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PubMed1997

A chronological evaluation of experimental brain infarct by diffusion-mapping and magnetization transfer contrast imaging.

BACKGROUND AND PURPOSE: There is a complex system of evolving physiochemical processes in the ischemic brain. The evaluation of this chain of processes is a major challenge of recent stroke studies. Two magnetic resonance imaging techniques: diffusion-weighted (DW) and magnetization transfer contrast (MTC) imaging were introduced in experimental studies and were shown to have sensitivity for different stages of brain infarct. MATERIALS AND METHODS: We used a reproducible middle cerebral artery (MCA) occlusion model in rat to examine infarcts of different time courses. Magnetic resonance T2-weighted (T2). DW, and MTC imaging were performed 3 h, 1 d, 3 d, 5 d, 2 w, 3 w, and 4 w after MCA occlusion. Haematoxylin/eosin (HE) stained sections, which revealed sub regions within infarct lesions, were compared to T2, DW, diffusion-mapping and MTC-mapping images. RESULTS: On DW images 3 hours post occlusion lesions were detected as an area with high signal intensity, while T2 imaging does not raise significant contrast of the lesion at this early stage. Three sub regions of the lesion having different ADCs, are discernible on diffusion-mapping images from 1 day to 7 days. The decrease of MTC effect was measured within the infarct lesion from core to marginal zone, from 7 days to 4 weeks. CONCLUSIONS: Diffusion-mapping imaging may help to examine brain infarction from 3 hours to 5 days. MTC imaging recognizes infarcts 7 days after the onset. Following this stage, MTC-mapping images may provide a quantitative method to assess infarct size.

Animals↗
PubMed1995

Scintigraphic detection of recurrence of medullary thyroid cancer.

A case of recurrent medullary thyroid cancer (MTC) was evaluated with 123I-MIBG, 99mTc(V)-dimercaptosuccinic acid (DMSA), and 201Tl scintigraphy. This patient had been operated on for MTC in the right thyroid. Recently a left neck mass was noticed, and was suspected of being a recurrence of MTC based on increased plasma calcitonin (CT) and carcinoembryonic antigen (CEA). He was operated on for the neck mass which revealed MTC, and papillary thyroid cancer was incidentally found in the left thyroid, but the CT and CEA levels remained high, and remaining MTC tumor was suspected. But the location of the tumor was unknown. Although 99mTc(V)-DMSA scintigraphy is generally believed to be superior in sensitivity to 123I-MIBG scintigraphy, it did not demonstrate the tumor site but 201Tl and 123I-MIBG did. Furthermore, 123I-MIBG scintigraphy has greater specificity for tumors which arise in the neural crest. Judging from the results of this case and cases reported in the literatures, both 123I-MIBG and 99mTc(V)-DMSA should be performed in the detection of recurrent MTC.

3-Iodobenzylguanidine↗
PubMed2005

Ret proto-oncogene mutations in apparently sporadic Turkish medullary thyroid carcinoma patients: Turkmen study.

OBJECTIVE: Medullary thyroid carcinoma (MTC) frequently occurs in a sporadic form, but a substantial number of cases are hereditary and appear as part of the multiple endocrine neoplasia type 2 (MEN2) syndromes. Germline mutations in ret proto-oncogene have been shown to be the underlying cause of MEN2 syndromes. DESIGN: We carried out a multi-center study that aimed to perform mutational analysis of so called sporadic MTC patients. METHODS: Fifty-six MTC patients verified by histopathologic examination were subjected to genetic analysis. Exon 10, 11, 13, 14, 15 and 16 of the ret gene were analyzed by DNA sequencing and restriction enzyme digestion method. RESULTS: Among 56 apparently sporadic MTC patients, we identified 6 (10.7%) ret germline mutation carriers. Three individuals carried mutations at codon 634 in exon 11, one at codon 618 in exon 10, and two at codon 804 in exon 14. Identification of the predisposition gene mutation has allowed DNA-based strategy for direct mutation detection in patients with apparently sporadic MTCs. A substantial number of patients with apparently sporadic MTC carried germline mutations and 50% of their first degree relatives are expected to have or to develop MTC and/or other endocrine tumors. CONCLUSIONS: These results indicate the importance of careful genetic surveillance of any patient with apparently sporadic MTCs.

Adult↗
PubMed1998

Analysis of RET proto-oncogene abnormalities in patients with MEN 2A, MEN 2B, familial or sporadic medullary thyroid carcinoma.

Medullary thyroid carcinoma (MTC) may occur either as a sporadic or familial (FMTC) disease. Multiple endocrine neoplasia (MEN) type 2, inherited as an autosomal dominant disease, is characterized by coexistence of MTC with other endocrine neoplasia. Activating mutations of the RET proto-oncogene, involving the somatic or the germinal cell lineage, are found in both inherited and acquired forms. In this study, RET mutations were screened in 47 individuals either affected by MTC or belonging to families with hereditary MTC. Exons 10, 11, 13, 14, 15 and 16 of the RET gene were amplified by polymerase chain reaction and examined by DNA sequence and/or restriction enzyme analysis to detect mutations in purified amplicons. Six MEN 2A families with a germline mutation at codon 634, one FMTC family carrying a mutation at codon 618 and two MEN 2B families with a mutation at codon 918 were identified. In affected members of a MEN 2A family no known RET mutations were observed. Besides, we identified a germline mutation in a patient with apparently sporadic MTC and in two out of three sons, indicating the presence of a sporadic misclassified familial disease. In all of the families examined we were able to distinguish the affected vs unaffected (not at risk) members. A somatic mutation of codon 918 was detected in three out of ten patients with apparently sporadic MTC.

Adult↗
PubMed2003

Gene therapeutic approaches for medullary thyroid carcinoma treatment.

Medullary thyroid carcinoma (MTC), a neoplasm of thyroid C-cells, is characterized by dominant activating mutations in the RET proto-oncogene. Currently therapy is restricted to surgical removal of all neoplastic tissue lacking alternative forms of treatment such as chemotherapy or radiotherapy. Therefore MTC is a particularly attractive target for gene therapeutic approaches. Many promising gene therapy strategies have been used in various animal models of MTC, showing enhanced antitumoral efficacy, and these will hopefully extend our current standard of care in the future. These approaches can tentatively be subdivided into four groups: (a) Inhibition of oncogenic RET signaling, (b) suicide gene therapy, (c) immunotherapy, and (d) combination of immunotherapy and suicide approaches. To block oncogenic signal transduction dominant-negative RET mutants were delivered into tumor cells and found to possess strong antineoplastic activity, including tumor growth suppression and increased animal survival. Suicide gene therapeutic approaches applied to MTC treatment featured either gene transfer of herpes simplex virus thymidine kinase with concomitant application of ganciclovir or delivery of nitric oxide synthase II. Here antitumor effects were attributed to the occurrence of substantial bystander activities. Immunotherapy approaches comprised stimulation of immune response by delivery of interleukin 2 or 12. Finally, treatment with herpes simplex virus thymidine kinase/ganciclovir in combination with interleukin 2 was found to be superior over either treatment alone. This review discusses the various gene therapeutic approaches applied to MTC treatment in detail, gives an overview on the diverse vector systems used to achieve efficient transduction of thyroid cancer cells, and points out the strategies employed to accomplish target cell selective gene expression thereby contributing to enhanced safety of gene therapy for MTC

Animals↗
PubMed1998

Targeting of cholecystokinin-B/gastrin receptors in vivo: preclinical and initial clinical evaluation of the diagnostic and therapeutic potential of radiolabelled gastrin.

The outstanding sensitivity of pentagastrin in detecting the presence of primary, recurrent or metastatic medullary thyroid cancer (MTC) suggests widespread expression of the corresponding receptor type in human MTC. Indeed, recent autoradiographic studies have demonstrated the presence of cholecystokinin (CCK)-B (= gastrin) receptors not only in more than 90% of MTCs but also in a high percentage of small cell lung cancers, stromal ovarian cancers, astrocytomas and several other tumour types. The aim of this study was to evaluate whether radiolabelled gastrin may be suitable for targeting CCK-B receptor-expressing tumours in vivo. For this purpose, the biodistribution of the radioiodinated human heptadecapeptide gastrin-I was studied in nude mice bearing subcutaneous xenografts of the human MTC cell line, TT. Initial therapy experiments were undertaken. Finally, the biodistribution of iodine-131- labelled gastrin-I was studied in a patient with metastatic MTC. At a peptide amount of approximately 1 microg, maximum tumour uptake (8.9+/-2.9%ID/g) was observed in animals at 1 h post injection, with tumour-to-blood ratios as high as 6.3+/-1.9. Physiological CCK-B receptors in the stomach, gallbladder and pancreas of the mice were targeted as well. The major route of excretion was renal, but strong evidence for a biliary excretion pathway also exists. Pilot therapy studies with 131I-labelled gastrin showed significant anti-tumour efficacy as compared with untreated controls. In accordance with the preclinical data, good receptor targeting was observed in the tumour sites, stomach, gallbladder and pancreas of a patient with metastatic MTC. These data suggest that gastrin and its analogues may represent a useful new class of receptor binding peptides for diagnosis and therapy of a variety of tumour types, including MTC and small cell lung cancer. Future preclinical and clinical studies will address in more detail the molecular features that render CCK-B receptor binding agents potentially useful candidates for in vivo scintigraphy and radionuclide therapy.

Aged↗
PubMed2000

Medullary carcinoma of the thyroid gland.

Medullary thyroid carcinoma (MTC) is an uncommon thyroid tumor that has attracted a great deal of interest because of its frequent presentation as a familial tumor and its primary involvement in the type II multiple endocrine neoplasia (MEN) syndromes MEN-IIA and MEN-IIB and familial medullary thyroid carcinoma (FMTC). The MTC tumor cells secrete the polypeptide hormone calcitonin, which serves as an excellent tumor marker, useful for defining the presence of disease, preoperatively or following thyroidectomy. The discovery that mutations in the RET proto-oncogene are associated with MEN-II syndromes was highly significant in that it demonstrated a clear correlation between genotype and phenotype; and most importantly it provided a mechanism whereby family members at risk could be identified by direct DNA analysis. Virtually all patients with MEN-IIA, MEN-IIB, and FMTC develop MTC; therefore there is a clear rationale for performing thyroidectomy as soon as a RET mutation has been identified. Because MTC appears to be much more aggressive in patients with MEN-IIB, thyroidectomy is performed during the first year of life in this setting, whereas in patients with MEN-IIA, where the tumor appears to be more indolent, the procedure can be safety delayed until age 5 years. Reoperative neck exploration in patients with evidence of persistent or recurrent MTC has been effective in a significant number of patients, although the success of the operation requires careful patient selection and preoperative assessment. MTC, as expressed in the MEN-II syndromes, is an excellent model to evaluate the usefulness of interventional therapy in patients demonstrated to have a genetic predisposition for cancer.

Carcinoma, Medullary↗
PubMed2000

Elastic properties of muscle-tendon complex in long-distance runners.

The purpose of this study was to investigate the elastic properties of muscle-tendon complex (MTC) in knee extensor muscles and the capacity for elastic energy utilization in long-distance runners (LDR) by comparing with data obtained from untrained individuals (CON). The elongation (L) of the tendon and aponeurosis of vastus lateralis muscle during isometric knee extension was determined by real-time brightness mode ultrasonography, while the subjects developed a gradually increasing torque from 0 (relaxed) to maximal effort (MVC) within 7 s. In addition, performances in two kinds of maximal vertical jumps, i.e. squatting (SJ) and counter-movement jumps (CMJ), were measured. The relationship between L muscle and force (F) was curvilinear and consisted of an initial region (toe region), characterized by a large increase in L with increasing F, immediately followed by a linear region. The slope of the regression equation for the L-F relationship in the range 50%-100% of MVC was defined as an index of MTC compliance, where the rate of the changes in L to that in muscle F at every 10% of MVC became almost constant. The maximal L (Lmax) and MTC compliance were significantly lower in LDR than in CON: 29.9 (SD 3.9) mm in LDR compared to 33.3 (SD 5.5) mm in CON for Lmax and 1.55 (SD 0.25) x 10(-2) mm.N-1 in LDR compared to 1.88 (SD 0.82) x 10(-2) mm.N-1 in CON for MTC compliance. Also, LDR showed significantly less elastic energy absorption (Ee) than CON, defined as the area below the L-F relationship curve from 0 to 100% of MVC. Not only jump heights but also the differences between the heights in SJ and CMJ, expressed as the percentage of the height in SJ, were significantly lower in LDR than in CON. The augmentation with counter-movement was significantly correlated to either MTC compliance (r = 0.554, P < 0.05) or Ee (r = 0.563, P < 0.05). Thus, the present results would indicate that MTC of vastus lateralis muscle is less compliant and its potential for energy storage during MTS lengthening is lower in LDR than untrained individuals. These elastic profiles of vastus lateralis muscle in LDR may be associated with their lower performances during CMJ.

Adult↗
PubMed2000

Differential diagnosis of calcitonin-secreting neuroendocrine carcinoma of the foregut by pentagastrin stimulation.

BACKGROUND AND AIMS: This study assessed the suitability of pentagastrin stimulation in hypercalcitoninaemia for differential diagnosis of neuroendocrine carcinoma of the foregut. PATIENTS: A prospective institutional study (March 1997-September 1999) was conducted involving all patients admitted to the pneumological and general surgical wards for small cell lung cancer (SCLC) or primary medullary thyroid carcinoma (MTC). Basal and stimulated serum calcitonin levels were measured using an improved immunoradiometrical assay for the monomeric form of calcitonin. RESULTS: Increased basal calcitonin levels were noted in six non-MTC patients (one mediastinal and one laryngeal neuroendocrine carcinoma, and four SCLCs). Because of chronic renal failure, one SCLC patient had to be excluded. The remaining five non-MTC patients with normal renal function were compared to eight primary MTC patients. In terms of pentagastrin stimulation, an increase in serum calcitonin levels of less than twofold the baseline significantly correlated with both non-MTC (r=0.85; P=0.005) and SCLC (r=0.81; P=0.024). Immunostaining of tissue specimens for calcitonin was positive in the patients with mediastinal and laryngeal neuroendocrine carcinoma and in all eight patients with primary MTC, but was negative in the two SCLC patients with adequate tissue samples. CONCLUSIONS: Irrespective of the pathophysiological background, pentagastrin stimulation affords a differential diagnosis in neuroendocrine carcinoma of the foregut when chronic renal failure is excluded.

Aged↗
PubMed1999

C-cell cancer--prevention and treatment.

INTRODUCTION: C-cell cancer of the thyroid or medullary thyroid carcinoma (MTC) exists in a sporadic and a hereditary form, the latter of which is part of the multiple endocrine neoplasia type-2 (MEN-2) syndromes. DISCUSSION: MTC metastasises early to local (lymph nodes) and distant sites (liver, lung, bone). Therefore, early detection is mandatory to enable a chance of cure. In sporadic MTC, the sensitive tumour marker calcitonin enables detection of the disease at an early stage. In hereditary MTC, more than 95% of the patients have germline RET mutations. Thus, MEN-2 has become the paradigm for the practice of molecular medicine, and gene carriers can be identified before MTC even occurs. Surgery is the only chance of cure and recently developed surgical techniques provide the therapeutic prerequisite to achieve calcitonin normalisation in both sporadic and hereditary MTC.

Carcinoma, Medullary↗
PubMed2006

Hereditary medullary thyroid cancer in Slovenia--genotype-phenotype correlations.

BACKGROUND: Medullary thyroid cancer (MTC) is a rare endocrine tumor that may be sporadic or inherited in settings of MEN2A, MEN2B and FMTC. Germline point mutations in the RET proto-oncogene are responsible for tumor occurrence, inheritance and great clinical variability. The aim of this study was to correlate the genotype and phenotype of patients with hereditary MTC (age at diagnosis, sex, TNM classification and clinical features). PATIENTS: Between 1997 and 2003 genetic testing was performed in 69 out of 98 patients with "sporadic" MTC. Carriage of mutation was found in 14 (20.2%) patients (index patients) and in 16 out of 31 (51.6%) of their relatives. One patient with MEN2B and codon 918 mutation was excluded from further analysis. METHODS: Genomic DNA was isolated from peripheral blood leukocytes. Exons 10, 11, 13, 14, 15 and 16 of the RET proto-oncogene were amplified in polymerase chain reactions. Point mutations of the RET gene were detected with single-strand conformation analysis and DNA sequencing. Detected mutations were confirmed with restriction enzyme analysis. RESULTS: Codon 634 mutations were detected in 15 patients (50%; aged 18-76 years; 6 families), codon 618 in nine patients (30%; aged 12-65 years; 4 families) and codon 790 in five patients (16.6%; aged 16-74 years; 3 families). The median age at diagnosis was 31 +/- 17.3, 33 +/- 15.9 and 36 +/- 23.8 years for patients with codon 618, 634 and 790 mutations. Selected by sex, females with codon mutations 618 and 634 versus 790 had median age at diagnosis of 34.5 +/- 15.6 years and 43.5 +/- 22.9 years, whereas the inverse result was observed in males (26.5 +/- 18.0 versus 16 years). The male/female ratio was 1:2 for patients with codon 618 and 634 mutations and 1:4 for patients with codon 790 mutations. Some of the data suggested correlation between specific genotypes, tumor size, stage of MTC and age at diagnosis. Pheochromocytoma (12 out of 15 patients) and primary hyperparathyroidism (6 out of 15 patients) were diagnosed solely in patients with codon 634 mutations. One patient with FMTC and Hirschprung disease was found in a family with codon 618 mutations. CONCLUSION: Correlation between tumor size, stage of MTC at diagnosis in view of patient's age, and specific genotype were indicated in our limited series and were more evident in female patients with codon 790 mutations. Later onset and a probably less aggressive course of MTC in these patients than in patients with other mutations should be considered in planning prophylactic thyroid surgery. MEN2A syndrome was related solely to codon 634 mutations.

Adolescent↗
PubMed2002

Evaluation of a new commercial assay for diagnosis of pulmonary and nonpulmonary tuberculosis.

A new commercial assay for the diagnosis of tuberculosis, the BDProbeTec ET Direct Detection assay (Becton Dickinson, USA), was evaluated using 351 respiratory and 372 nonrespiratory specimens. The results were compared to detection of Mycobacterium tuberculosis complex (MTC) by conventional culture. Among the 351 respiratory specimens, MTC bacteria were identified in 150, of which 85 were positive by both microscopy and the assay. Sixty-five specimens culture positive for MTC were microscopy negative; of these, 39 were positive in the assay. All 26 specimens culture positive for nontuberculous mycobacteria (NTM) were negative by the assay. Of 175 specimens culture negative for MTC, 3 were falsely positive by the assay and 1 yielded inhibition. The overall sensitivity and specificity values were 82.7% and 98.5%, respectively. The sensitivity for microscopy-positive and -negative respiratory specimens was 100% and 60%, respectively. After correction for discrepancies, the specificity was 99% compared with notification data. The BDProbeTec ET assay detected 66 of 67 microscopy-positive and 50 of 125 microscopy-negative nonrespiratory specimens. The result for one specimen was inconclusive. All nine specimens containing NTM were negative by the assay. Of 171 specimens culture negative for MTC, 6 were falsely positive by the assay. The overall sensitivity and specificity values obtained with nonrespiratory specimens were 60.7% and 96.7%, respectively. After examining discrepancies by reviewing the patients' histories, the specificity was 98.9%. The sensitivity was 98.5% in microscopy-positive specimens and 40.3% in microscopy-negative specimens. The overall inhibition rate was 0.3%. The BDProbeTec ET assay is a fast, effective, and user-friendly system that can be used for rapid detection of MTC bacteria in respiratory and microscopy-positive nonrespiratory specimens as an important supplement to smear and culture.

Bacteriological Techniques↗
PubMedDate not supplied

Detection of occult medullary thyroid cancer recurrence with 2-deoxy-2-[F-18]fluoro-D-glucose-PET and PET/CT.

PURPOSE: 2-deoxy-2-[F-18]fluoro-D-glucose (FDG)-positron emission tomography (PET) has an established role in restaging of various cancers, including papillary and undifferentiated thyroid carcinoma. However, controversies exist regarding its ability to reliably assess recurrent medullary thyroid cancer (MTC). We were therefore prompted to review our experience with FDG-PET for detection of occult MTC. METHODS: This is a retrospective study (Apr 1, 1997-Mar 31, 2004) of 13 patients with histologic diagnosis of MTC, who had PET examinations. The group included six men and seven women, 15-62 years old (average: 48+/-13). The PET scan request was triggered by rising levels of calcitonin and negative anatomical imaging studies. RESULTS: Recurrent/metastatic disease was identified by PET in seven (54%) of the 13 patients. The lesions were located in superior mediastinum (4), cervical lymph nodes (3), thyroid bed (2), lung (1) and liver (1). The calcitonin levels ranged from 52 to 5,090 pg/ml (average: 1,996 pg/ml) in patients with negative PET scans and from 132 to 9,500 pg/ml (average: 3,757 pg/ml) in patients with positive studies. The sensitivity and specificity of FDG-PET for disease detection in this cohort were 85.7% (95% CI: 48.7-97.4) and 83.3% (95% CI: 43.6-96.9), respectively. CONCLUSION: Our findings suggest a significant role for FDG-PET in patients with suspected MTC recurrence, with sensitivity of 85.7% and specificity of 83.3% for disease detection. FDG-PET provides additional information in a significant fraction of cases (54%) and could be used for restaging of patients with MTC and elevated levels of biomarkers (calcitonin). Additional studies are necessary to further evaluate the role of FDG-PET in MTC.

Adolescent↗
PubMed1990

Evaluation of children with multiple endocrine neoplasia type IIb following thyroidectomy.

Medullary thyroid carcinoma (MTC) develops in all patients with multiple endocrine neoplasia type IIb (MEN IIb), a rare syndrome that either occurs sporadically or is inherited in an autosomal dominant pattern. The MTC in patients with MEN IIb has been reported to be biologically aggressive with onset at a young age and rapid progression as evidenced by widespread metastases and death, frequently in the teenage years. Seven children, aged 2 to 11 years (mean, 7 years), from three kindreds with MEN IIb were evaluated for evidence of tumor recurrence 3 to 10 years following thyroidectomy. In one child, age 11, a thyroid mass was palpable preoperatively. However, in the remaining six children (aged 2 to 10 years), the diagnosis of MTC was established by an increased concentration of plasma calcitonin (CT), either basally or following pentagastrin (Pg) stimulation. All patients underwent total thyroidectomy with removal of central lymph nodes from the neck. At the time of surgery, six children were found to have bilateral macroscopic MTC, five without and one with cervical metastases. One child (age 2 years) had C-cell hyperplasia, a premalignant precursor of MTC. Currently, five of the seven children are without evidence of recurrent disease clinically and have normal plasma CT levels (less than 0.3 ng/mL) following calcium (Ca) and Pg stimulation 3, 3, 10, 10, and 10 years after thyroidectomy. Two of the seven children have biochemical evidence of residual MTC.(ABSTRACT TRUNCATED AT 250 WORDS)

Biomarkers, Tumor↗
PubMed1984

Pentagastrin promotes prolactin release in patients with medullary carcinoma of the thyroid.

Both calcitonin and gastrin have been found in the mammalian central nervous system, including the pituitary. Following a pentagastrin infusion in several patients with medullary carcinoma of the thyroid, we noted a coincident increase in plasma calcitonin and prolactin (PRL) levels. In order to evaluate further the influence of pentagastrin on human PRL release, a pentagastrin infusion was administered to 13 patients with active medullary carcinoma of the thyroid (MTC), eight subjects with inactive MTC, eight family members without MTC, and ten normal subjects. Plasma mean +/- SE PRL levels were significantly (P less than 0.01) increased in the active MTC patients from 7.6 +/- 0.5 to 12 +/- 1.4 ng/mL by 15 minutes post pentagastrin. Plasma mean +/- SE calcitonin levels increased in parallel with the plasma PRL levels from 0.28 +/- 0.1 to a peak of 1.9 +/- 0.9 ng/mL at 5 minutes post pentagastrin. A significant (P less than 0.05) correlation was found between the percentage increase in plasma calcitonin concentrations and plasma PRL levels at five and ten minutes post pentagastrin stimulation in this group of active MTC patients. Significant increases in serum calcitonin levels in the other groups post pentagastrin were of lesser magnitude and were not associated with a significant increase in PRL release. This latter observation suggested that neither the stress of the infusion nor the multiple endocrine neoplasia type 2 nor the pentagastrin was responsible for the observed increase in plasma PRL levels in the active MTC patients. These findings suggest, but do not prove, that calcitonin is a PRL-releasing factor in humans.

Calcitonin↗
PubMed1975

Comparative analysis of deletion and base-change mutabilities of Escherichia coli B strains differing in DNA repair capacity (wild-type, uvrA-, polA-, recA-) by various mutagens.

Dose-response curves were compared for deletions [ColBR (resistant to colicin B) mutations being more than 80% deletions] and base changes (reversion of argFam to prototrophy argplus) induced in the same set of E. coli strains (wild-type for DNA repair, uvrA-, polA- and recA-) by N-methyl-N'-nitro-N-nitrosoguanidine (NTG), ethyl methanesulfonate (EMS), hydroxylamine (HA), 4-nitroquinoline I-oxide (4NQO), mitomycin C (MTC, UV and X-rays. All these agents induced deletions as well as base changes in the wild-type strain. Thus chemical mutagenesis differed in E. coli and bacteriophages in vitro, for HA, NTG, EMS and perhaps UV produced only point mutations in phage Tr. The patterns of deletion and base-change mutability in E. coli were surprisingly similar. (I) The recombination less recA- strain was mutable by only three (NTG, EMS, HA) of the seven mutagens for either deletions or base changes. (2) The uvrA- strain, unable to excise pyrimidine dimers, was very highly mutable by 4NQO and UV but immutable by MTC for both deletions and base changes. (3) The polA- strain, defective in DNA polymerase I due to a non-suppressible mutation, was very highly mutable by HA and highly mutable by MTC and 4NQO for both deletions and base changes but was highly mutable only for deletions by UV and X-rays, remaining normally mutable by the other agents for both deletions and base changes despite its high sensitivity to their inactivating action. We conclude that errors in the recA-dependent repair of induced DNA damage (after 4NQO, MTC, UV and X-rays) or errors in replication enhanced by damage to the replication system or to the template strands (after NTG, EMS, and HA) give rise to deletions as well as to base changes. From a comparative analysis of 14 dose-response curves for deletions and base changes, we conclude that the order of mutagenic efficiency relative to killing is (EMS, NTG) greater than (UV, 4NQO) greater than HA greater than (X-rays, MTC), and that X-rays, 4NQO, HA and MTC induce more ColBR deletions than Argplus base changes, whereas UV and EMS induce ColBR deletions and Argplus base changes at nearly equal rates and the specificity of NTG is intermediate between these two types.

Base Sequence↗
PubMedDate not supplied

Vasopressin, prolactin and growth hormone in Alzheimer's disease: their evaluation after metoclopramide stimulation.

Recent studies have shown that there is a relationship between an alteration of central neurotransmitters and the modification of some biohumoral parameters in Alzheimer's Disease (AD). In this study the authors evaluated, after metoclopramide (MTC) stimulation, the concentration curve of vasopressin (AVP), prolactin (PRL) and growth hormone (HGH) in the plasma of 34 subjects (20 males and 14 females, mean age 70.5+/-6.9 years; 17 were AD patients, the others constituted the control group). MTC increased AVP serum concentration in healthy (P <0.001), but not in AD patients. This result seemed to be due to the lack of 'procholinergic' action of the drug in the AD patients probably due to an alteration in their cholinergic pathways. The PRL response to MTC was reduced only in the AD female group (P <0.005), suggesting an alteration in dopaminergic control. Lastly, the HGH response in AD did not differ in the two groups, neither in basal conditions, nor after MTC stimulation. The absence of HGH response both in AD and in healthy subjects, demonstrated the ineffectiveness of MTC stimulation. We can conclude that AVP and PRL responses to MTC stimulation efficiently separated the two groups (AD and controls); the former test showing a higher discriminant power than the latter.

Journal Article↗
PubMed1982

Membrane lesions in cultured mouse neuroblastoma cells exposed to metal compounds.

Tritiated 2-deoxy-D-glucose (dGlc) was rapidly taken up into cultured mouse neuroblastoma C1300 cells (clone 41A3). Upon perfusion the preloaded cultures slowly released radioactivity as [3H] 2-deoxy-D-glucose-6-phosphate ([3H]dGlc-6-P) (rate const. = 0.017 min-1) from a pool corresponding to 74% (t1/2 = 41 min) of the total radioactivity incorporated. Destruction of the plasma membrane of the cells by means of Triton X-100 (1.0%) resulted in a rapid and total release of the radioactivity. CH3HgCl, HgCl2, (C2H5)3SnCl and K2Cr2O7 all caused an increase in the passive cell membrane permeability to [3H]dGlc-6-P. A membrane toxic concentration (MTC) was defined as the concentration of the tested metal compound giving rise to an increase in the relative efflux from 1.0 to 1.2 during 60 min perfusion. Using this MTC-value, the membrane toxicity of the compounds could be ranked in the following order: CH3HgCl (MTC = 9 x 10(-7) M) greater than HgCl2 (MTC = 6 x 10(-6) M) greater than (C2H5)3SnCl (MTC = 3 x 10(-4) M) greater than K2Cr2O7 (MTC = 7 x 10(-4) M). Since this differential toxicity is in accordance with other reports it is concluded that 2-deoxy-D-glucose (dGlc) may be used together with 41A3 cells to screen metal compounds for their membrane toxicity.

Animals↗