Measurements of temperament in the identification of children who stutter.

As an empirical check on widely held stereotypes and some assumed temperament proclivities of children at risk for stuttering, parents of at-risk children and a gender- and age-matched control group completed the 'Parent Childhood Temperament Questionnaire for 3-7-Year-Olds'. A discriminant analysis on the nine temperament dimensions revealed four dimensions which combined to discriminate significantly between the two groups, resulting in correct classification of 86.36% of the 22 children. The t-tests of difference on the four discriminating dimensions revealed that 'Mood', 'Adaptability', and 'Rhythmicity' were statistically significant in the direction of more positive temperament for at-risk children than for the control group. Results are discussed with respect to aetiology, stereotype, and the need for clinicians to focus parents on concrete behaviours when reporting on the emotional and behavioural style of their child.

A pharmacokinetic comparison of murine and chimeric forms of the 99mTc-labelled 174H.64 monoclonal antibody.

The monoclonal antibody (MoAb) 174H.64 (Truscint SQ, Biomira Inc.) is a murine-derived MoAb reacting with an extracellular surface component of the cytoskeletal matrix ectopically expressed on squamous-cell carcinoma cell-surface membranes. A chimeric form of this MoAb has also been produced by genetically modifying the Fc portion of the MoAb by the insertion of a human Fc fragment. During this process the isotype was altered from an IgG1 (murine) to an IgG3 (chimeric). Pilot and phase I/II clinical trials of the murine and chimeric 99mTc-labelled 174H.64 MoAbs have been undertaken at selected European and North American sites. As part of this evaluation serum, urine and image data were collected at specific time intervals and used to obtain a kinetic model to describe the in vivo distribution of the MoAbs. A two-compartment model of the form: C(t) = C1 e-lambda 1t + Cz e-lambda zt was found to best describe the serum distribution of radioactivity of both the murine and chimeric MoAbs. The initial distribution half-lives were 2.9 +/- 0.7 hours and 2.7 +/- 0.2 hours, and the terminal elimination half-lives were 17.6 +/- 3.8 hours and 22.5 +/- 1.3 hours for the murine and chimeric MoAbs, respectively. No significant difference was found between the kinetic model parameters of two MoAbs at the 95% level. Assuming a similar clinical efficacy, these MoAbs could then be used interchangeably, with the chimeric MoAb offering potential advantages in reducing HAMA response.

Imaging tumor hypoxia and tumor perfusion.

Tumor perfusion and oxygenation status have been suggested as factors which may influence treatment outcome in cancer patients. Nuclear medicine assays of tumor perfusion [99mTc-hexamethylpropylenamine oxime (HMPAO)] and tumor hypoxia [123I-iodoazomycin arabinoside (IAZA)] have recently been developed and described. We report on measurements of perfusion and oxygenation status of 27 tumors in 22 patients using these probes. An inverse correlation between tumor uptake of HMPAO and IAZA was measured (p < 0.05), with severe perfusion deficit usually associated with an increased uptake of the hypoxic marker. This trend was observed for limited stage small-cell lung carcinoma, squamous-cell carcinoma of the head and neck, soft-tissue sarcoma, brain metastases from small-cell lung carcinoma and adenocarcinoma of the prostate as a group, but not for glioblastoma multiforme. Whereas each imaging agent can yield information about the physiological status of tumor and normal tissue, the information resulting from their combined use could be important in cancer therapy.

MAb 170H.82: an evaluation of a novel panadenocarcinoma monoclonal antibody labelled with 99Tcm and with 111In.

A novel method for generating monoclonal antibodies against synthetic tumour-associated glycoconjugates has been developed. One of these monoclonal antibodies, designated 170H.82, was derived against the TF antigen and has been shown in vitro to have a wide range of reactivity with adenocarcinoma. This antibody has been labelled with 111In and 99Tcm and has been evaluated in pilot clinical trials involving 48 patients with a range of adenocarcinoma. Overall clinical accuracy with the radiolabelled antibody was 92%, with the antibody appearing to have particular clinical utility in gynaecological and breast cancers. Single photon emission computed tomographic (SPECT) imaging was shown to improve the quality of the images and to improve the diagnostic sensitivity. We believe that this unique antibody, labelled with 99Tcm, appears to offer promise for routine clinical use in the evaluation of patients with a range of primary and metastatic adenocarcinoma.

Non-invasive assessment of human tumour hypoxia with 123I-iodoazomycin arabinoside: preliminary report of a clinical study.

Non-invasive predictive assays which can confirm the presence or absence of hypoxic cells in human tumours show promise for understanding the natural history of tumour oxygenation, and improving the selection of patient subsets for novel radiotherapeutic strategies. Sensitiser adducts have been proposed as markers for hypoxic cells. Misonidazole analogues radiolabelled with iodine-123 have been developed for the detection of tumour hypoxia using conventional nuclear medicine techniques. In this pilot study, we have investigated one such potential marker, 123I-iodoazomycin arabinoside (123I-IAZA). Patients with advanced malignancies have undergone planar and single-photon emission computed tomographic (SPECT) imaging after intravenous administration of 123I-IAZA. We have observed radiotracer avidity in three out of ten tumours studied to date. Normal tissue activity of variable extent was also seen in the thyroid and salivary glands, upper aerodigestive tract, liver, intestine, and urinary bladder. Quantitative analysis of those images showing radiotracer avidity revealed tumour/normal tissue (T/N) ratios of 2.3 (primary small cell lung carcinoma), 1.9 (primary malignant fibrous histiocytoma) and 3.2 (brain metastasis from small cell lung carcinoma) at 18-24 h post injection. These preliminary data suggest that the use of gamma-emitter labelled 2-nitroimidazoles as diagnostic radiopharmaceuticals is feasible and safe, and that metabolic binding of 123I-IAZA is observed in some, but not all tumours. The inference that tumour 123I-IAZA avidity could be a non-invasive measure of tumour hypoxia deserves independent confirmation with needle oximetry.

Enhancing effect of dextran sulfate sodium on colorectal carcinogenesis by 1,2-dimethylhydrazine in rats.

Four groups were used, each consisting of 24 male ACI rats. Group I received a single subcutaneous injection of 20 mg 1,2-dimethylhydrazine (DMH)/kg body weight and was fed on basal diet until the termination of the experiment. Group II received the same single injection as in group I and then, starting one week later, was fed the diet containing 1% dextran sulfate sodium (DS-M-1). Group III received an injection of 0.9% sodium chloride and then DS-M-1 diet. The control group was given neither DMH nor DS-M-1 diet. The experiment was terminated after 40 weeks. A significantly higher incidence of colorectal carcinoma was observed in group II, as compared with group I (P less than 0.02). These data demonstrate the enhancing effect of DS-M-1 on colorectal carcinogenesis.

Carcinogenicity of dextran sulfate sodium in relation to its molecular weight.

The carcinogenicity of dextran and 3 kinds of dextran sulfate sodium with different molecular weights and almost the same sulfur content were compared in ACI rats. Dextran sulfate sodium of molecular weight 54,000 showed a strong carcinogenic activity when it was given orally as 2.5% diet, whereas dextran sulfate sodium of molecular weight 520,000 and 9500 and dextran showed no significant carcinogenicity, i.e. the peak of carcinogenic activity of dextran sulfate sodium appeared at molecular weight 54,000, and dextran sulfates with larger or smaller molecular weights had no carcinogenic activity.

Induction of intestinal tumors in rats by dextran sulfate sodium.

The carcinogenicity of dextran sulfate sodium was studied in inbred ACI rats. In group 1, 10 male rats were fed a 10% dextran sulfate sodium diet; in group 2, 14 male and 12 female rats were fed a 5% dextran sulfate sodium diet; and in the control group, 9 male and 9 female rats were given the basal diet without dextran sulfate sodium. After the start of the feeding regimen, all rats given the 10% dextran sulfate sodium diet died of severe diarrhea and anemia within 14 days and 15 of 23 surviving rats fed a 5% dextran sulfate sodium diet developed intestinal tumors between 134 and 215 days. These tumors were induced in the colon and cecum and consisted of adenomas, adenocarcinomas, and papillomas.

Broader aspects of clinical toxicology.

This contribution indicates how the student of clinical toxicology may be helped to acquire understanding of and perspective in toxicological risk assessment and the principles of risk-benefit evaluation. The student has to grasp the importance of decision-making in the face of inadequate, inappropriate, or even misleading scientific data. Informed decisions can only result from balanced judgment based on integration of the student's knowledge in various disciplines coupled with some perspective gained from experience of historically-important object lessons in clinical toxicology. Various approaches that may be used to drive these lessons home are discussed. Above all, the instruction should, in conjunction with knowledge of nutrition, play a vital role in expanding the often narrow horizons of the medical graduate or other health professional as far as preventive medicine is concerned. Essential in this respect is the preparation of the student to maintain a continuing interest in and familiarity with the changing climate of toxicological research, thought, and opinion.

Implications for human health.

To analyze the implications for human health, the toxicologist requires four sets of data: the results of toxicity and other studies in animals; quantitative data on actual or potential human exposure; whatever information is available on effects of exposure in man; and the statistical extrapolations from the dose-response relationships in animals to the (usually) much lower levels of human exposure. Professional expertise in toxicology is essential to assess the nature and severity of the toxic effects observed in animals, including such characteristics as potential for progression, irreversibility and production of incapacity. Given sufficient data, an estimate can be arrived at of the likelihood that such effects will be elicited in human populations of differing susceptibilities. The criteria by which the overall implications for human health can be judged comprise both the direct effects on man, as well as the indirect consequences stemming from environmental impacts.

Chromatographic methods for the analysis of hexachlorobenzene and possible metabolites in monkey fecal samples.

The separation and identification of hexachlorobenzene (HCB), pentachlorobenzene (QCB), and pentachlorophenol (PCP) by thin layer, high-pressure liquid, and gas chromatography are reported. Satisfactory results were obtained with reverse phase thin layer and high-pressure liquid chromatography. The 2 gas chromatographic columns tested gave adequate separation of HCB and QCB. A PCP methylation process using dimethyl sulfate was attempted. Procedures are presented for extraction, cleanup, separation, and identification of HCB and possible metabolites from feces of a rhesus monkey treated with 14C-HCB. Recovery of radioactivity in excess of 96% was attained in extracts from feces by these methods. Preliminary evidence suggests the formation of PCP and possibly other polar metabolites from HCB in the rhesus monkey.