed in mice transplanted with ARO cells and injected with BOPP and BPA. Only in mice treated with the neutron beam and injected with the boronated compounds we observed a 100% control of tumor growth. Two groups of mice received different total absorbed doses: 3.00 and 6.01 Gy, but no further improvement in the outcome was found compared to the previous results using BPA alone (4.3 Gy).

Biodistribution of p-borophenylalanine (BPA) in dogs with spontaneous undifferentiated thyroid carcinoma (UTC).

Human undifferentiated thyroid carcinoma (UTC) is a very aggressive tumor which lacks an adequate treatment. The UTC human cell line ARO has a selective uptake of BPA in vitro and after transplanting into nude mice. Applications of boron neutron capture therapy (BNCT) to mice showed a 100% control of growth and a 50% histological cure of tumors with an initial volume of 50 mm(3) or less. As a further step towards the potential application in humans we have performed the present studies. Four dogs with diagnosis of spontaneous UTC were studied. A BPA-fructose solution was infused during 60 min and dogs were submitted to thyroidectomy. Samples of blood and from different areas of the tumors (and in one dog from normal thyroid) were obtained and the boron was determined by ICP-OES. Selective BPA uptake by the tumor was found in all animals, the tumor/blood ratios ranged between 2.02 and 3.76, while the tumor/normal thyroid ratio was 6.78. Individual samples had tumor/blood ratios between 8.36 and 0.33. These ratios were related to the two histological patterns observed: homogeneous and heterogeneous tumors. We confirm the selective uptake of BPA by spontaneous UTC in dogs and plan to apply BNCT in the future.

A new animal model for human undifferentiated thyroid carcinoma.

An animal model of undifferentiated thyroid carcinoma (UTC), which may be useful for studying tumorigenesis and response to new therapies, is described. The UTC human cell line ARO was implanted into the back of the nude mice. The histology, induction of metastasis, and biokinetics of in vivo and in vitro growth, as well as cytogenetic and molecular aspects were studied. The tumor showed extensive viability with high mitotic activity. At 117 days, the tumors reached a size of 1,700 mm(3) and showed a central necrotic portion with a thin layer of viable cells. When the number of passages in the mouse increased the growth rate decreased. The cytogenetic and molecular studies did not show differences between the original line and the sublines that could explain this phenotypic change. Moreover, the original ARO cell line and its sublines showed a complex clonal karyotype including structural alterations with deletions and translocations involving chromosomes 5, 7, 8, 9p, 11p, 17q 19p, and 20q that were consistent with earlier reported data in UTC. This work provides an animal model of UTC pheno- and genotypically similar to the original human tumor, which may be useful for exploring new therapeutic modalities.

Short-term methadone administration reduces alcohol consumption in non-alcoholic heroin addicts.

- Methadone, a synthetic opioid agonist, is commonly used for the treatment of heroin dependence. Depending on how alcohol addiction is defined, rates of alcoholism vary among those attending methadone maintenance treatment (MMT) programmes. Most of the current literature has shown that alcohol consumption increases during medium- or long-term MMT. However, up to now, no data have been reported on changes in alcohol intake among a population of heroin addicts with no alcohol-dependence diagnosis after short-term methadone administration. Thus, the aim of our study was to investigate alcohol consumption changes in a population of non-alcoholic heroin addicts during the first 4 weeks of a treatment programme (TP). The TP consisted of either MMT or non-methadone maintenance treatment (N-MMT) with a minimum duration of 1 year. A total of 359 heroin-addicted out-patients [274 males (76.3%)], all of whom met DSM-IV criteria, were enrolled in the study, over a period of 4 months. Out of these 359 patients, 32 subjects (8.9%) dropped out, whereas 327 subjects (91.1%; 249 males) continued the TP [105 (32.1%; 78 males) in the MMT group and 222 (67.9%; 171 males) in the N-MMT group]. A significant reduction in daily alcohol intake was observed in the MMT group, but not in the N-MMT group after the first 4 weeks of the TP. The results of the present study suggest a possible effect of short-term methadone administration in reducing alcohol consumption in a population of non-alcoholic heroin-addicted patients.

Selective uptake of p-borophenylalanine by undifferentiated thyroid carcinoma for boron neutron capture therapy.

Undifferentiated thyroid carcinoma (UTC) lacks an effective treatment. Boron neutron capture therapy (BNCT) is based on the selective uptake of 10B-boronated compounds by some tumors, followed by irradiation with an appropriate neutron beam. The radioactive boron originated (11B) decays releasing 7Li, gamma rays and alpha particles, and these latter will destroy the tumor. In order to explore the possibility of applying BNCT to UTC we have studied the biodistribution of BPA. In in vitro studies, the uptake of p-10borophenylalanine (BPA) by the UTC cell line ARO, primary cultures of normal bovine thyroid cells (BT), and human follicular adenoma (FA) thyroid was studied. No difference in BPA uptake was observed between proliferating and quiescent ARO cells. The uptake by quiescent ARO, BT, and FA showed that the ARO/BT and ARO/FA ratios were 4 and 5, respectively (p < 0.001). In in vivo studies, ARO cells were transplanted into the scapular region of NIH nude mice, and after 2 weeks BPA (350 or 600 mg/kg body weight) was injected intraperitoneally. The animals were sacrificed between 30 and 150 minutes after the injection. With 350 mg, tumor uptake was highest after 60 minutes and the tumor/normal thyroid and tumor/blood ratios were 3 and 5, respectively. When 600 mg/kg body weight BPA were administered, after 90 minutes the tumor/blood, tumor/normal thyroid, and tumor/distal skin ratios for 10B concentrations per gram of tissue were approximately 3, showing a selective uptake by the tumor. The present experimental results open the possibility of applying BNCT for the treatment of UTC.

Influence of nicotinamide on the radiosensitivity of normal and goitrous thyroid in the rat.

Radioiodine is used to treat thyroid cancer and hyperthyroidism. In order to reduce radiation hazard to the patient and to people in contact with the patient it would be desirable to obtain the same therapeutic effect with lower activities of the radioisotope. This could be achieved by the simultaneous administration of a compound that increases tissue radiosensitivity. In this study we analyzed the use of nicotinamide (NA) as a radiosensitizer to radioiodine, to increase 131I efficacy. NA administered during 30 days to Wistar rats failed to alter thyroid weight. The influence of NA on radiothyroidectomy induced by increasing doses of 131I was examined in otherwise nontreated rats. NA produced a significant increase in the ablation caused by radioiodine. Goiter was then induced by the administration of methylmercaptoimidazol (MMI) to rats, followed by the treatment with radioiodine with and without simultaneous administration of NA. Thyroid weight per 100 g of body weight ratio was not changed by NA alone; 131I administration caused a 25% decrease in goiter size, while 131I plus NA produced a reduction of the ratio of 46% (p < 0.01 vs. NA). No changes were observed in adenosine diphosphate (ADP)-ribosilation of thyroid nuclear protein in NA-treated rats. Thyroid blood flow (determined by 86Rb uptake) was increased by 84% by NA. In conclusion, nicotinamide has a significant radiosensitizing effect to 131I both in normal and goitrous rats. This action is because of an increase in thyroid blood flow, which probably enhances tissue oxgenation.

[Effect of dietary supplementation with gamma-linolenic acid on the growth of a human lung carcinoma implanted in nude mice]. / Efecto de la suplementación dietética con acido gama-linolenico sobre el crecimiento de un carcinoma de pulmón humano implantado en ratones atímicos.

We have studied the effect of a gamma-linolenic acid (18:3 n-6, GLA)-supplemented diet on the growth of a human lung mucoepidermoid carcinoma (HLMC) implanted in athymic mice and on its uptake of human low density lipoproteins labeled with 99mTc (99mTc-LDL). Mice bearing the HLMC were divided into two experimental groups. One of them was administered a control diet (C diet) and the other one was given a diet supplemented with 25 mg GLA/g pellet (GLA diet) for three weeks (Table 1). A tumor growth inhibition with the GLA diet was evident at the second week of treatment, and a marked inhibition (56%) was reached at the end of the third week (Fig. 1). The GLA diet produced some changes in the total fatty acid composition of tumor, plasma and liver of host mice: GLA and arachidonic acid (20:4 n-6, AA) induced significant increases, whereas oleic (18:1 n-9, OA) and linoleic acids (18:2 n-6, LA) were decreased (Table 2). Tumors of those animals fed both diets were labeled by 99mTc-LDL, and no difference was observed in the ratio of tumor/liver and tumor/kidney uptake of host animal (Table 3). Results obtained using this experimental model suggest that the inhibitory effect of GLA on tumor growth is not related to the LDL tumor uptake.

Efecto de la suplementación dietética con acido gama-linolenico sobre el crecimiento de un carcinoma de pulmón humano implantado en ratones atímicos. / [Effect of dietary supplementation with gamma-linolenic acid on the growth of a human lung carcinoma implanted in nude mice]

We have studied the effect of a gamma-linolenic acid (18:3 n-6, GLA)-supplemented diet on the growth of a human lung mucoepidermoid carcinoma (HLMC) implanted in athymic mice and on its uptake of human low density lipoproteins labeled with 99mTc (99mTc-LDL). Mice bearing the HLMC were divided into two experimental groups. One of them was administered a control diet (C diet) and the other one was given a diet supplemented with 25 mg GLA/g pellet (GLA diet) for three weeks (Table 1). A tumor growth inhibition with the GLA diet was evident at the second week of treatment, and a marked inhibition (56

) was reached at the end of the third week (Fig. 1). The GLA diet produced some changes in the total fatty acid composition of tumor, plasma and liver of host mice: GLA and arachidonic acid (20:4 n-6, AA) induced significant increases, whereas oleic (18:1 n-9, OA) and linoleic acids (18:2 n-6, LA) were decreased (Table 2). Tumors of those animals fed both diets were labeled by 99mTc-LDL, and no difference was observed in the ratio of tumor/liver and tumor/kidney uptake of host animal (Table 3). Results obtained using this experimental model suggest that the inhibitory effect of GLA on tumor growth is not related to the LDL tumor uptake.

Iron miners--a ten year follow-up.

1167 workers of Lorraine (France) iron mines, a random sample of 5600 workers aged 35 to 55 years, at work in 1975 constituted the initial cohort that was examined twice at 5-year intervals after the first examination. A questionnaire on respiratory symptoms and smoking habits (MRC questionnaire) plus questions on the work history of each participant was completed, vital capacity (VC), forced expiratory volume in one second (FEV1.0), residual volume (RV) and fractional uptake of CO (FuCO) were measured at the first examination and repeated five and ten years later. At the end of the ten year follow-up, 522 subjects were re-examined, 186 were lost to follow-up, 328 answered a mail questionnaire, and 111 had died. The total number of deaths was not different from that of the general population, but for lung cancer the standardized mortality ratio (SMR) was significantly increased (SMR = 3.7). For the miners re-examined, frequency of bronchitis and decrease of functional tests were more related to age and smoking habits than to occupation.

[Respiratory health of children and atmospheric pollution. I. Respiratory symptoms]. / Santé respiratoire des enfants et pollution atmosphérique. I. Symptômes respiratoires.

The impact on the respiratory system of complex industrial pollution (dust, sulphur dioxide, nitrogen oxides, hydrocarbons) was assessed by an analytical epidemiological study in a population of school children in the northeast of France. The parents of 375 children aged from 9-12 (middle school course 1 and 2) from the polluted zone and 523 children of the same age in a neighboring zone which was not polluted have filled in standardised questionnaires (respiratory symptoms, previous infections and allergies, frequency of infection in infancy; tobacco habits, professional and educational attainments of the parents, domestic environment). In the exposed children the majority of respiratory symptoms were more frequent (e.g., respiratory sounds in the boys, 15.6% against 7.9% p less than 0.01) and the absenteeism from school was more numerous (66.9% against 59.1% p less than 0.01). However, the interpretation of the results had to take into account the existence of confusing factors: parental smoking habits and the use of coal fires increased the prevalence of symptoms in the polluted zone, whereas a less crowded population worked in the inverse direction; likewise the educational level of the parents was higher in the polluted zone. After adjusting for these confusing factors, the frequency of rhinitis and absenteeism from school was significantly higher in exposed children.

[Respiratory health of children and atmospheric pollution. II. Ventilatory function]. / Santé respiratoire des enfants et pollution atmosphérique. II. Fonction ventilatoire.

Respiratory function (forced vital capacity-FVC; forced expired volume in one second-FEV1; maximal mid-expiratory flow-DEMM; peak flow-DP; maximal expiratory flow at 75-50-25% of vital capacity CV-DEMx) was studied in children of comparable age, sex and height (9 to 12 years) in a polluted zone (the exposed group n = 223) and a neighboring non-polluted zone (the control group n = 211) in the north of Lorraine. There was no significant difference in ventilatory function between the two groups. Amongst other factors capable of influencing the ventilatory function in the children we found an influence of parental smoking habits (particularly the mothers) identifiable in the non-exposed zone, above all in boys. A sub-segment analysis identified that in the absence of parental smoking, there was a negative influence of open coal fires. The discordance between the results of the measures of respiratory function and the prevalence of different respiratory symptoms, of acute infections and absenteeism from school, is probably explained by the interference of other factors which were not controlled in this study (e.g., ethnic factors and physical activity) and by the moderate level of the pollution; an over-reporting of respiratory symptoms by parents in the exposed zone could not be excluded.