A possible mechanism of action of the neurotoxic agent iminodipropionitrile (IDPN): a selective aggregation of the medium and heavy neurofilament polypeptides (NF-M and NF-H)

Juvenile male rats treated acutely with the neurotoxic agent, iminodipropionitrile showed no changes in the levels of total neurofilament subunit mRNA or protein for up to 28 days. However, the drug promoted aggregation of the neurofilaments, both spontaneously upon isolation and in an in vitro reassembly assay. This observation correlated with a basic pI shift of the heavy neurofilament subunit, due to a yet to be identified modification. Because of the crucial involvement of this neurofilament subunit in axonal integrity, it is likely that iminodipropionitrile produces a major portion of its neurotoxicity through this mechanism.

Thyroid carcinoma in single cold nodules and in cold nodules of multinodular goiters.

OBJECTIVE: To examine the frequency of malignant growth in a nonfunctioning solitary thyroid nodule (SN) and in multinodular goiter (MNG). METHODS: We performed fine-needle aspiration biopsy (FNAB) of cold nodules in 154 patients. Eight patients with unsatisfactory FNAB specimens were excluded from the study. Of the remaining 146 patients, 95 (89 women and 6 men) had MNG. The other 51 patients (46 women and 5 men) had SN. The overall age range was 25 to 86 years (mean, 52). RESULTS: Of the 95 patients with MNG, 16 had abnormal cytologic findings and underwent surgical excision. Of these 16 patients, 12 had thyroid cancer (6 papillary, 3 follicular, and 3 Hürthle cell). Of the 51 patients with SN, 8 had suspicious cytologic findings, and 5 had surgical histologic evidence of thyroid cancer (3 papillary and 2 follicular). Four patients with papillary thyroid cancer (three from the MNG group and one from the SN group) had a history of exposure to neck irradiation. After exclusion of the patients with a history of neck irradiation, the rate of malignant involvement in cold nodules in the MNG group was 9.78%, in comparison with 8% in the group with SN (P = 0.89). Within the MNG group, 25% of the thyroid malignant lesions were of the Hürthle cell type. CONCLUSION: Multinodularity of a goiter should no longer be considered an indicator of probable benign disease. In the assessment of all thyroid nodules, both SN and those in MNG, a thyroid scan can be helpful, and it should be followed by FNAB and cytopathologic examination of any nonfunctioning lesions. The incidence of malignant involvement in cold nodules of MNG does not differ significantly from that found in SN.

Cloning of a cDNA encoding the rat high molecular weight neurofilament peptide (NF-H): developmental and tissue expression in the rat, and mapping of its human homologue to chromosomes 1 and 22.

Neurofilaments (NFs) are the intermediate filaments specific to nervous tissue. They are probably essential to the tensile strength of the neuron, as well as to transport of molecules and organelles within the axon. Three peptides with apparent molecular masses of approximately 68 (NF-L), 145 (NF-M), and 200 (NF-H) kDa appear to be the major components of NF. The expression of these peptides is specific to nervous tissue and is developmentally regulated. Recently, complete cDNAs encoding NF-L and NF-M, and partial cDNAs encoding NF-H, have been described. To better understand the normal and pathophysiology of NFs we chose to clone the cDNA encoding the rat NF-H peptide. Using monoclonal antibodies that recognized NF-H, we screened a rat brain lambda gt11 library and identified a clone that contained a 2100-nucleotide cDNA insert representing the carboxyl-terminal portion of the NF-H protein. Anti-fusion protein antibodies recognized the NF-H peptide on immunoblots and stained fibrillar structures only in neurons. The cDNA recognized a 4500-nucleotide polyadenylated mRNA that was present only in nervous tissue and a 3500-nucleotide mRNA in adrenal. Brain NF-H mRNA levels were tightly developmentally regulated and paralleled the levels of NF-H peptide on immunoblots. Nuclear runoff studies showed that the 20-fold developmental increase in the NF-H message was due only in part to a 4-fold increase in its transcription rate. Levels of NF-H mRNA varied 20-fold among brain regions, with highest levels in pons/medulla, spinal cord, and cerebellum, and lowest levels in olfactory bulb and hypothalamus. Transcription studies revealed only a 2-fold difference in the transcription rates among these brain regions. Based on these results, we infer that half of the developmental increase and most of the interregional variation in the levels of the NF-H mRNA are mediated through message stabilization. Sequence information revealed that the carboxyl-terminal region of the NF-H peptide contained a unique serine-, proline-, alanine-, glutamic acid-, and lysine-rich repeat. The serine residues are likely sites of phosphorylation in the mature peptide. Genomic blots revealed a single copy of the gene in the rat genome and two copies in the human genome. In situ hybridizations performed on human chromosomes mapped the NF-H gene to chromosomes 1 and 22. Whether one copy is a pseudogene remains to be determined.