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Human squamous carcinoma cell lines that were highly and minimally sensitive to bleomycin were established from clinical specimens and designated as SCCKN and SCCTF, respectively. Although these cell lines showed a similar growth doubling time in vitro, SCCTF was approximately ten times less sensitive to bleomycin than SCCKN. The bleomycin high and low sensitivities were stable even at the 70-cell passage level in vitro. In addition, nude mouse tumors produced by SCCTF were less sensitive to bleomycin that those produced by SCCKN, and the ratio of the mean tumor weight in bleomycin-treated mice to that in control mice was 89.2% in SCCTF and 18.8% in SCCKN. As compared with SCCKN, SCCTF also was less sensitive to peplomycin (5-fold), mitomycin C (2.3-fold), cis-diamine dichloroplatinum (2.5-fold), and vincristine (6.5-fold). Analyses of low bleomycin sensitivity showed that SCCTF had an approximately 20% decreased cellular accumulation and retention of bleomycin, 1.2-fold increase of bleomycin hydrolase activity, elevated DNA repair activity, and increased poly(adenosine diphosphate-ribose) polymerase activity as compared with SCCKN.
A highly sensitive silver staining method for detecting proteins in sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) was developed. It is based on the silver nitrate staining method but also employs an azo dye, calconcarboxylic acid (NN), as a silver-ion sensitizer. It increases silver binding on protein bands or spots by the formation of a silver-dye complex and also increases the reducing power of silver ions to metallic silver by NN itself with formaldehyde. After a 2 h gel fixing step, the protocol including sensitization, silver-ion impregnation, and reduction steps can be completed in 1 h. The sensitivity is superior to that of silver stain with glutardialdehyde as a silver-ion sensitizer. The detection limit of NN-silver stain is 0.05-0.2 ng protein. Considering the high sensitivity without using glutardialdehyde, the NN-silver stain would be useful for routine silver staining of proteins.
Eighteen patients with early maculopathies of various etiologies were tested with pattern and focal electroretinograms (macular ERGs), with high (400 cd/M2) and moderate (40 cd/M2) stimulus intensities and a four-alternative forced choice (4AFC) contrast sensitivity test in addition to intensive clinical examinations. High spatial frequency contrast sensitivity loss on the 4AFC test was the most striking and consistent feature of all cases. The only eyes not outside normal contrast sensitivity limits were three in which diagnosis was uncertain and the patients had not recognized any problem, including two marginal solar burns. Maculopathy also substantially reduced macular ERG amplitudes. Criterion scores on these tests separated patients from normals more effectively than other noninvasive procedures and only missed one eye detected by contrast sensitivity. Latencies were affected but the delays were of no clinical significance in the individual case. Stimulus intensity was not critical. The results indicate that contrast sensitivity testing and macular ERGs are very reliable indices of central visual dysfunction at a stage when visible macular changes are too subtle for confident diagnosis. Contrast sensitivity has appeal because of its reliability, objectivity, simplicity, and noninvasive nature. It is equally applicable to children and adults. Pattern and focal ERGs can establish that the visual deficit has a retinal origin and can provide the most reliable objective confirmation.
The ATP- and sulphonylurea-sensitivity of the ATP-sensitive K-channel was measured in human pancreatic B cells. In inside-out patches, half-maximal inhibition of channel activity was produced by 10 mumol/l ATP (with 2 mM Mg2+) and ATP-inhibition was partially antagonised by ADP. A significantly lower sensitivity to ATP was found in whole-cell recordings. Tolbutamide inhibited whole-cell ATP-sensitive K-currents half-maximally at 18 mumol/l; the sensitivity to tolbutamide was somewhat less in the inside-out patch. Ca-activated K-channels were unaffected by tolbutamide (10 mmol/l). These results resemble those found for rodent B cells and suggest that sulphonylureas exert their therapeutic effects in Type 2 (non-insulin dependent) diabetes by inhibition of the ATP-sensitive K-channel.
This study reports photopic spectral sensitivity curves (351-709 nm) for four individual roach, Rutilus rutilus, determined by two choice appetitive training. All four curves show four sensitivity maxima at 361-398 nm, 421-448 nm, 501-544 nm and 634-666 nm which are related to the four known roach photopic visual pigments (Avery et al. 1982). The overall shape of the curves at long wavelengths indicates inhibitory interactions between the red and green cone mechanisms. That the high behavioural sensitivity in the UV is caused by a specific ultraviolet visual pigment and is not due to aberrant stimulation of the other cone types is shown by the redetermination of spectral sensitivity at short wavelengths (351-501 nM) following the selective bleaching of the three longer wavelength visual pigments. This depresses the blue sensitivity to a greater degree than the relatively unaffected UV sensitivity maximum. Spectral transmission data from two corneas and four lenses show that they transmit considerable amounts of light in the near UV.
Leucocytes from human peripheral blood were acid eluted and sensitized in vitro with increasing concentrations of radiolabelled myeloma IgE. This sensitization step was performed with or without 30% IgE depleted serum. After the IgE binding, cells were washed and submitted to a challenge with monoclonal anti-IgE for the determination of the cellular sensitivity and reactivity in a histamine release assay. A sample of each of the sensitized cells was analyzed for its radioactivity and the number of basophils quantified, thus allowing the determination of the mean number of IgE molecules per basophil. Raising the IgE concentrations in the sensitization procedure led to an increase of the IgE on the basophil membrane, and to a concomitant elevation of the cell sensitivity. The presence of serum during the binding of IgE onto the cells lowers slightly the binding of IgE to the basophils but decreases strongly the cellular reactivity.
AIMS/HYPOTHESIS: The aim of this prospective study was to investigate predictors of deteriorating glucose tolerance in subjects of British extraction. METHODS: A total of 156 non-diabetic subjects (86 with a family history of type 2 diabetes) underwent a 75-g OGTT and anthropometric assessment at baseline and 5 years later. Pancreatic beta cell function and whole-body insulin sensitivity were studied by model assessment. Subjects were classified as progressors if glucose tolerance moved one or more steps from normal, impaired fasting glucose, impaired glucose tolerance and diabetes over the follow-up period. RESULTS: At baseline, the progressors (n=22) had increased adiposity and a higher proportion of familial diabetes and abnormal glucose tolerance than non-progressors. Baseline pancreatic beta cell sensitivity to changes in glucose (p<0.02) and whole-body insulin sensitivity (p<0.0001) were decreased in the progressors. Logistic regression revealed that baseline and follow-up changes in beta cell glucose sensitivity and insulin sensitivity, rather than the classical clinical predictors (adiposity, familial diabetes and glucose levels), were the key independent predictors of progression (explaining over 50% of the progression). CONCLUSIONS/INTERPRETATION: Impaired pancreatic beta cell glucose sensing and whole-body insulin sensitivity predict progression to hyperglycaemia. Strikingly, these pathophysiological changes override the importance of the clinical risk factors and highlight potential metabolic targets for prevention strategies.
RATIONALE: Vulnerability for development of substance abuse is often associated with a "sensation-seeking" or "thrill-seeking" phenotype. In an animal model, rats more reactive in a novel environment (high responders, HR) are more sensitive to stimulant/reinforcing effects of amphetamine and are more likely to self-administer this drug, than are less reactive animals (low responders, LR). OBJECTIVE: We tested whether HR and LR also differ in sensitivity to effects of morphine on locomotor activity. METHODS: Male Sprague-Dawley rats were categorized as HR or LR based on motor responses to novelty (sorting day; S). After 1 day (B) of baseline activity measurements, subjects were tested daily after SC injections of either morphine (10 mg/kg) or saline for 7 days and again on day 10. Beginning 5 days later, four daily injections of saline and 1.0-10 mg/kg morphine were tested in all animals. RESULTS: LR and HR were similar in the onset and overall magnitude of sensitization and tolerance following daily morphine administration. HR were more sensitive than LR to locomotor stimulant effects of acute morphine. However, LR had more robust and persistent context-specific increases in activity due to conditioning than did HR, and expression of sensitization was apparent in all behavioral variables. CONCLUSIONS: These results provide further evidence that phenotypic differences between HR and LR may, in part, be associated with differences in the endogenous opioid systems. Differences in sensitivity to acute versus repeated morphine suggest that at least in relation to opioid drugs, these phenotypes may reflect different aspects of drug vulnerability rather than simply the presence or absence of it.
Rhythmic electrical stimulation of the snail foot leads to sensitization of the defensive reflex. This sensitization has dynamics similar to those of posttetanic potentiation of the amplitude of the acetylcholine-evoked influx current of defensive behavior command neurons in the common snail. It is likely that an increase in the cholinosensitivity of the somatic membrane of defensive behavior command neurons in the common snail may be involved in the mechanism of sensitization of the animal's defensive response. Methiothepin, an antagonist of serotonin receptors, prevented the posttetanic potentiation of the acetylcholine-evoked influx current as well as behavioral sensitization. Serotonin, like methiothepin, also impaired posttetanic potentiation of the acetylcholine-evoked influx current. It is suggested that methiothepin-sensitive serotonin receptors are involved in the postsynaptic mechanism of behavioral sensitization.
Mouse 3T3 fibroblasts have a loop diuretic sensitive Na+ transport system, responsible for more than 50% of the total Na+ influx. This transport system is dependent on the simultaneous presence of all three ions; Na+, K+, (Rb+) and Cl- in the extracellular medium. The same requirement for these three ions was also found for the loop diuretic-sensitive K+ efflux. In addition, the sensitivities of Na+ influx and Rb+ efflux for the two loop diuretics, furosemide and bumetanide were found to be similar. The similar ionic requirement and sensitivity towards loop diuretics of the two fluxes, support the hypothesis, that this loop diuretic-sensitive Na+ influx in mouse 3T3 cells, is accompanied by the net loop diuretic-sensitive K+ efflux.
Recent reports suggest that lower levels of chloroquine accumulation in chloroquine-resistant isolates of Plasmodium falciparum are achieved by energy-dependent chloroquine efflux from resistant parasites. In support of this argument, a rapid chloroquine efflux phenotype has been observed in some chloroquine-resistant isolates of P. falciparum. In this study, no relationship was found between chloroquine sensitivity and the rate of [3H]chloroquine efflux from four isolates of P. falciparum with a greater than 10-fold range in sensitivity to chloroquine. All the isolates tested displayed the rapid efflux phenotype, irrespective of sensitivity. However, chloroquine sensitivity of these isolates was correlated with energy-dependent rate of drug accumulation into these parasites. Verapamil and a variety of other compounds reverse chloroquine resistance. The reversal mechanism is assumed to result from competition between verapamil and chloroquine for efflux protein translocation sites, thus causing an increase in steady-state accumulation of chloroquine and hence a return to sensitivity. Verapamil accumulation at a steady-state is increased by chloroquine, possibly indicating competition for efflux of the two substrates. Increases in steady-state verapamil concentrations caused by chloroquine were identical in sensitive and resistant strains, suggesting that similar capacity efflux pumps may exist in these isolates. These data suggest that differences in steady-state chloroquine accumulation seen in these isolates can be attributed to changes in the chloroquine concentrating mechanism rather than the efflux pump. It seems likely that chloroquine resistance generally in P. falciparum, results at least in part from a change in the drug concentrating mechanism and that changes in efflux rates per se are insufficient to explain chloroquine resistance.
The sensitivity of Na+ channels to inhibition by Cd2+ and Zn2+ was studied in 22Na+ uptake experiments after stabilization of an open conformation of the Na+ channels with different neurotoxins and in voltage clamp experiments. Six different cell types of neuronal, cardiac or skeletal muscle origin were surveyed. Three cell types possess Na+ channels that are highly sensitive to tetrodotoxin (TTX) (Kd = 1-5 nM) and three possess Na+ channels that are resistant to TTX (Kd = 0.3-1 microM). The 22Na+ uptake experiments using veratridine or batrachotoxin to activate Na+ channels indicated that TTX-resistant Na+ channels are more sensitive to the inhibitory action of Cd2+ (IC50(Cd2+) = 0.2 mM) and of Zn2+ (IC50(Zn2+) = 50 microM) than TTX-sensitive Na+ channels (IC50(Cd2+) = 5 mM, IC50(Zn2+) = 2 mM). Electrophysiological experiments showed that high concentrations of Cd2+ (IC50 = 2 mM) are necessary to inhibit both TTX-sensitive and TTX-insensitive Na+ channels when the channels are activated by voltage steps. The results suggest that Cd2+ acts competitively with veratridine or batrachotoxin and that the difference in the effects of Cd2+ and Zn2+ on 22Na+ fluxes in TTX-sensitive and TTX-resistant cells is related to differences at the site of action of alkaloid neurotoxins.
Three major ion transport systems, the nitrendipine-sensitive Ca2+ channels, the tetrodotoxin-sensitive Na+ channel and the ouabain-sensitive (Na+ + K+)-ATPase, have been studied in skeletal muscle from rat and chick after chronic denervation. It is shown that the situation found for the Ca2+ channel differs dramatically from that found for the Na+ channel and the (Na+ + K+)-ATPase and that regulation of the nitrendipine-sensitive Ca2+ channel in denervated muscle also differs widely from that of the tetrodotoxin-sensitive Na+ channel and the ouabain-sensitive (Na+ + K+)-ATPase which show a quite similar evolution.
Using microfluorometry of quin 2, a Ca2+-sensitive dye, we characterized the release and uptake of Ca2+ by the norepinephrine-sensitive Ca2+-storage site and the caffeine-sensitive one. The norepinephrine-sensitive Ca2+-storage site was readily depleted in Ca2+-free medium and almost completely replenished by loading with 1.0 mM Ca2+ solution for 3 min, whereas the caffeine-sensitive site was scarcely affected. Furthermore, norepinephrine has little effect on the caffeine-sensitive Ca2+-storage site in Ca2+-free medium, and vice versa. We conclude that the location and mechanisms of release and uptake of Ca2+ of these two Ca2+-storage sites differ in the case of rat aortic vascular smooth muscle cells in primary culture.
We investigated larval sensitivity to UV and repair of UV- and X-ray-induced lesions in the DNA of the ebony strain compared to a wild-type strain (Canton S). The ebony strain was previously characterized as being more sensitive to UV-induced killing of embryos than Canton S. Also the ebony strain is more sensitive to X-rays for induction of larval killing, dominant lethals and recessive lethals. In this paper it is demonstrated that (1) ebony larvae are more sensitive to killing by UV and less proficient in photoreactivation (PR) ability than Canton S larvae; (2) the ebony strain has a defect in PR repair of endonuclease-sensitive sites induced in the DNA of primary cell cultures by UV irradiation; (3) the ebony strain has a defect in the repair of single-strand breaks induced in the DNA by X-rays (again in primary cell cultures), at least early on in the repair incubation. A rough localization of the UV sensitivity and the PR ability is presented and the possible relevance of the biochemical to the genetic results is discussed.