Nicotinamide, Fluosol DA and Carbogen: a strategy to reoxygenate acutely and chronically hypoxic cells in vivo.

The effect of Nicotinamide and/or treatment with Fluosol DA and Carbogen breathing on the radiation response of 500-750 mg SCCVII and KHT tumours has been evaluated. Pretreatment with Fluosol DA/Carbogen or Nicotinamide resulted in relatively modest enhancements of radiation damage with enhancement factors of 1.1 and 1.3 being observed using an in vivo/in vitro clonogenic end-point. A combination of Nicotinamide and Fluosol DA/Carbogen resulted in a larger enhancement factor of 1.6 over the radiation dose ranges studied. These modification factors reflect a value close to that expected for a fully aerobic response in this survival range. Growth delay studies in the SCCVII tumour provided similar results. Using a recently developed fluorescence activated cell sorting technique, which utilizes the in vivo pharmacokinetic and DNA binding properties of the bisbenzamide stain Hoechst 33342, the effect of Nicotinamide and/or Fluosol DA/Carbogen schedules on the occurrence of acute hypoxia was assessed. The results clearly show that Nicotinamide significantly reduces the amount of 'acute hypoxia', but has a lesser effect on 'chronic' hypoxic cells. However, combinations of Nicotinamide and Fluosol DA/Carbogen significantly increase the response of both 'acutely' and 'chronically hypoxic' cells. The results provide evidence that a combination of Nicotinamide and Fluosol DA/Carbogen can provide an effective way of reoxygenating both acutely and chronically hypoxic cells.     

Peripheral refraction for distance and near vision in emmetropes and myopes

We investigated the relationship between myopia and peripheral refraction for distance and near vision by measuring peripheral refractive errors in 10 myopic and 10 emmetropic participants at viewing distances of 2.5 and 0.4 m. Measurements were made at the fovea, and at eccentricities of 10 degrees , 20 degrees and 30 degrees in the temporal and nasal hemispheres of the horizontal visual field. Our results showed that peripheral astigmatism increased with increasing eccentricity, but there was no significant difference between refractive error groups except at 30 degrees eccentricity in the temporal retina. Considering the Mean Spherical Equivalent errors, emmetropes became relatively myopic at peripheral eccentricities, but there was little change in myopes. The effect of viewing distance on astigmatism or Mean Spherical Equivalent error was not significant. Our results do not support the view that myopia is associated with changes in peripheral refraction during distance or near vision.     

Tyrosine-rich crystals in pleomorphic adenomas of parotid glands

Histochemical methods for proteins were applied to crystals found in pleomorphic adenomas of the parotid. Positive reactions were obtained with methods for tyrosine, tryptophan, arginine and sulphydryl groups, and indicate a greater complexity of composition than has previously been acknowledged.     

Corticotropin releasing factor (CRF): studies in alcohol preferring and non-preferring rats

Electroencephalographic (EEG) responses to corticotropin releasing factor (CRF) as well as CRF concentrations in several brain regions were measured in two lines of rats which have been genetically selected for alcohol preferring (P) or non-preferring (NP) behaviors. Fifteen rats were implanted with chronic electrodes and EEG spectra were evaluated following intracerebroventricular (ICV) administration of CRF (0.15 nmol) or saline. P rats demonstrated a significantly increased EEG response to CRF in the theta frequency range (ANOVA: PREF × DRUG 4–6 Hz,P<0.03; 6–8 Hz,P<0.05) in frontal cortex. A significantly lower concentration of CRF was found in the P rats in hypothalamus (P<0.02), amygdala (P<0.003), prefrontal cortex (P<0.01), and cingulate cortex (P<0.02). The finding that P rats had an increased response to exogenously administered CRF, taken together with decreased CRF concentrations, suggests that CRF receptors may be up-regulated in these animals. Differences in the regulation of CRF neurons may contribute to the expression of behavioral preference for ethanol consumption in these rat lines.Presented in part at the 1990 RSA meeting, Toronto, Canada     

Potentiation of the tumor cytotoxicity of melphalan by vasodilating drugs

Previous studies have shown that several vasoactive drugs can selectively reduce blood flow and increase hypoxia in experimental tumor systems. Our studies with one such agent, the vasodilator hydralazine, have clearly demonstrated that it can increase the tumor cytotoxicity of drugs which are known to be more toxic under hypoxic conditions. We have now extended our investigations to determine whether such selective reductions in tumor blood flow induced by hydralazine can increase the tumor cytotoxicity of other classes of cancer chemotherapeutic drugs. Our initial studies have involved the alkylating agent melphalan. Administration of hydralazine (5 mg/kg IP) at various times before or after melphalan results in increased tumor cytotoxicity in the Lewis lung carcinoma. An enhancement factor of between 2 and 3 was obtained in this tumor system. Similar results are observed if the vasodilator cadralazine is used. In contrast to the enhancement of the tumor cytotoxicity of melphalan by hydralazine, systemic toxicity is only increased by a factor of 1.2. Therefore, therapeutic gain may accrue from the use of vasodilating agents in combination with melphalan. Studies using spheroids to establish the mechanism responsible for the enhanced tumor cytotoxicity indicate that both hypoxia and pH can influence melphalan toxicity.     

Blood flow modification in the SCCVII tumor: effects of 5-hydroxytryptamine, hydralazine, and propranolol.

The effects of hydralazine, 5-hydroxytryptamine (5-HT), and propranolol on blood flow in the SCCVII tumor were assessed using laser Doppler flowmetry. Both hydralazine and 5-HT, at doses of 1 and 5 mg/kg, reduced blood flow, as did propranolol at 10 mg/kg. Hydralazine and 5-HT at doses of 0.25 mg/kg slightly increased tumor blood flow, and a 10-20% increase in blood flow was also observed after 1 mg/kg of propranolol. However, propranolol at 1 mg/kg enhanced the blood flow reduction observed with 1 mg/kg of hydralazine. The concomitant administration of hydralazine and propranolol at these doses also translated into increased potentiation of the tumor cytotoxicity of the hypoxic cell cytotoxin RSU-1069.     

Comparison of noninvasive and direct measurements of intracranial pressure

After creating "fontanelles" in infant rhesus monkeys, we measured intracranial pressure of these monkeys directly with an indwelling cannula and indirectly with a Ladd 1700 sensor. Values obtained with the Ladd sensor placed over the shaven fontanelle closely approximate directly measured pressure in acute experiments in these animals and in human cadavers. Application of the device is simple and application pressure need not always be the same for multiple determinations. The response time is 1.6 cm H2O/sec, which is adequate to record changes in intracranial pressure caused by changes in the partial pressure of CO2 in arterial blood.     

Pendred’s syndrome

A case of Pendred’s syndrome is described. It appears that Pendred’s syndrome is due to the Pleotropic effect of one gene.