[Iodine status and the used of iodized antiseptics in the mother-newborn pair]. / Statut en iode et utilisation d'antiseptiques iodés chez le couple mère/nouveau-né.

Iodine status was evaluated by assessment of urinary iodine excretion in 221 mothers and their 223 newborns. During the first month after childbirth, 59.3 per cent of the mothers and 26.5 per cent of the newborns received applications of iodized antiseptic containing Polyvidone-iodine. 50.2 per cent of the newborns and 24.9 per cent of the mothers had a urinary iodine of more than 20 micrograms/dl (iodine excess). For the mothers and the newborns who had received applications of iodized antiseptic, 38.2 per cent and 74.6 per cent had an iodine excess, respectively. This iodine excess is directly related to use of iodized antiseptic. Such high iodine levels may contribute to the risk of thyroid disorders, and particularly to transient congenital hypothyroidism at a critical age for normal development of the nervous system.

Retinoic acid receptors alpha and gamma mediate the induction of "tissue" transglutaminase activity and apoptosis in human neuroblastoma cells.

All-trans retinoic acid (RA) reduces human neuroblastoma growth by inducing either differentiation or apoptosis. The apoptotic program in these cells is regulated by RA and is paralleled by the transcriptional induction of "tissue" transglutaminase (tTG). tTG is a protein cross-linking enzyme, which specifically accumulates in cells undergoing apoptosis in various in vivo and in vitro systems. In neuroblastoma cells, tTG is detected exclusively in the cells expressing the S-type phenotype and showing an increased apoptosis. The present study was undertaken to identify the retinoid receptors which are involved in the regulation of tTG and apoptosis as well as in the in vitro neuronal differentiation of the human SK-N-BE(2) neuroblastoma cell line. We have previously characterized the retinoid acid receptors expressed in this cell line. In the present study, by using synthetic retinoids selectively activating RAR/RXR isoforms, we have identified the RAR/RXR receptors involved in the induction of either apoptosis or differentiation. We have also studied the effect of the selective RA analogs on tTG activity. We observed that while RARalpha- and RARgamma-selective retinoids alone were able to induce tTG activity, only the combined stimulation of both RARalpha and RARgamma induced apoptosis. Conversely, several combinations of RAR/RXR closely mimicked the differentiation effects observed with all-trans retinoic acid. These results indicate that, at variance with differentiation, the induction of apoptosis in human SK-N-BE(2) neuroblastoma cells is under the specific control of RARalpha and RARgamma. These data seem relevant for the reported ability of RARgamma to suppress the clinically malignant tumor phenotype in patients.

Iliosacral screw fixation for pelvic obliquity in neuromuscular scoliosis. A long-term follow-up study.

STUDY DESIGN: This was a retrospective review of a consecutive series of patients with neuromuscular spinal deformity who underwent posterior fusion and pelvic fixation using a long construct and an iliosacral screw. OBJECTIVES: To evaluate the risks and benefits of iliosacral screw fixation. SUMMARY OF BACKGROUND DATA: Neuromuscular scoliosis with pelvic obliquity poses one of the most challenging instrumentation problems, mainly because of the poor bone quality frequently found within the sacrum. Complications include failure of instrumentation, loss of sacral fixation, loss of lumbar lordosis, and a high rate of nonunion. METHODS: One hundred fifty-four patients with neuromuscular scoliosis and pelvic obliquity underwent posterior arthrodesis with pelvic fixation using an iliosacral screw. Anteroposterior scoliosis Cobb angle, frontal pelvic obliquity, and sacral inclination angle were measured before surgery, immediately after surgery, and at the 5-year and 3-month follow-up examination. Influence of etiology, severity of deformity, and associated anterior release at the scoliotic curve above also were assessed. RESULTS: Correction of scoliosis Cobb angle ranged from 53% to 70%, and loss of correction ranged from 3% to 14% at the last follow-up examination. Correction of pelvic obliquity ranged from 60% to 84%, and loss of correction was mild. Sacral inclination angle approached normal values in all patients, except for those with myelomeningocele who had preoperative pelvic retroversion. Loss of correction ranged from 0.3 degree to 5.4 degrees at the last follow-up examination. Complications and loss of correction mostly were encountered in patients with myelomeningocele and spinal muscular atrophy. CONCLUSIONS: Iliosacral screw fixation in neuromuscular scoliosis is technically standardized and easy and offers mechanically efficient and stable fixation.

Expression and retinoid modulation of N-arginine dibasic convertase and an aminopeptidase-B in human neuroblastoma cell lines.

Under retinoic acid exposure, the three SK-N-BE(2)-derived human neuroblastoma cell lines, BE(2)-NA, BE(2)-SA and BE(2)-M17 undergo mainly differentiation, apoptosis or continue to proliferate, respectively. We have used this model system to study the modulation of the transcriptional expression of putative processing enzymes, two novel metallopeptidases; i.e. N-arginine dibasic convertase (NRD convertase; EC 3.4,24,61) and an aminopeptidase-B after exposure of the cells either to retinoic acid or to synthetic retinoid analogs. The data indicate that the two respective enzymes are differently modulated in the various cell lines. Whereas aminopeptidase-B expression is enhanced in most cases, NRD convertase appears to undergo opposite regulation in proliferating versus differentiating neuroblastoma cells. It is concluded that both genes might contain retinoic acid regulatory elements (RARE) in their promoters.

Regulation by retinoic acid of insulin-degrading enzyme and of a related endoprotease in human neuroblastoma cell lines.

Physiologically, the action of insulin-like growth factors (IGFs) is controlled at different levels, from its transcription start by tissue-specific and development-specific transcriptional factors to its degradation by peptidases such as insulin-degrading enzyme (IDE). Since IGF-II is the major autocrine/paracrine growth factor for neuroblastoma cells, we studied the expression and the role of IDE in this system. Here, we show that (a) IDE is expressed in several human neuroectodermal tumor cell lines, including neuroblastoma cell lines; (b) in a neuroblastoma cell line, IDE expression is up-regulated by retinoic acid, a well-known inducer of neuronal differentiation and/or programmed cell death; (c) IDE is probably not the only IGF-degrading enzyme present in these cells, since the activity of a novel thermolysin-like metalloendopeptidase, clearly distinct from IDE, is also detected. The TME activity is inhibited by IGF-I, Des-IGF-I, and IGF-II, and it is down-regulated by retinoic acid. Since retinoic acid plays a relevant role in controlling the growth of these cells and affects the expression of IDE, we have also: (a) identified the retinoic acid receptors (RARs) and retinoid X receptors (RXRs) expressed in these cell lines and (b) by means of synthetic retinoid analogues identified the RAR/RXR isoforms whose activation may be sufficient to induce the expression of the IDE gene. These results provide evidence that complex posttranslational molecular mechanisms participate in the autocrine/paracrine growth control of the IGF-II loop in neuroblastomas involving proteolytic systems.

PACAP stimulates c-fos mRNAs in small cell lung cancer cells.

The effects of PACAP on c-fos mRNA using small cell lung cancer (SCLC) cell was investigated. PACAP-27 (100 nM) increased c-fos mRNA 5-fold using NCI-N417 cells. The increase was concentration dependent with 0.1 nM PACAP-27 half maximally increasing c-fos mRNA. Also the increase in c-fos mRNA caused by PACAP was time dependent; being maximal after 1 hour and returning to basal values after 4 hours. PACAP-38 but not PACAP(28-38) increased c-fos mRNA. One uM PACAP(6-38), a PACAP receptor antagonist, inhibited the increase in c-fos mRNA caused by 1 nM PACAP. These data indicate that PACAP stimulates nuclear oncogene expression in SCLC cells.

Bombesin stimulates c-fos and c-jun mRNAs in small cell lung cancer cells.

The effects of bombesin/gastrin-releasing peptide (BN/GRP) on c-fos and c-jun gene expression were investigated using small cell lung cancer (SCLC) cells. BN (10 nM) increased c-fos mRNA fivefold using NCI-H345 or NCI-H510 cells. The increase was concentration dependent with 1 nM BN half-maximally increasing c-fos mRNA. Also, the increase in c-fos mRNA caused by BN was time dependent, being maximal after 1 h and returning to basal values after 4 h. GRP and GRP(14-27) but not GRP(1-16) increased c-fos mRNA. BW2258U89 (1 microM), a GRP receptor antagonist, had no effect on basal c-fos but inhibited the increase in c-fos mRNA caused by 10 nM BN. Also, BN transiently increased c-jun mRNA twofold and the increase caused by BN was blocked by BW2258U89. These data suggest that GRP receptors may regulate nuclear oncogene gene expression in SCLC cells.

TGF alpha-PE40 inhibits non-small cell lung cancer growth.

The ability of a chimeric toxin containing transforming growth factor alpha (TGF alpha) and truncated Pseudomonas exotoxin A to inhibit NSCLC growth was investigated. TGF alpha-PE40 inhibited binding of 125I-EGF to NSCLC cell lines with an IC50 value of 0.5-3 micrograms/ml. Similarly, other forms of the fusion protein, TGF alpha-PE38 and TGF alpha-PE40Asp553, which have active TGF alpha binding domains, inhibited specific 125I-EGF binding to NSCLC cells with IC50 values of 0.1-2 and 0.05-05 microgram/ml respectively. TGF alpha-PE40 inhibited 35S-methionine uptake by NSCLC cells with an ED50 value of 1-30 ng/ml. TGF alpha-PE38, which has one of the two disulfide pairs of PE40, inhibited amino acid uptake with ED50 values of 3-50 ng/ml whereas TGF alpha-PE40Asp553, which lacks ADP ribosylation activity, had an ED50 > 100 ng/ml. TGF alpha-PE40 inhibited colony formation of NSCLC cells with an LD50 value of 0.008-0.1 ng/ml. Similarly, TGF alpha-PE38 inhibited NSCLC colony formation with LD50 values of 0.002-0.1 ng/ml whereas TGF alpha-PE40Asp553 had an LD50 > 10 ng/ml. Also, TGF alpha-PE40 and TGF alpha-PE38 inhibited NSCLC xenograft formation in nude mice whereas TGF alpha-PE40Asp553 was inactive. These data suggest that TGF alpha-PE40 and TGF alpha-PE38 may be useful agents to inactivate NSCLC cells.

Phorbol esters regulate preprogastrin-releasing peptide messenger RNA in small cell lung cancer cells.

The expression of preprogastrin-releasing peptide (GRP) mRNA was studied using human small cell lung cancer (SCLC) cells. By Northern analysis, preproGRP mRNA was stimulated by 4 beta-phorbol 12-myristate 13 alpha-acetate (PMA) in a concentration- and time-dependent manner in these cells. In cell line NCI-H209, the addition of 10(-6) M PMA increased a 0.9-kb mRNA after 8 h. An inactive phorbol ester, 4 alpha-PMA, had little effect on preproGRP mRNA. A nuclear run-on assay indicated that 10(-6) M PMA increased preproGRP transcription 3-fold, whereas beta-actin and glyceraldehyde 3-phosphate dehydrogenase transcription was unaltered. In contrast, PMA had little effect on beta-actin mRNA expression. PMA (1 microM) in the presence of 100 microM 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H7), a protein kinase C inhibitor, had little effect on preproGRP mRNA. Addition of PMA after protein kinase C down-regulation did not alter preproGRP mRNA. PMA (1 microM) caused translocation of protein kinase C from the cytosol to the membrane of SCLC cells. Also, PMA (10(-6) M) stimulated and H7 (10(-4) M) reduced SCLC growth in vitro. When new synthesis of preproGRP mRNA was blocked by the addition of actinomycin D, preproGRP mRNA remained stable for 15 h. These data suggest that PMA induces transcription of GRP mRNA in SCLC cells.

A vasoactive intestinal peptide antagonist inhibits non-small cell lung cancer growth.

The most prevalent lung cancer, non-small cell lung cancer (NSCLC) has receptors for vasoactive intestinal peptide (VIP). Here the effects of a VIP antagonist (VIP-hyb) on NSCLC growth were investigated. In vivo, when VIPhyb (10 micrograms, s.c.) was daily injected into nude mice, xenograft formation was significantly inhibited by approximately 80%. In vitro, VIP (100 nM) stimulated colony formation approximately 2-fold, whereas 1 microM VIPhyb inhibited colony formation by approximately 50% when adenocarcinoma cell line NCI-H838 was used. The attenuation of tumor proliferation is receptor mediated, as VIPhyb inhibited specific 125I-labeled VIP binding to cell lines NCI-H157 and NCI-H838 with an IC50 of 0.7 microM. VIP (10 nM) increased the cAMP levels 5-fold when cell line NCI-H838 was used, and 10 microM VIPhyb inhibited the increase in cAMP caused by VIP. Northern blot analysis and radioimmunoassays have shown VIP mRNA and VIP-like immunoreactivity in NSCLC cells. These data suggest that VIP may be a regulatory peptide in NSCLC and that VIPhyb is a VIP receptor antagonist that inhibits proliferation.

Neuromedin B is present in lung cancer cell lines.

Previously, high levels of gastrin-releasing peptide and its mRNA were detected in classic small cell lung cancer cell lines. Here the ability of lung cancer cell lines to synthesize neuromedin B (NMB), a structurally similar mammalian bombesin-like peptide, was investigated. By radioimmunoassay, NMB (0.1-0.7 pmol/mg of protein) was detected in 23 of 33 lung cancer cell lines. In contrast, gastrin-releasing peptide (0.1-12.9 pmol/mg of protein) was detected in 16 of 32 cell lines. Using gel filtration and high pressure liquid chromatography techniques, the main peak of immunoreactive NMB coeluted with synthetic NMB. By Northern analysis, a 0.8-kilobase mRNA species was present, using poly(A) mRNA derived from two of three lung cancer cell lines. Using a more sensitive S1 nuclease protection assay, NMB mRNA was present in most of the 15 lung cancer cell lines examined. These data suggest that NMB may be a regulatory peptide in lung cancer.

Epidermal growth factor receptor monoclonal antibodies inhibit the growth of lung cancer cell lines.

The ability of monoclonal antibody (MAb 108), an immunoglobulin G (IgG)2a against the epidermal growth factor receptor (EGF-R), to interact with lung cancer cell lines was investigated. 125I-EGF bound with high affinity to non-small-cell lung cancer (NSCLC) cells, and MAb 108 inhibited specific binding of nine NSCLC cell lines in a dose-dependent manner (IC50 = 0.3-3 micrograms per ml). 125I-MAb 108 bound with high affinity (kd = 2 nM) to a single class of sites (Bmax = 70,000 per cell) using NSCLC neuroendocrine cell line NCI-H460. Specific 125I-MAb 108 binding was inhibited with high affinity by MAb 108 but not by a control antibody IgG using large-cell carcinoma cell line NCI-H1299. 125I-MAb 108 binding was not internalized at 37 degrees C using NSCLC neuroendocrine cell line NCI-H460 and adenocarcinoma cell line NCI-H23. Also, 1 microgram per ml of MAb 108 but not of a control IgG inhibited the clonal growth of NCI-H23 and squamous cell carcinoma cell line NCI-H157 in vitro. Also, MAb 108 inhibited xenograft formation of cell lines NCI-H460, NCI-H157, and NCI-H727 in nude mice in vivo. After a palpable tumor had formed using NCI-H460 cells, injection of 100 micrograms of MAb 108 (intraperitoneally three times weekly) inhibited xenograft volume in nude mice by approximately 50%. These data suggest that MAb 108 may interact with EGF receptors on lung cancer cell lines and inhibit NSCLC proliferation.