Successful surgical removal of occult metastases of medullary thyroid carcinoma recurrences with the help of immunoscintigraphy and radioimmunoguided surgery.

Patients with recurrent or metastatic medullary thyroid carcinoma (MTC) were referred for pretargeted immunoscintigraphy (Affinity Enhancement System; AES) and radioimmunoguided surgery (RIGS). Data collected from 13 patients establish that whole-body AES immunoscintigraphy revealed metastases < 360 mg and RIGS detected micrometastases (5-15 mg). All tissue samples removed by the surgeon were diagnosed by histology and immunohistochemistry of calcitonin to check the accuracy of IS and RIGS results. AES immunoscintigraphy is very sensitive. Of 34 metastases or recurrences detected, 22 had escaped physical examination or conventional imaging. The accuracy of RIGS was 86%, its sensitivity 75%, and its specificity was 90% (n = 208). IS and RIGS detected occult tumors that would have escaped surgery, clearly demonstrating clinical benefit. Serum calcitonin (normal, 10 pg/ml) and carcinoembryonic antigen (normal, 5 ng/ml) of two patients were restored to normal. In patients whose tumors were discovered, progression of their disease was slowed, as evidenced by the large decrease in serum calcitonin and carcinoembryonic antigen, an important prognostic factor. Surgery was canceled in one case where IS detected distant metastases out of surgical reach. Thus, AES immunoscintigraphy and RIGS might be of valuable help for the surgical management of medullary thyroid carcinoma.     

Supersensitivity to the Antinociceptive Effect of a 5-HT1 Receptor Agonist after Lesion of Raphe-Spinal Serotonergic Neurones

Abstract: The actions of the 5-hydroxytryptamine type-1B (5-HT₁) receptor agonist 1(m-chlorophenyl)piperazine (mCPP) on response latencies in the tail-flick test and tail skin temperature were examined in mice after pretreatment with the 5-HT neurotoxin, 5,6-dihydroxytryptamine (5,6-DHT). All the compounds were given intrathecally. The level of 5-HT in spinal cord was reduced by 79% 4 days after intrathecal injection of 5,6-DHT (10 μg). There was a significant relationship between the tail-flick latency and tail skin temperature, and the reduced baseline tail-flick latencies induced by 5,6-DHT were non-significant after the change in skin temperature was taken into account. Intrathecal mCPP (5 μg) significantly increased the tail-flick latency and significantly reduced the tail skin temperature in 5,6-DHT pretreated animals when compared to control animals. These differences in tail-flick latencies could not be explained by alterations in skin temperature. The results provide evidence that neurotoxic lesion of descending 5-HT pathways induces supersensitivity to the antinociceptive effect of 5-HT₁ receptor stimulation.     

Diphenyl diselenide and ascorbic acid changes deposition of selenium and ascorbic acid in liver and brain of mice

Sodium selenite (Na2SeO3) is the selenium form used in the composition of dietary supplements, and diphenyl diselenide (PhSe)2 is an important intermediate in organic synthesis, which increases the risk of human exposure to this chemical in the workplace. These compounds have been reported to inhibit the cerebral and hepatic aminolevulinic acid dehydratase (ALA-D) in vitro, and now we show that ascorbic acid can reverse some alterations caused by in vivo selenium exposure, but not ALA-D inhibition. The effect of Na2SeO3 or (PhSe)2 and ascorbic acid on selenium distribution, total non-protein thiol, ascorbic acid content (liver and brain) and haemoglobin was also examined. Mice were exposed to 250 micromol/kg (PhSe)2, or 18.75 micromol/kg Na2SeO3 subcutaneously, and to ascorbic acid, twice a day, 1 mmol/kg intraperitonially, for 10 days. Hepatic ALA-D of mice treated with (PhSe)2 was inhibited about 58% and similar results were observed in the animals that received ascorbic acid supplementation (P<0.01, for (PhSe)2-treated and (PhSe)2+ascorbic acid-treated mice). The haemoglobin content decreased after treatment with (PhSe)2 (P<0.01). However, the haemoglobin content of the (PhSe)2+ascorbic acid group was significantly higher than in the (PhSe)2-treated mice (P<0.05), and similar to control (P>0.10). Ascorbic acid treatment decreased significantly the hepatic and cerebral deposition of Se in (PhSe)2-exposed mice (P<0.01). Hepatic non-protein thiol content was not changed by treatment with (PhSe)2, ascorbic acid or (PhSe)2+ascorbic acid. Hepatic content of ascorbic acid was twice that in mice that received (PhSe)2, independent of ascorbic acid treatment (P<0.001). The results of this study suggest that vitamin C may have a protective role in organodiselenide intoxication.     

BCL2L10 is a predictive factor for resistance to azacitidine in MDS and AML patients

Azacitidine is the leading compound to treat patients suffering myelodysplastic syndrome (MDS) or AML with less than 30% of blasts, but a majority of patients is primary refractory or rapidly relapses under treatment. These patients have a drastically reduced life expectancy as compared to sensitive patients. Therefore identifying predictive factors for AZA resistance is of great interest to propose alternative therapeutic strategies for non-responsive patients. We generated AZA-resistant myeloid cell line (SKM1-R) that exhibited increased expression of BCL2L10 an anti-apoptotic Bcl-2 member. Importantly, BCL2L10 knockdown sensitized SKM1-R cells to AZA effect suggesting that increased BCL2L10 expression is linked to AZA resistance in SKM1-R. We next established in 77 MDS patients that resistance to AZA is significantly correlated with the percentage of MDS or AML cells expressing BCL2L10. In addition, we showed that the proportion of BCL2L10 positive bone marrow cells can predict overall survival in MDS or AML patients. We propose a convenient assay in which the percentage of BCL2L10 expressing cells as assessed by flow cytometry is predictive of whether or not a patient will become resistant to AZA. Therefore, systematic determination of BCL2L10 expression could be of great interest in newly diagnosed and AZA-treated MDS patients.     

Caries experience as predictor for caries incidence

The caries increment (filled surfaces) from the ages 7 to 15 years were compared in children with three or fewer (low prevalence group) or eight or more filled surfaces (high prevalence group) at the age of 8. The children participated in a fortnightly fluoride mouthrinsing program (10 ml of 0.2% NaF). Following 8 years of dental treatment and caries prophylaxis, the caries increments were 11.4 (s.d. = 7.7, n = 23 subjects) and 17.1 (s.d. = 9.6, n = 39 subjects) surfaces, i.e. significantly different (t = 2.376). Significantly (t = 4.034) more fillings had been required in the high than in the low prevalence group (31.1 +/- 17.1 vs. 15.5 +/- 9.6). The "risk group" could be identified at the ages of 7 to 8 by high caries prevalence and high ratio fillings/caries increment. Social class and number of teeth accounted more for the initial caries prevalence than for the caries increment. Correlation analyses revealed a significant, but not strong (r = 0.50), association between caries prevalence at the age of 7 and increment of fillings.     

Determinants of 6-month maternal satisfaction with breastfeeding experience in a multicenter prospective cohort study

Although a personally defined experience, successful breastfeeding is usually measured with regard to duration. This study investigated the determinants of maternal satisfaction with breastfeeding experience for 907 mothers enrolled in a prospective cohort study. Despite a median breastfeeding duration (18 weeks) that fell short of recommendations, 822 mothers (90.6%) rated their breastfeeding experience as very or fairly satisfactory. Anticipated breastfeeding duration was a determinant of satisfaction only for women who actually breastfeed < 2 months; in this subgroup of mothers, satisfaction rates ranged from 84.6% for those who anticipated breastfeeding < 2 months to 69.8% for those who anticipated breastfeeding > 4 months (P = .01). Smoking during pregnancy and experiencing breastfeeding difficulties after discharge were independently associated with decreased satisfaction. Eliciting the mother's expectations regarding breastfeeding duration may help the lactation consultant in providing appropriate guidance. Future studies should assess maternal satisfaction using validated instruments.     

Apparent hyperalgesia after lesions of the descending serotonergic pathways is due to increased tail skin temperature

It has been suggested that the descending serotonergic pathways exercise a tonic inhibition on nociception in the spinal cord. In this study 5,6-dihydroxytryptamine (5,6-DHT, 20 micrograms base) injected intrathecally in rats reduced spinal serotonin concentration to 3.5% of control levels without significantly affecting spinal noradrenaline. The lesion reduced the mean tail-flick latency by approximately 35% and increased the mean tail skin temperature by approximately 3.5 degrees C; both parameters gradually returned to normal values within 2-3 weeks. Both in controls and in lesioned animals there was a highly significant negative correlation between tail skin temperature and tail-flick latency. Multiple regression analysis showed that the effect of lesioning on tail-flick latency was non-significant when the effect of skin temperature was taken into account. Thus the reduced tail-flick latency after lesions of descending serotonergic pathways, usually interpreted as increased nociception, may be due to changes in tail skin temperature.     

Acute effects of nomifensine on in vivo uptake and metabolism of dopamine, noradrenaline and serotonin in the rat brain

Nomifensine, in contrast to all other antidepressants, inhibits the neuronal uptake of dopamine. The effect of this drug (10 mg/kg intraperitoneally) on the metabolism of dopamine, serotonin and noradrenaline was studied in the rat brain. After 1.5 hours, nomifensine increased the concentrations of homovanillic acid (HVA) in corpus striatum and total (free and conjugated) 3-methoxy, 4-hydroxyphenylglycol (MOPEG) in mesencephalon, but had no effect on the 5-hydroxyindoleacetic acid (5-HIAA) in pons/medulla oblongata and mesencephalon. The effect was identical with that of desipramine (25 mg/kg) on MOPEG and of imipramine (25 mg/kg) on 5-HIAA. Two methods ordinarily used for estimating turnover rates of monoamines were compared: accumulation of acid metabolites after probenecid (measuring efflux of metabolites from the brain) and accumulation of monoamine precursors after decarboxylase inhibition (measuring amine synthesis). The efflux was reduced for 5-HIAA and MOPEG but increased for HVA after nomifensine. Imipramine had the same effect on 5-HIAA and desipramine on MOPEG. Desipramine decreased the efflux of HVA from corpus striatum. In contrast, nomifensine did not change the synthesis of noradrenaline and serotonin significantly. Imipramine reduced the synthesis of serotonin in pons/medulla oblongata. In corpus striatum nomifensine, unlike imipramine, increased the concentration of 5-HIAA and synthesis of serotonin in spite of a decrease in efflux, probably because of a secondary effect from the dopaminergic action. The conclusion was made that there were more than one compartment of monoamine metabolites. The antidepressants could to some extent lead to a shift in the metabolism to sites more distant to the transport mechanism.