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As a prerequisite to pharmacological analysis of the excitatory effects of serotonin (5-HT) on piriform pyramidal cells and interneurons, this study first examined the physiological characteristics of these two cell types. Intracellular recordings confirmed that the subpopulation of 5-HT-activated cells located at the border of layers II and III are indeed interneurons. Voltage clamp recordings in pyramidal cells showed that the increase in excitability produced by 5-HT in these cells was the result of voltage- and Ca(2+)-dependent outward currents with the characteristics of IM and IAHP. Pharmacological studies were designed to discriminate 5-HT2 from 5-HT1C responses in interneurons and pyramidal cells of piriform cortex. The 5-HT antagonist spiperone, which has a much higher affinity for 5-HT2 receptors than for 5-HT1C receptors, blocked the excitatory effect of 5-HT at lower concentrations in interneurons (IC50 = 31 nM) than in pyramidal cells (IC50 = 2.1 microM). Similarly, ritanserin, a drug which also has a higher affinity for 5-HT2 than 5-HT1C receptors, blocked the effect of 5-HT at lower concentrations in interneurons (IC50 = 400 nM) than in pyramidal cells (IC50 = 8.1 microM). In contrast, LY 53857, an antagonist with higher affinity for 5-HT1C than for 5-HT2 receptors, blocked the effect of 5-HT at lower concentrations in pyramidal cells (IC50 = 26 nM) than in interneurons (IC50 = 364 nM). The 5-HT1C partial agonist/5-HT2 antagonist mCPP produced agonist-like effects in only 66% of pyramidal cells tested indicating that not all pyramidal cells may express 5-HT1C receptors. In that both spiperone and ritanserin have higher affinity for 5-HT2 receptors than for 5-HT1C receptors and LY 53857 has a higher affinity for 5-HT1C receptors than for 5-HT2 receptors, these data suggest that in piriform cortex excitatory effects of 5-HT are mediated by 5-HT1C receptors in pyramidal cells an by 5-HT2 receptors in interneurons.

A novel microdialysis technique suitable for parallel measurements of neurotransmitter release and single unit recordings from brain slices is presented. The effects of 3,4-methylenedioxymethamphetamine (MDMA) on slices of dorsal raphe nucleus and frontal cortex in a perfusion chamber for electrophysiological measures were studied. MDMA caused measurable release of serotonin which, in the case of the dorsal raphe, was of similar duration as the period of reduced cell firing induced by MDMA. Tryptophan potentiated the action of MDMA. Possible additional applications of this technique are discussed.

In a slice preparation of rat piriform cortex, both intracellular and extracellular techniques were used to examine the pharmacological and electrophysiological actions of serotonin (5-HT). Bath application of 5-HT resulted in either depolarization (57%), hyperpolarization (34%) or no change (9%) in membrane potential of cells in the pyramidal cell layer (layer II) of piriform cortex. Additionally, when KCl-containing electrodes were used, 5-HT induced an increase in depolarizing synaptic potentials in 41% of these cells. It was concluded that these potentials were reverse inhibitory post-synaptic potentials (IPSPs) because they were blocked by bicuculline and tetrodotoxin. The induction of IPSPs by 5-HT was blocked by the 5-HT2-selective antagonist ritanserin. By recording extracellularly in the presence of 5-HT, a group of 5-HT-activated, putative interneurons was found at the border of layers II and III of piriform cortex, 5-HT but not norepinephrine activation was blocked by ritanserin. The actions of 5-HT were mimicked by the 5-HT2 agonist alpha-methyl-5-HT; the 5-HT2 partial agonist, 2,5-dimethoxy-4-methyl-amphetamine had a small agonist action of its own and blunted the effect of 5-HT. Activation of a larger group of putative interneurons by the more universal excitant N-methyl-D-aspartate showed that the 5-HT-activated interneurons represented 23% of the interneurons located on the border between layers II and III. We conclude that 5-HT induces IPSPs in layer II pyramidal cells by activating a subpopulation of interneurons at the border of layers II and III of piriform cortex.

Repair and repopulation following X irradiation of clamped-off murine anaplastic MT tumours was investigated using the established method of (Dn-D1)/(n-1). Repair was complete in 4 h, similar in extent to that reported in other tumours, and within the range of that reported for normal tissues. Subsequent repopulation commenced after 4 days and was equivalent to 1.8 Gy/day recovered dose, corresponding to a clonogenic cell number doubling time of 1.8 days. However, estimates of repair and repopulation may have been in error because the chronically hypoxic cells in this tumour alone have the ability to recover from potentially lethal damage (PLD) and so are more radioresistant than cells rendered acutely hypoxic by clamping. Because of this, even clamping off tumours at irradiation does not render all cell populations equally radioresistant, and so reoxygenation between fractions could result in an underestimate of repair and repopulation. Further, the differing sensitivity between acutely and chronically hypoxic cells renders the apparent OER a function of dose (i.e., oxygen not truly dose-modifying to chronically hypoxic cells). Consequently it is incorrect to assume a constant OER in order to compare repair in tumours irradiated under hypoxic conditions with that in normal tissues irradiated under aerobic conditions. It will be argued here that in the case of the present tumour neither reoxygenation nor the choice of OER will have qualitatively altered the conclusion reached from the conventional method.

The pattern of reoxygenation in the murine anaplastic MT tumour was investigated using the established method of determining the hypoxic fraction, at intervals after a priming X-ray dose, from test doses given either to unclamped or clamped-off tumours. Little reoxygenation was apparent whilst the tumour was increasing in size for 12--72 hours after a single dose of 20.3 Gy, but extensive reoxygenation was evident whilst the tumour was shrinking at nine days after a dose of 50 Gy. However, the degree of reoxygenation may have been underestimated, especially after the smaller priming dose. This is because only the chronically hypoxic cells in this tumour have the ability to recover from potentially lethal damage (PLD) and so are more radioresistant than cells rendered acutely hypoxic by clamping. Because of this, even when tumours are clamped off during irradiation, the resulting survival curve is biphasic and the apparent effect of the clamp becomes a function of the X-ray dose used. The larger the dose, the smaller the observed effect of the clamp, so the greater the apparent hypoxic fraction and hence the smaller the apparent degree of reoxygenation.

In principle, radiation sensitizers with therapeutic ratios greater than that of misonidazole can be obtained either by increasing sensitizing efficiency, decreasing toxicity or preferably both. This paper illustrates, firstly that a 5-nitroimidazole (S73-0662) with an electron affinity close to that of metronidazole shows sensitizing efficiency similar to misonidazole both in vitro and in vivo. The suggestion is made that this compound should receive a detailed toxicological study to ascertain if its toxicity is lower than misonidazole. Secondly, Imuran, a 5-substituted 4-nitroimidazole and one of a series of compounds which show sensitizing efficiencies in vitro much greater than would be predicted from electron affinity considerations, also shows good sensitization in vivo. Compounds in this series are generally metabolically unstable and the positive results with Imuran in vivo provide a direction for future synthesis of novel sensitizers.

Treatment of mice (some bearing Lewis Lung tumors), with penicillin (PEN) at 500 mg/l drinking water for one week prior to treatment with misonidazole (MIS), resulted in: the elimination of their anaerobic cecal flora; a decrease in MIS-induced neurotoxicity; an increase in pharmacological exposure to MIS; a decrease in MIS chemopotentiation; a probable increase in MIS radiosensitization; an increase in MIS induced hypothermia. Assuming no chemical interaction between PEN and MIS, these observations indicate that the intestinal microflora can influence the activity of MIS in vivo. Therefore their influence should be considered in all sensitizer-related studies in vivo. The observed reduction in the neurotoxic but not the radiosensitizing potential of MIS following PEN treatment indicates a therapeutic benefit.

Three fractionated X-ray schedules were used, with and without the electron-affinic radiosensitizer of hypoxic cells, Ro-07-0582, to determine the local control of first-generation transplants of spontaneous mammary tumours in C3H mice. Three or five fractions were given in either four or nine days overall time. The results were compared with acute skin reactions in other mice caused by the same treatment schedules. For a given skin reaction, the local control of tumours varied widely, from good to bad, when different X-ray only schedules were used. All three schedules using Ro-07-0582 however yielded good results. It appears that the use of the hypoxic-cell radiosensitizer took the unreliability out of these short fractionated treatments.

Using a quantitative cytochemical technique for measuring beta-glucuronidase activity in the peripheral nerves of mice, we have investigated the effectiveness of four potential adjuncts for reducing the dose limiting neurotoxicity of misonidazole (MISO) in the clinic. Under the conditions used, the most effective adjunct was the steroid anti-inflammatory agent dexamethasone. When given over the week previous to MISO treatment, this agent almost completely eliminated the MISO neurotoxicity as determined at week 4 after commencement of MISO dosing. The second most effective adjunct was phenytoin, the third flurbiprofen and the last adjunct, phenobarbitone, was ineffective. Dexamethasone, phenytoin and phenobarbitone all reduced the clearance half-life of MISO and hence the drug exposure dose calculated as the area under the curve of MISO tissue concentration against time. However, no correlation was evident with these parameters and MISO neurotoxicity in the mouse. Dexamethasone, whilst affording protection against MISO toxicity, did not alter the radiosensitivity of the anaplastic MT tumour.

The effect of the 2-nitroimidazole Ro 03-8799 (8799) on the activity of 11 chemotherapeutic agents against the anaplastic MT tumour in mice has been determined by soft agar cloning. The 8799, whilst producing little cytotoxicity by itself, potentiated the cytotoxic actions of the alkylating agents melphalan and cyclophosphamide, and the nitrosoureas BCNU, CCNU and MeCCNU. This potentiation was influenced by the time interval between the administration of 8799 and the chemotherapeutic agents, and also by the site of tumour implantation. However, 8799 did not potentiate the cytotoxicities of the compounds CBDCA, cisplatin, adriamycin, vincristine, 5-fluorouracil and bleomycin. A review is included of the reported in vivo effects of nitroimidazoles on the chemotherapeutic agents investigated here.

Pre-operative X-irradiation of s.c. implanted first-generation mammary tumours in C3H mice, using either 500 rad or two fractions of 350 rad, produced no improvement in the success of surgery in causing local control or in reduction of distant metastases. The metastasis rate was just significantly higher after the two-fraction treatment of the implanted tumour than after surgical removal alone. The results are in agreement with previously published results on carcinomas and a sarcoma but contrast with those for murine lymphomas.

Electron affinity as measured by the one-electron reduction potential, E17, is the major factor influencing radiosensitizing efficiency in vitro. RSU 1069 has an electron affinity (E17 = -398 mV) similar to misonidazole; however, the ability of this compound to sensitize hypoxic cells is considerably greater than that of misonidazole, e.g. 0.2 mM RSU 1069 gives an enhancement ratio of 2.2 compared to 1.5 for the same concentration of misonidazole. Radiosensitization studies with the MT tumour in vivo also showed RSU 1069 to be a more efficient sensitizer than misonidazole. An administered dose of only 0.08 mg g-1 RSU 1069 yielded an enhancement of 1.8 to 1.9 using tumour cell survival and tumour cure as end-points. The ability of RSU 1069 to potentiate the cytotoxic action of melphalan towards the MT tumour was also examined. RSU 1069 (0.08 mg g-1) given to mice 1 h before melphalan resulted in an enhancement of 3.0. In contrast, previous studies had shown with a series of nitroimidazoles including misonidazole that Ro 03-8799 was the most effective potentiating agent, but this only gave an enhancement of 2.3 at a 10-fold higher dose than RSU 1069. RSU 1069 is a compound of substantial promise both as a radiosensitizer and chemopotentiating agent and warrants further investigation.

Electron affinity as measured by the one-electron reduction potentian, E7(1), is the major factor influencing radiosensitizing efficiency in vitro. RSU 1069 has an electron affinity (E7(1) = 398 mV) similar to misonidazole; however, the ability of this compound to sensitize hypoxic cells is considerably greater in vitro than that of misonidazole, e.g., 0.2 mM RSU 1069 gives an enhancement ratio of greater than 2.0 compared to 1.4 for the same concentration of misonidazole. Radiosensitization studies with the MT tumor in vivo also showed RSU 1069 to be a more efficient sensitizer than misonidazole. An administered dose of 0.08 mg/g RSU 1069 yielded an enhancement of 1.8 to 1.9 using tumor cell survival and tumor cure as end-points. At least a 10-fold higher dose of misonidazole is required for a similar degree of sensitization. Low doses of RSU 1069 also radiosensitize the Lewis lung and B16 experimental tumors. The ability of RSU 1069 to potentiate the cytotoxic action of melphalan and other cytotoxic drugs towards the MT tumor was also examined. RSU 1069 (0.08 mg/g) given to mice 1 hour before melphalan gave an enhancement of 2.8.

Out of 64 consecutive unselected patients with acute myeloid leukaemia studied during 1973-6, five developed clinical evidence of spread to the central nervous system (CNS). Neuroradiological examination showed cerebral deposits in three, in whom rapid symptomatic relief was obtained with radiotherapy. In two of these patients who developed solid intracranial deposits haematological remission could be reinduced or maintained; they were still alive 86 and 134 weeks later. When patients presented with spread to the CNS complicating generalised uncontrolled leukaemia they had short survivals. CNS infiltration may respond dramatically to appropriate treatment provided that it is not associated with generalised uncontrolled leukaemia, which has a poor prognosis. In view of this, routine "prophylaxis" of the CNS in adult acute myeloid leukaemia does not seem justified at present.

The acetylcholinesterase and cholinesterase activities in the mouse cerebellum were unchanged following misonidazole treatment. Inhibition of acetylcholinesterase activity only occurred at concentrations of misonidazole which were in excess of those obtained clinically. These findings indicate that the clinical neurotoxicity of the drug cannot be attributed to an effect on cholinesterases.

Local tumour control has been determined at 150 days after single doses of 240 kV x-rays given with or without 1 mg/g body weight of the hypoxic cell radiosensitizer Ro-07-0582. The dose required to control 50% of the tumours (TCD50) was reduced from 4380 to 2410 rad, yielding an enhancement ratio of 1·82 ± 0·07 s.e.mean. This compares favourably with the corresponding single dose gain factor for fast neutrons, which was about 1·7.

The activity against murine anaplastic MT tumours of the chemotherapeutic agent melphalan, either alone or in combination with one of 6 nitroimidazole compounds, was assayed using an in vivo-in vitro tumour excision assay. The melphalan alone proved cytotoxic to the tumour, whereas relatively little cytotoxicity was produced by any of the nitroimidazoles alone. When the nitroimidazole were given in combination with melphalan, dose-modifying potentiation of its cytotoxicity was observed. Maximum potentiation occurred when the nitroimidazoles were given 0--30 min before the melphalan, although some potentiation was still evident when they were given up to 2 h before or after. There was no threshold in nitroimidazole dose required to produce this potentiation, the degree of potentiation increasing with dose, albeit at a diminishing rate, to give maximum dose-modification factors of about 3. The 6 nitroimidazole compounds in order of increasing effectiveness as potentiators of melphalan activity were: METRO, Ro 05-9963, MISO, RSU 1047, Ro 03-8800 and Ro 03-8799. This order corresponds to the increasing electron affinity of these compounds. The most effective compound here, Ro 03-8799, was about twice as effective as the most widely used nitroimidazole in such studies, MISO.

Many nitroimidazole compounds have been shown to potentiate the activity of melphalan against the murine anaplastic MT tumor. The degree of potentiation achieved by these compounds probably depends on their octanol-water partition coefficient and electron affinity: for the greater the partition coefficient of electron affinity, the greater the potentiation. The mechanism of this potentiation remains uncertain. However, it is not due to either nitroimidazole-induced hypothermia, or to the elimination of the recovery from melphalan-induced potentially lethal damage (PLD).

Congenital abnormalities of the bony labyrinth and internal auditory meatus range from complete absence to minor anomalies compatible with normal cochlea function. A 'follow-up' survey to assess the hearing of 56 patients with abnormalities of the inner ear shown by tomography was made. The hearing levels are discussed in relation to the tomographic appearances and comparison made with other series of inner ear abnormalities demonstrated both radiographically and histologically.

C3H mice were implanted with pieces of spontaneous mammary carcinoma which were irradiated or removed surgically when they had grown to 6·5 mm mean diameter. The incidence of lung metastases was determined from samples taken at various times up to 6 months later. Single x-ray doses and fractionated schedules up to 15 fractions in 18 days were used, no significant difference being observed in the results for all these schedules.On the major question of whether radiation caused an increase in the number of lung metastases the study is inconclusive. The incidence of metastases was found to be 8% if the implanted tumour was cured by the radiation, whereas if the radiotherapy did not cure the tumours the incidence was 35%. This difference between the two groups was significant. If tumours recurred locally after radiotherapy and were then removed surgically, the incidence of lung metastases was significantly greater than that after surgery of unirradiated tumours. The incidence of metastases was similar after curative surgery and after curative radiotherapy.

The x-ray dose required to cure half the mice bearing first generation transplanted mammary carcinomata 150 days after irradiation was determined. NDPP proved to be a relatively poor radiosensitizer in mice, for although a maximum enhancement ratio of 1-3 was obtained when x-rays produced from a 1-4 MeVp electron accelerator were given between 10 and 17 min after the administration of NDPP, this was at a drug concentration sufficient to cause marked kidney abnormalities in 5-10% of the mice.

The neurotoxicity of a homologous series of 1-substituted, 2-nitroimidazole compounds, synthesized in this laboratory, has been studied in mice. This involves measurement of the enzyme beta-glucuronidase in the distal sciatic, tibial and common peroneal nerves. The amount of compound required to give a known neurotoxic response, in terms of elevated beta-glucuronidase (arbitrarily set at 60% increase) has been determined. A correlation between increased number of methylene groups (N) in the side chain and neurotoxicity has been shown. A correlation between increased neurotoxicity and effective octanol; water coefficient, at pH 7.4, was also established. A more soluble version of the n = 4 member of the homologous series, that is the compound RSU 1047 (NSC 328897), and misonidazole also fit this correlation of partition coefficient and dose.

We have carried out a randomized blind trial comparing iopamidol (Niopam) and sodium meglumine ioxaglate (Hexabrix) in cerebral angiography in 50 patients. There was no significant difference in the degree of pain or movement produced by the contrast media. The degree of heat felt was slightly greater with iopamidol than with ioxaglate. Both were very well tolerated by patients, producing only a mild or moderate sensation of heat, and in only a few instances slight pain during the injections. No difference in radiographic quality was observed. We conclude that both media are a significant advance over the conventional ionic media and the choice between them will be determined by factors of neurotoxicity, ease of use and cost.

In previous experiments the highest proportions of tumours controlled for 150 days at a particular level of skin reaction were obtained with five or nine fractions of X rays in nine or ten days respectively. Poor results were obtained for the same numbers of fractions given in 4 or 18 days respectively. The present work reports results of three "non-standard" fractionation schedules: two with equal doses given at 12-hour intervals over four or nine days and one with eight decreasing doses given at decreasing intervals over 11 days. The two 12-hour interval schedules gave results which were equal to the best obtained by any other schedule tested. The 8F/11d non-uniform schedule, however, gave mediocre results in spite of being close to the previously optimum overall time. When these results are compared with previously published results from the same tumour system two, phases of optimum fractionation are demonstrated. At short overall times, up to four days, the situation is finely balanced, so that fraction size and interval matter greatly and results of the schedules vary from good to bad. At longer overall times, of nine days or more in these tumours, the response is no longer so variable. Eighteen days (two to three times the average volume doubling time) is too long for any successful treatment with this system, presumably because of proliferation in the tumour.

Using Chinese hamster V79 cells in vitro a study has been made of the radiosensitizing properties of 4- or 5-nitroimidazoles substituted in the 2, 5 or 4 position with various halo, sulphur ether, sulphonamide, sulphonate, ether or nitro groups. Values of E17 (the one-electron reduction potential measured versus the normal hydrogen electrode at pH7) vary in the range -178 to -565 mV. All the compounds, with one exception, are more efficient radiosensitizers than would be predicted from their redox potentials, and the factor, C1.6/C1.6, by which a compound is more efficient has been calculated. The second-order rate constants, k2, for reaction of these nitroimidazoles with glutathione and/or dithiothreitol were determined. Within each class of nitroimidazole there is a trend for k2 to increase with increasing redox potential. However, there is no clear trend between k2 and C1.6/C1.6. The concentration required to cause a 50 per cent depletion of intracellular glutathione was determined for selected compounds, as was the ability of glutathione-S-transferase to catalyse reaction with thiols. These observations suggested that the relative thiol reactivity measured under chemically controlled conditions does not necessarily indicate thiol reactivity intracellularly. Studies using the MT tumour in mice showed that the high levels of radiosensitization seen in vitro could not be duplicated in vivo. This was attributed to thiol reactivity, resulting in low metabolic stability and rapid depletion of sensitizer in vivo.

It has recently been reported that compounds more lipophilic than misonidazole are better potentiators of CCNU tumor cytotoxicity in vivo. There is now a need to extend these studies to include other tumors and cytotoxic drugs. In the present study we have shown that misonidazole (MISO) can potentiate cyclophosphamide cytotoxicity in the Lewis lung carcinoma but not in the B16 melanoma. Further studies in the Lewis lung carcinoma, using 15 1-substituted 2-nitroimidazoles possessing a range of octanol:water partition coefficient (P) (from 0.18- greater than 100) have shown that potentiation increases with increasing lipophilicity. The most efficient compounds at administered dose levels of 1.0 and 2.0 mumol/g were Ro-07-1902, benznidazole (Ro-07-1051) and RSU 1050 which possess octanol:water partition coefficients in the range of 2.5-10. However, on the basis of an equitoxic administered dose (1/2LD50/2d), little difference in potentiation is seen over the range of P studied.

The tumour used, designated MT1, is a more radiosensitive form of the anaplastic MT tumour previously described. No explanation for the increased radiosensitivity was found, but it was shown not to be due to infection or to a change in immunological status, growth rate or histology. The sensitivity has remained constant throughout the present work. No cytotoxicity in the tumour was observed when 1 mg/g body weight of Ro-07-0582 was injected immediately after a single dose of X-rays; indeed a small protective effect was seen. A radiosensitization enhancement of 1-5 was achieved with a relatively low drug dose of Ro-07-0582 in a 5F/4d fractionated regime. The interval between the injection of a low dose of Ro-07-0582 and the start of irradiation was found to be critical, the optimum interval being 45-60 min. The subsequent incidence of distant metastases was not increased by the use of Ro-07-0582 at the time of "primary" tumour irradiation.

The drug BW12C, which increases the oxygen affinity of hemoglobin, reduces oxygen availability to tissues. This results in protection against radiation damage to the hemopoietic system and epidermal Langerhans cells in CBA mice. The drug also protects against beta-irradiation damage in pig epidermis. BW12C increases the hypoxic cell fraction in tumors and histological examination of an experimental T cell lymphoma shows that the induced hypoxia leads to tumor necrosis.

A series of nitroimidazoles containing aziridine and alkyl-substituted aziridine functions has been synthesized. The 2-nitroimidazole compounds examined all show greater radiosensitizing efficiency in vitro than misonidazole. The 4- and 5-nitroimidazole analogues are also more efficient than equivalent compounds which do not contain the alkylating aziridine moiety. All the compounds show increased toxicity towards hypoxic cells relative to aerobic cells, but this toxicity is reduced by alkyl-substitution of the aziridine ring. In vivo toxicity can also be reduced by modification of the aziridine function, but such alterations appear to have less effect upon the high radiosensitizing efficiency of these compounds in vivo. As a consequence of this study, compounds of potentially improved therapeutic utility compared to RSU-1069, the first reported member of this class, have been identified.

Congenital deformities of the external and middle ears were shown by tomography in 246 patients. Surgical exploration has been undertaken at some time in many of these ears. The appearance of the tomograms and their significance were reviewed in the light of the operative findings and the authors' experience of congenital ear lesions. In nearly every case a middle ear cavity could be demonstrated although this varied from a normally aerated middle ear and mastoid in association with an isolated unilateral atresia of the external auditory meatus to a small slit-like hypotympanum in patients with craniofacial abnormalities. The ossicles were nearly always present but deformed. The typical appearances of the ossicles and the frequently aberrant pathways of the facial nerve are described.

A quantitative, cytochemical assay for measuring lysosomal enzymes in the peripheral nerves of mice has been developed. That the time course of lysosomal enzyme changes after misonidazole (MISO) treatment reflects the degree of neurotoxicity of this agent in the mouse, has been confirmed by the use of two known neurotoxic compounds: methyl mercury and acrylamide. This effect is specific to the peripheral nerves and was not found in liver, kidney, heart or cerebral cortex. Enzyme activities varied with mouse strain and sex, as did the response to MISO treatment. Of the mice studied, female C57 gave the greatest increase in beta-glucuronidase activity. With the MISO dose of 0.6 mg/g/dose the increased enzyme activity was independent of the route of administration and appeared to approach a plateau after 5 daily doses.

An homologous series of 1-(omega-morpholino)alkyl-2-nitroimidazoles, previously reported to be more efficient hypoxic cell radiosensitizers than misonidazole (MIS) in vitro, were evaluated in vivo using the murine Lewis Lung carcinoma. When given i.p. the compounds were 3-20 times more acutely toxic (LD50/2d) than MIS and this toxicity increased with both the number of methylene groups (n) in the side chain and the lipophilicity of the compounds. The compounds sensitized the tumour to single doses of X-rays. On the basis of equimolar administered dose, the most effective compounds, n = 2, 4 and 5, were as efficient as MIS. However, on the basis of the measured concentration of drug in the tumour at the optimum time of irradiation the compounds with n = 4 and n = 5 were less efficient than expected from previously published data in vitro. This is attributed to the basicity of the morpholino nitrogen in these compounds such that at physiological pH the compounds are primarily in an ionized form and hence poorly able to penetrate hypoxic cells.

Three cases of multiple sclerosis, all confirmed pathologically, are described in whom both the unusual clinical features and the CT scan appearances suggested cerebral tumours. The failure of mass effect reliably to differentiate plaques and tumours on a CT scan is stressed and the literature relating to CT scanning in multiple sclerosis is reviewed.

In congenital deafness it is important that the radiological examination should exclude any deformities of the bony labyrinth or internal auditory meatus as well as demonstrating lesions of the middle and external ears. Radiological assessment of inner ear abnormalities should be used as a guide both to the feasibility of reconstructive surgery to the middle and external ears and for the future training of the child. Inner ear abnormalities demonstrated by tomography in 56 patients are discussed in relation to the cochlea function. The importance of demonstrating the central bony spiral of the cochlea and of assessing the size and shape the internal auditory meatus is stressed.

We have examined the survival parameters of anaplastic "MT" tumour cells following irradiation with 60Co gamma rays in vitro acd in vivo, comparing colony formation in soft agar and monolayer. Following in vitro irradiation under oxic or hypoxic conditions, or in vivo hypoxic irradiation, we found that the D0 values were about 30% greater when measured in soft agar compared with monolayer (soft agar, oxic D0 = 1.6 Gy, hypoxic D0 = 3.7 Gy; monolayer, oxic D0 = 1.2 Gy, hypoxic D0 = 2.8 Gy). However, other parameters were similar for each assay (oxic and hypoxic n approximately 11; hypoxic fraction in vivo approximately 0.07; PLD repair in naturally hypoxic cells increased the D0 by a factor of approximately 1.3). Recently, McNally and Sheldon (1977) measured cell-survival parameters for this tumour using only a monolayer colony assay, and from these estimated TCD50 for the tumour. However, their estimate was lower than the directly measured value of 79 Gy. We have also estimated TCD50 from our cell-survival data after correction for RBE (we used gamma rays while McNally and Sheldon used 250 kV X rays). Like McNally and Sheldon we were unable to predict the measured TCD50 from our monolayer data, even when PLD repair was taken into account. However, the soft agar data with PLD repair could predict the observed TCD50.

A randomized blind trial of iopamidol and meglumine calcium metrizoate (Triosil 280, Isopaque Cerebral) for cerebral angiography was performed in 20 patients. The Iopamidol was better tolerated and caused significantly less discomfort in patients than metrizoate. There was no difference in the quality of the radiographs. A further 13 patients also received Iopamidol for cerebral angiography with similar results. No adverse effects were observed in any of the patients. Our evidence suggests that Iopamidol has significant advantages over currently available contrast media for cerebral angiography.

First-generation transplants of spontaneous mouse mammary carcinomas have been used extensively for radiobiological investigations of fractionated irradiation schedules, r.b.e. of fast neutrons and effectiveness of radiosensitizers, as reported elsewhere. The present work investigates the growth characteristics of the tumours; the criteria for the choice of end-points used in the definition of 'local control' of irradiated tumours; the reason for a decrease of 30 per cent in X-ray dose required to control tumours in females as compared with male mice; the proportion of hypoxic cells and its variation with time (reoxygenation) after a single dose of 1500 rad of X-rays; and the repair capacity of tumour cells within 24 hours after a substantial first dose of X-rays. Evidence is presented that the male-female difference was due to a higher proportion of hypoxic cells in tumours in male than in female mice. The repair of sub-lethal injury in tumour cells made hypoxic was slightly less than in skin made hypoxic but not significantly so. In the two-dose experiments on clamped tumours, no evidence of induced synchrony was found.