Lindane inhibition of [35S]TBPS binding to the GABAA receptor in rat brain.

The inhibition of [³⁵S]t-butylbicyclophosphorothionate ([³⁵S]TBPS) binding to the GABA_A receptor by the insecticide γ-hexachlorocyclohexane, lindane, was studied in several brain regions and using different membrane preparation methods, both in vitro and after dosing the animals with the chemical. In the latter studies, the amount of lindane remaining in the membrane suspensions used for binding assays was determined. In vitro data showed values of IC₅₀ from 150 to 1675 nM, varying in function of the membrane preparation method used. This may account for the discrepancies in IC₅₀ values found in the literature. IC₅₀ values within the range of 150–250 nM were determined using extensively washed membranes from several brain regions, so no evidence arose for brain regional differences in the affinity of lindane for the TBPS binding site. After different schedules of acute treatment with lindane, we found a manifest relationship between the extent of the observable inhibition of [³⁵S]TBPS binding and the lindane amount remaining in the membrane suspensions used for binding assays. This relationship was in good agreement with the in vitro data, so no support for an in vivo acute regulation of the binding site was obtained.     

Enhanced neurotoxicity of 3,3'-iminodipropionitrile following carbon tetrachloride pretreatment in the rat.

The consequences of 3,3'-iminodipropionitrile (IDPN) exposure in animals merits attention both because of its unique neurotoxic effects and as a potential model compound of human dyskinetic disorders. An important question that remains to be determined is whether IDPN itself or a putative active metabolite is responsible for the neurotoxic actions of the chemical in vivo. The present work tested the hypothesis that IDPN must be metabolized by the liver to an active metabolite to become neurotoxic. Thus a reduction in IDPN neurotoxicity would be expected when liver function is compromised. Male Long-Evans rats were given ip injections of saline, 100 (IDPN1) or 200 (IDPN2) mg/kg of IDPN for three days. Half of the animals in each IDPN dose group received corn oil po and the other half 1 g/kg of the hepatotoxicant carbon tetrachloride (CCl4) for three days, starting one day before IDPN administration. Body weights were obtained regularly after exposure. Horizontal and vertical motor activity, and acoustic startle response were monitored prior to, and 1,3,9 and 16 weeks after IDPN exposure. An observational rating score was obtained at 1, 3 and 9 weeks. Auditory thresholds for 5- and 40-kHz tones were estimated by reflex modification procedures at 10 weeks. Animals receiving IDPN2 alone displayed the overt behavioral signs characteristic of IDPN intoxication (postural disturbances, head dyskinesias, backward walking, circling, increased motor activity, and decreased startle response). They also showed weight loss, hyperactivity, a transient rearing deficit, decreased startle amplitudes and elevated auditory thresholds for low- and high-frequency tones. None of these symptoms were observed in the animals treated with CCl4 alone, and only a mild transient effect on the observational rating score was shown by the IDPN1 alone animals. In contrast, IDPN1/CCl4 resulted in the same or higher toxicity than the IDPN2 treatment. IDPN2/CCl4 resulted in severe toxicity (38% mortality over a two-week period) and enhanced body weight and behavioral effects compared to IDPN2 alone group. Impairment of xenobiotic biotransformation was confirmed by elevated pentobarbital sleeping time in animals under the same CCl4 dosing regimen. In conclusion, pretreatment with hepatotoxic dosages of CCl4 leads to increased toxicity of IDPN. This suggests that hepatic transformation of the chemical is not required for the manifestation of IDPN-induced neurotoxicity, but instead may be involved in the detoxification of this compound.     

Changes in diastolic function in heart rejection: role of Doppler echocardiography]

In acute cardiac rejection, left ventricular diastolic function is altered. To study these abnormalities and their utility in cardiac allograft rejection, we studied 56 cardiac transplant recipients. All patients were assessed with endomyocardial biopsy and Doppler echocardiography done in the same day. A total of 163 Doppler studies were recollected. Cardiac transplant recipients were excluded during the early 6 weeks postoperative period. Totally, 100 biopsies were normal, 48 positive for mild rejection (Billingham Gde I-II) and 15 positive for moderate or severe rejection (Billingham Gde III-IV). Compared to negative biopsies, during acute rejection left ventricular wald thickness significantly increased (p < 0.05); isovolumic relaxation period and pressure half-time significantly decreased (p < 0.05, p < 0.001 respectively). Nevertheless, increase in peak early mitral flow velocity was only significantly associated with severe rejection (p < 0.001). Correlating only progressive shortening of isovolumic relaxation period parameter in the diagnosis of graft rejection, we forward a high sensibility (85%) and low specificity (57%). Thus, Doppler echocardiographic evaluation of left ventricular diastolic function provides a non-invasive tool for early detection of acute rejection monitoring after the early postoperative period.     

Follow up of growth and steroids in premature adrenarche

In a follow up study of 34 patients with premature adrenarche we examined serum adrenal androgen levels and growth. The majority (28/34) showed an upward bend in the growth curve which, at the mean age of 2.3 years, preceded other signs of adrenarche on average by 3.8 years. Pubertal growth spurt was missing or reduced in 50% of the patients (8/16), however, final height did not differ from that expected from parental heights. Adrenal androgens did not remain elevated at adolescence. The mean age at menarche for all the girls was 0.5 years younger than in the general population.Conclusion Our findings imply that premature adrenarche may start earlier than previously recognized. Compared to ordinary growth these children seen to use a greater part of their potential for adult height already at that early age.     

Regional distribution of a high-affinity enkephalin-degrading peptidase ('enkephalinase') and effects of lesions suggest localization in the vicinity of opiate receptors in brain.

The distribution of a high affinity enkephalin-dipeptidylcarboxypeptidase between regions of mouse brain is markedly heterogenous and parallels that of opiate receptors. Furthermore intrastriatal administration of kainic acid as well as interruption of the nigrostriatal dopaminergic pathway by 6-hydroxydopamine (6-OHDA) lead to similar decreases in this peptidase activity and in the number of opiate receptors. On the contrary, no correlation was found between low affinity enkephalin degrading enzymes and opiate receptors.     

Thyroid cancer susceptibility and THRA1 and BAT-40 repeats polymorphisms.

Although genetic and environmental factors have been identified in the etiology of thyroid cancer, the specific genetic implications in sporadic thyroid tumors are poorly understood but, as in other common cancers, low-penetrance susceptibility genes are believed to be crucial in the tumorigenesis processes. Here, we have carried out a case-control study to investigate whether there is an association between THRA1 CA repeat or BAT-40 A repeat polymorphisms and thyroid cancer risk. The THRA1 repeat resides in the thyroid hormone receptor-alpha1 gene, which is associated with thyroid cancer and whose expression depends on the THRA1 repeat size. We also analyzed the BAT-40 repeat that maps to chromosome 1, a region known to be involved in thyroid cancer. This repeat is located in the 3-beta-hydroxysteroid dehydrogenase gene that is associated with prostate cancer susceptibility. The THRA1 repeat was genotyped in 212 thyroid cancer patients and 141 controls of a Spanish population. From these individuals, 207 patients and 138 controls were also analyzed for the BAT-40 marker. No significant difference in the THRA1 allele distribution between patients and controls was found, although short alleles (<128 bp) might have some protective effect on thyroid cancer risk of carriers (odds ratio, 0.50; 95% confidence interval, 0.22-1.13; P = 0.094). By contrast, the BAT-40 allele distribution in patients was significantly different with respect to control (P = 0.035). Essentially, the difference were found in the genotypes involving the 111- to 115-bp allele range, which seem to be associated with a protective effect on thyroid cancer susceptibility in the studied population (odds ratio, 0.18; 95% confidence interval, 0.01-0.57; P = 0.02). Therefore, our results indicate that the BAT-40 containing region and to a less extend the thyroid hormone receptor-alpha1 gene are related to thyroid cancer susceptibility. To our knowledge, this is the first study reporting the identification of genetic factors for thyroid cancer susceptibility.     

Paraaortic sentinel lymph node detection in intermediate and high-risk endometrial cancer by transvaginal ultrasound-guided myometrial injection of radiotracer (TUMIR)

ObjectiveWe aimed to evaluate the accuracy of sentinel lymph node (SLN) mapping with transvaginal ultrasound-guided myometrial injection of radiotracer (TUMIR) to detect lymph node (LN) metastases, in patients with intermediate and high-risk endometrial cancer (EC), focusing on its performance to detect paraaortic involvement.MethodsProspective study including women with preoperative intermediate or high-risk EC, according to ESMO-ESGO-ESTRO consensus, who underwent SLN mapping using the TUMIR approach. SLNs were preoperatively localized by planar and single photon emission computed tomography/computed tomography images, and intraoperatively by gamma-probe. Immediately after SLN excision, all women underwent systematic pelvic and paraaortic lymphadenectomy by laparoscopy.ResultsThe study included 102 patients. The intraoperative SLN detection rate was 79.4% (81/102). Pelvic and paraaortic drainage was observed in 92.6% (75/81) and 45.7% (37/81) women, respectively, being exclusively paraaortic in 7.4% (6/81). After systematic lymphadenectomy, LN metastases were identified in 19.6% (20/102) patients, with 45.0% (9/20) showing paraaortic involvement, which was exclusive in 15.0% (3/20). The overall sensitivity and negative predictive value (NPV) of SLNs by the TUMIR approach to detect lymphatic involvement were 87.5% and 97.0%, respectively; and 83.3% and 96.9%, for paraaortic metastases. After applying the MSKCC SLN mapping algorithm, the sensitivity and NPV were 93.8% and 98.5%, respectively.ConclusionThe TUMIR method provides valuable information of endometrial drainage in patients at higher risk of paraaortic LN involvement. The TUMIR approach showed a detection rate of paraaortic SLNs greater than 45% and a high sensitivity and NPV for paraaortic metastases in women with intermediate and high-risk EC.