Immunocryosurgery for basal cell carcinoma: results of a pilot, prospective, open-label study of cryosurgery during continued imiquimod application

Background/aim  Theoretical considerations support the combination of cryosurgery and topical imiquimod to treat basal cell carcinomas (BCC). The aim of the present study was to test the feasibility and efficacy of 'cryosurgery during continued imiquimod application' ('immunocryosurgery') to treat 'high-risk-for-recurrence' BCCs.
Methods  Thirteen patients with 21 biopsy-proven tumours (4 of 21 relapses after prior surgery) were included. After 2–5 weeks (median, 3) of daily 5% imiquimod cream application, the tumours were treated by liquid N₂ cryosurgery (spray, two cycles, 10–20 s) and imiquimod was continued for additional 2–12 weeks (median, 4). The outcome after at least 18 months of follow-up (18–24 months) is currently reported.
Results  Nineteen of 21 tumours responded promptly to immunocryosurgery; two tumours required additional treatment cycles to clear. Thus, the clinical clearance rate was 100%. Only 1 of 21(5%) tumour relapsed after at least 18 months of follow-up (cumulative efficacy: 95%).
Conclusions  'Immunocryosurgery' is a promising non-surgical combination modality to treat 'high-risk-for-recurrence BCCs'. Initial evidence is suggestive of an at least additive effect of the two combined modalities. Further studies comparing immunocryosurgery directly with cryosurgery and imiquimod monotherapies will confirm the reported results.     

Increased salt retention and hypertension from non-steroidal agents in the elderly

We studied blood pressure and natriuretic responses to acute salt loading, and the effect of non-steroidal anti-inflammatory agents on these responses, in five healthy normotensive women aged 65 to 71 years. Five women aged 25 to 31 years acted as controls. Intravenous saline loading, with and without prior ingestion of ibuprofen, was 15 ml/kg/h for 3 h. Baseline blood pressures were higher in the elderly. Saline infusion without ibuprofen raised systolic blood pressure (SBP) by about 25 mmHg in the older group only. Ibuprofen increased baseline SBP in the elderly (129 +/- 6 vs. 116 +/- 5 mmHg, p < 0.05). Saline loading after ibuprofen again raised blood pressure by about 25 mmHg in the elderly only. The elderly group showed markedly increased sodium excretion during saline loading, but this was reduced by ibuprofen. Ibuprofen had no effect on SBP or sodium excretion in controls. Ageing appears to increase susceptibility to salt retention and hypertension from non-steroidal anti-inflammatory agents.      

Uroscopy in the 21st century: high-field NMR spectroscopy

From the experiments described, it can be seen that there are different research approaches that can be taken and these are summarized in Table 1. Whereas much scientific research is principally hypothesis led, there remains, nevertheless, an important place for exploratory research. High resolution NMR can measure, directly and simultaneously, a wide range of endogenous metabolites in biological fluids and has the unique capability of providing structural information on the metabolites detected. It has proved to be a powerful research tool with which to study inherited metabolic diseases, renal disease, drug metabolism, and toxicity, and can be used to monitor the effects of drug therapy. For instance, by using a library of experimental toxins one can map the metabolic profile of site-specific nephron injury. With this approach in man one could eventually take an unknown disease such as Balkan nephropathy and predict the initial site of tubular injury, the mode of injury and therefore the kind of toxin capable of producing that injury. NMR spectroscopic techniques are still advancing rapidly, with ever increasing sensitivity and sophistication of NMR pulse sequences to enhance structural elucidation in complex mixtures. Given the advances in directly coupled HPLC-NMR and even HPLC-NMR-mass spectroscopy it is likely that these technologies in conjunction with pattern recognition will make major contribution to our understanding of renal processes and provide new diagnostic insights in the 21st century.      

Spinocerebellar ataxia type 7 (SCA7): a neurodegenerative disorder with neuronal intranuclear inclusions

Autosomal dominant cerebellar ataxia with progressive macular degeneration is caused by a CAG/glutamine repeat expansion in the SCA7 gene/protein. Neuronal intranuclear inclusions were detected in the brain of an early onset SCA7 case with the 1C2 antibody directed against an expanded polyglutamine domain. Nuclear inclusions were most frequent in the inferior olivary complex, a site of severe neuronal loss in SCA7. They were also observed in other brain regions, including the cerebral cortex, not considered to be affected in the disease. Using confocal microscopy we showed that some inclusions were ubiquitinated, but to varying degrees, ranging from <1% in the cerebral cortex to 60% in the inferior olive. In addition, we also observed cytoplasmic staining using the 1C2 antibody, particularly in the supramarginal gyrus, the hippocampus, the thalamus, the lateral geniculate body and the pontine nuclei. These data confirm that the presence of intranuclear inclusions in neurons is a common characteristic of disorders caused by CAG/polyglutamine expansions, but unlike what has been reported for Huntington's disease, SCA1 and SCA3/MJD, in SCA7 the inclusions were not restricted to the sites of severe neuronal loss.      

Effect of chronic elevation of plasma calcium concentration by PTH or vitamin D3 on blood pressure and hypotensive activity of nifedipine in rats

The influence of a chronically elevated total plasma calcium concentration on blood pressure and heart rate was investigated in conscious normotensive rats. The plasma calcium concentration was elevated by continuous subcutaneous infusion with parathormone (PTH) after parathyreoidectomy, and by oral treatment with vitamin D₃. In both groups an elevated blood pressure was observed at the 1st day of treatment only. Blood pressure was returned to pretreatment values from the second day of treatments onaards. No significant changes in heart rate, due to hypercalcaemia, were observed. In hypercalcaemic rats, the calcium entry inhibitor nifedipine proved more potent in reducing blood pressure than in normocalcaemic control animals. Hydralazine was equipotent in reducing blood pressure in both groups. It is suggested, that the vasoconstrictor effects of a chronically elevated total plasma calcium concentration in conscious rats does not obviously result in a chronically elevated blood pressure, but rather in an enhanced sensitivity of the blood pressure towards calcium entry blockade.     

Asymmetric distribution of calbindin-D28K in the ganglia habenulae of an elasmobranch fish

Summary Using an antibody raised against a purified chick duodenal vitamin D-dependent calcium-binding protein, the presence and distribution of calbindin has been studied immunohistochemically in the habenular ganglia of the dogfish. In the more developed left ganglion, a positive reaction was clearly observed in the neurons of the medial nucleus, whereas in the lateral nucleus, only some scarce, hardly immunostained cells appeared. In the neurons of the right habenula however, no immuno-reactivity was observed. The distribution of vitamin D-dependent calcium-binding protein in the dogfish habenulae is therefore asymmetrical. This may be due to differences in the neuronal activity between the two ganglia.     

Effects of the irreversible α-adrenoceptor antagonists phenoxybenzamine and benextramine on the effectiveness of nifedipine in inhibiting α 1- and α 2-adrenoceptor mediated vasoconstriction in pithed rats

Summary In pithed normotensive rats, i.v. injection of the selective ₁-adrenoceptor agonist cirazolien produced vasoconstriction which was largely resistant to inhibition by nifedipine. On the other hand, the pressor effects of the selective ₁-adrenoceptor agonists St 587 and Sgd 101/75 were much more effectively blocked by nifedipine, although not as effectively as the pressor effects to the selective ₂-adrenoceptor agonist B-HT 920. The sensitivity to inhibition of vasoconstriction in pithed rats to the different agonists increased in the order cirazoline St 587 ₁-, but not to ₂-adrenoceptor activation was dose-dependently enhanced. The potency of nifedipine to inhibit ₁-vasoconstriction by cirazoline, St 587 and Sgd 101/75 was increased maximally to the level of efficacy at which nifedipine antagonized B-HT 920-induced vasoconstriction. The dose of phenoxybenzamine required to maximally increase the potency and efficacy of nifedipine to antagonize vasoconstriction of the ₁-adrenoceptor agonists was inversely related to the level of sensitivity to blockade by nifedipine of the vasoconstriction they produced. In contrast, pretreatment of rats with the irreversible antagonist, benextramine (10 mg/kg, i.v., –100 to –60 min) did not increase the potency or efficacy of nifedipine to antagonize vasoconstriction to cirazoline, St 587, Sgd 101/75 or B-HT 920, despite irreversible blockade of ₁- and ₂-adrenoceptors. These data suggest that phenoxybenzamine, but not benextramine, selectively inhibits the ₁-adrenoceptor mediated vasoconstrictor mechanism that is independent of influx of extracellular calcium. Moreover, the results show that the existence of receptor reserve or the number of ₁-adrenoceptors activated does not determine the relative contribution of calcium influx-independent mechanisms in ₁-adrenoceptor-mediated vasoconstriction.Preliminary data were communicated at the Joint Meeting of the French and German Pharmacological and Toxicological Societies, Freiburg i. Br., September 19–22, 1983 (Timmermans et al. 1983a) and at the Winter Meeting of the British Pharmacological Society, London, January 1984 (De Jonge et al. 1984)