Neutron therapy for locally advanced head and neck squamous cell carcinoma: optimum dose search

28 patients with locally advanced primary squamous cell carcinoma of the head and neck received neutron therapy and were randomized between two dose levels: 145 cGy n gamma x twelve fractions, three fractions per week (total 17.4 Gy n gamma). 155 cGy n gamma x twelve fractions, three fractions per week (total 18.6 Gy n gamma). Acute toxicity for skin, mucous membrane, salivary and subcutaneous tissues was graded using the EORTC/RTOG scoring system. Analysis indicates 17.4 Gy n gamma as "safe". A further twelve patients are to be assigned to the higher dose (18.6 Gy n gamma) before making a final dose selection.     

Epilepsy and the GABA-hypothesis a brief review and some examples

A brief review is given with regard to the GABAergic alterations in experimental and genetic models of epilepsy and human epilepsy, illustrating, among others, that agents exist, both convulsants and anticonvulsants, that are capable of interacting with GABA's synthesis, storage, extraneuronal release, presynaptic reuptake, postsynaptic destruction and activation. The so-called "GABA-hypothesis" of epilepsy implies that a reduction of GABA-ergic inhibition results in epilepsy while an enhancement of GABAergic inhibition results in an antiepileptic effect. The examples presented, in support of the "GABA-hypothesis", concern the effects of some exogenous [pentylenetetrazol (PTZ) and methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM)] and some endogenous convulsants on the postsynaptic GABAA receptor. The studied endogenous convulsants were the guanidino compounds which are known to increase in uremia and hyperargininemia. PTZ and DMCM dose-dependently reduced GABA responses on mouse neurons in cell culture. The benzodiazepine receptor antagonist CGS 9896 antagonized the DMCM- but not the PTZ-induced inhibition of GABA-responses. The guanidino compounds guanidine, methylguanidine, creatinine, guanidinosuccinic acid (increased in uremia) and arginine, homoarginine, alpha-keto-delta-guanidinovaleric acid and argininic acid (increased in hyperargininemia) decreased both GABA- and GLY-responses. The guanidino compounds were equally potent in decreasing GABA- and GLY-responses and CGS 9896 did not antagonize the guanidino compound-induced inhibition of GABA responses. The presented results indicate that the studied convulsants inhibit GABAergic inhibition through interaction with distinct sites at the postsynaptic GABAA receptor. The demonstrated effect might, in agreement with the "GABA-hypothesis", underlie the epileptogenicity of these compounds in animal models and might have pathophysiological importance in uremia and hyperargininemia.     

Thyroid carcinoma mimicking a toxic adenoma

A young woman with a thyroid papillary carcinoma behaving as an autonomously hyperfunctioning nodule is described. Only 17 similar patients have been seen in the past 25 years. It is emphasized that hyperthyroidism does not exclude malignant disease in hot nodules. This possibility suggests that all thyroid nodules, either cold or hot, require careful management. Therefore, in at risk cases, surgery could be the most useful treatment.     

Changes in the transmural distribution of antioxidant enzyme activities across the left ventricle heart wall from rats fed ad libitum or food-restricted during growth and aging

Data on vulnerability to injury and on the larger age-related accumulation of lipofuscin in the subendocardial myocardium prompted us to investigate the changes in the levels and in the transmural distribution of catalase (C), glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activities across the left ventricle heart wall of rats fed ad libitum a standard diet or submitted to intermittent feeding during growth and aging. Enzyme activities were assayed by standard techniques on subepicardial, midmyocardial or subendo- cardial tissue obtained by cutting the heart wall into 100-microm-thick sections at the cryostat. The levels of GSH-Px and of C (but not of SOD) activity increased with age and reached their highest values in the subendocardial region by adulthood or senescence, respectively. No effect was observed of intermittent feeding on age-related changes in enzyme levels and transmural distribution.     

Cardiovascular effects of eating,atenolol and their interaction: beta1-adrenergic modulation does not play a predominant role in the genesis of postprandial effects

1. Eight healthy subjects were investigated on four occasions at least 1 week apart when they either ate a standard 3100 kJ cold meal or fasted. One hour earlier, either 50 mg atenolol or placebo was administered. 2. Eating was followed by prominent changes of systolic cardiovascular function: a rise of heart rate (+7, 95% CI: 4 to 9 beats min(-1)), systolic BP (+5, CI: 1 to 8 mmHg), a drop of diastolic BP (-6, CI:-9 to -3 mmHg), shortening of the pre-ejection period PEP (-11, CI: -13 to -9 ms) and electromechanical systole QS2c (-13, CI: -17 to -8 ms), a rise of the estimated cardiac output CO (+1.3, CI: 1.0 to 1.6 1 min(-1)) and a reduction of the calculated total peripheral resistance TPR (-306, CI: -389 to -222 dyn s cm(-5)). 3. Eating was also followed by an increase of the non-renal clearance of sorbitol (as a measure of hepatic blood flow) and this change was larger than proportional to the increase of CO. The plasma renin activity rose after the meal but the venous plasma noradrenaline and adrenaline concentrations were not affected. 4. The postprandial effects peaked over the first 1-2 h after the meal but remained well detectable up to 4 h after eating. 5. The administration of 50 mg atenolol before the meal reduced the postprandial effects to the same extent as the atenolol effects in the fasting state. This lack of interaction (or mere arithmetic additivity) indicates that the efferent beta1-adrenergic tone does not play a predominant role in the modulation of postprandial cardiovascular changes.     

The use of natural interferon alpha conjugated to a monoclonal antibody anti mammary epithelial mucin (Mc5) for the treatment of human breast cancer xenografts

Summary An immunoconjugate composed of natural interferon (nIFN) bound in a noncleavable fashion to a monoclonal antibody (MoAb) recognizing a breast epithelial membrane mucin (Mc5) was used to treat xenografts of a human mammary carcinoma cell line (MCF-7) growing in nude mice. The immunoconjugate (nIFN/Mc5) was administered as 20 intralesional (i.l.) injections to 1 of 2 xenografts in each animal. It was found that nIFN/Mc5 produced a significant enhancement of the growth inhibitory actions of nIFN on the injected tumors. Further enhancement was obtained when nIFN or nIFN together with Mc5 (at a dose 10 times larger than that present in nIFN/Mc5) were added to the immunoconjugate. Biodistribution experiments showed that the uptake of¹²⁵I-nIFN/Mc5 by the tumors was greater and its elimination slower than for¹²⁵I-nIFN alone or conjugated to irrelevant mouse IgG₁. In addition, the immunoconjugate up-regulated the antigenic expression of a breast epithelial membrane mucin by the carcinoma cells, an up-regulation which was not significantly different from that produced by nIFN alone. The contralateral noninjected tumors exposed to systemic levels of the immunoconjugate showed an enhancement of antitumor effects, but to a lesser extent than the injected tumors. These findings suggest that the enhancement of the growth inhibitory action of the immunoconjugate was related to the specific binding of Mc5 which targeted the IFN to the carcinoma cells and impeded its elimination. It is likely that the targeting was favored by the IFN-mediated up-regulation of antigenic expression by the carcinoma cells, thereby producing a cascade of interrelated effects. The results of this study point out the feasibility and potential usefulness of IFN treatment by means of immunoconjugates as well as the worth of pursuing and improving this form of therapy.     

Substance P effects on intraspecific aggressive behaviour of isolated male mice: an ethopharmacological analysis

Adult male mice of the Swiss CD1 strain were used to evaluate the effects on isolation-induced aggressive behaviour of a single intravenous administration of substance P (SP; 0.25, 1.0 or 2.5mg/kg dose). All mice were injected 15min before testing (10min videotaped dyadic encounters with an isolated male untreated opponent). Control mice were injected with vehicle. All animals were tested again 24h later in a drug-free state. SP treatment produced a decrease in offensive scores (Attacks and Rattling behaviour), a longer latency to the first Attack episode, and enhanced defensive displays. These effects were reversed 24h later. In no case did SP treatment affect locomotor activity levels or freezing behaviour. A role of SP in the regulation of murine aggressive response is strongly suggested through a direct action of the drug on the central nervous system and specifically on the hypothalamus.     

Difenoxin and loperamide: studies on possible mechanisms of intestinal antisecretory action

Summary Experiments have been performed to determine whether the antisecretory (antidiarrhoeal) actions of difenoxin and loperamide are mediated by enteric neurones. An iso-osmotic perfusion solution was circulated around the lumen of the jejunum of anaesthetised rats. Vasoactive intestinal peptide was infused intra-arterially to induce net fluid secretion which was inhibited by difenoxin (ED₅₀, 0.23 mg/kg) and loperamide (ED₅₀, 0.5 mg/kg). However, neither were able to restore the fluid transport rate to the control level of absorption.The antisecretory effects of difenoxin (0.77 mg/kg) and loperamide (0.6 mg/kg) were blocked by the opiate receptor antagonist naloxone (2 mg/kg). Their effects were also abolished by pretreatment with the 5-HT synthesis inhibitor p-chlorophenylalanine (PCPA; 200 mg/kg; with desmethylimipramine given beforehand to protect noradrenergic nerves and enhance 5-HT depletion). The effect of difenoxin was blocked with methiothepin (1 mg/kg) and methysergide (30 g/kg) but not ketanserin (30 g/kg), ritanserin (30 mg/kg), ondansetron (10 g/kg) or ICS 205-930 (3 mg/kg). None of the above 5-HT receptor antagonists modified the antisecretory effect of loperamide. The antisecretory effect of difenoxin but not loperamide was prevented by phentolamine (2 mg/kg) and by pretreatment with 6-hydroxydopamine (150 mg/kg) total.It is concluded that both difenoxin and loperamide inhibit net fluid secretion by indirect mechanisms. It is proposed that the initial action is on enteric -opiate receptors and that this results in the release of 5-HT. In the case of difenoxin, the 5-HT may act on 5-HT₁-like receptors to release noradrenaline. However, the major difference in the mechanism of action of loperamide compared to difenoxin is that it does not utilize noradrenaline as the final mediator of its antisecretory action.Correspondence to A. De Luca at the above address     

Blood styrene concentrations in a “normal” population and in exposed workers 16 hours after the end of the workshift

Summary Blood styrene was measured by a gas chromatography-mass spectrometry method in 81 normal people and in 76 workers exposed to styrene. In the normal subjects, styrene was also tested in alveolar and environmental air. Styrene was found in nearly all (95%) blood samples. Average styrene levels in the normal subjects were 221 ng/1 in blood (Cb), 3 ng/1 in alveolar air (Ca) and 6 ng/1 in environmental air (Ci). Styrene levels did not differ significantly between smokers and non-smokers, 95% of values being below 512 ng/1 in Cb, 7 ng/1 in Ca and 15 ng/l in Ci. In workers with an average exposure to styrene of 204 g/l, at the end of the workshift, mean blood styrene concentration was 1211 g/l. In blood samples collected at the end of the Thursday shift, styrene levels were significantly higher (1590 g/1) than those found at the end of the Monday shift (1068 g/l. A similar difference was found in samples taken the morning after exposure (60 and 119 g/l, respectively). Significant correlations between blood and environmental styrene were found both at the end of the shift and the morning after exposure (r=0.61 and 0.41, respectively). In workers occupationally exposed to styrene, 16 h after the end of the workshift, blood styrene (94 g/l) was significantly higher than that found in the normal subjects (0.22 g/l). The half-life of blood styrene was 3.9 h.     

PCR (polymerase chain reaction) and the future of molecular testing

Molecular testing is no longer exotic, distant, or complex. It's moving into your lab and revolutionizing the rapid diagnosis of pathogenic organisms as well as your role as a laboratorian.