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PubMed1990

Hypothalamic warm-sensitive neurons possess a tetrodotoxin-sensitive sodium channel with a high Q10.

We have investigated the ionic current responses to temperature of dissociated cells from the preoptic and anterior hypothalamus (PO/AH) of rat, using the 'whole-cell' configuration. The majority of the recorded neurons showed a linear increase in a non-inactivating inward current during warming (30-40 degrees C), and the Q10 was about 2. However, about 24% of PO/AH neurons were markedly sensitive to warming and the increase in non-inactivating inward current to a rise in temperature in the hyperthermic range (35-40 degrees C) had a high Q10 (4.3-7.0). This increase in current in the hyperthermic range was reversibly blocked by tetrodotoxin (TTX). The inward current in neurons with a Q10 of 2 was not affected by TTX. The results show that some neurons in the PO/AH possess a non-inactivating sodium channel that is highly temperature-sensitive in the hyperthermic range. These neurons are presumably the 'primary' warm-sensitive neurons.

Action Potentials↗
PubMed1982

Cytotoxic T lymphocytes directed against HLA-Bw 35-linked target determinants show differences in sensitivity toward antibiotics during sensitization period.

Recently, we demonstrated that the outcome of human CML was influenced by the presence of antibiotics in the culture medium, In earlier studies we had found that cytotoxic T lymphocytes could recognize HLA-Bw 35-linked target determinants. These so-called Bw35 a and b determinants showed mendelian segregation. We describe in this article a difference between the Bw35 a and b cytotoxic T cells in their sensitivity toward antibiotics. The lysis against the Bw35 b cytotoxic determinant was not influenced by either the presence or the absence of antibiotics during the sensitization period, whereas the lysis against the Bw35 a cytotoxic determinant was drastically diminished when the effector cells were cultured in the absence of antibiotics during the sensitization period.

Anti-Bacterial Agents↗
PubMed1984

Convergence of hepatoportal glucose-sensitive afferent signals to glucose-sensitive units within the nucleus of the solitary tract.

Units which are activated by ascending impulses from the liver within the nucleus of the solitary tract (NTS) were identified by electrical stimulation delivered to the hepatic branch of the vagus. Responses of descending units were eliminated by a collision test. The units which showed decreased firing rates during portal infusion of isotonic glucose solution were also glucose-sensitive so that they showed decreased firing rates during topical application of glucose by means of micro-electro-osmotic techniques. It is concluded that glucose-sensitive neurons exist within the NTS and also that they are functionally linked with hepatoportal glucose-sensitive afferent units.

Animals↗
PubMed1988

A cell line with decreased sensitivity to the methyl mercury-induced stimulation of alpha-amanitin sensitive RNA synthesis in isolated nuclei.

1. In nuclei isolated from cells of the B50 rat neuroblastoma line the stimulatory effect of methyl mercury on alpha-amanitin-sensitive RNA synthesis is very much reduced compared to the stimulatory effect in HeLa nuclei (see: Frenkel G. D. and Randles K. (1982) Specific stimulation of alpha-amanitin-sensitive RNA synthesis in isolated HeLa nuclei by methyl mercury. J. biol. Chem. 257, 6275-6279). 2. The stimulatory effect of another mercury compound, p-hydroxymercuribenzoate, was also much less pronounced in the B50 nuclei. 3. Similar results were obtained with nuclei isolated from B50 cells which had been induced to differentiate by exposure to dibutaryl cyclic AMP. 4. Nuclei isolated from cells of another rat neuroblastoma line (B35), and nuclei from cells of a human neuroblastoma line both exhibited levels of stimulation similar to that of HeLa nuclei. 5. The B50 and HeLa cells were also compared as to their sensitivity to other effects of methyl mercury.

Amanitins↗
PubMed1990

DNA-break repair, radioresistance of DNA synthesis, and camptothecin sensitivity in the radiation-sensitive irs mutants: comparisons to ataxia-telangiectasia cells.

Induction and rejoining of DNA single-strand breaks (ssb) and double-strand breaks (dsb) after gamma-irradiation were measured, respectively, by alkaline and neutral sucrose gradient sedimentation methods. The radiosensitive mutants irs1, irs2, and irs3 showed no significant difference from wild-type V79 hamster cells in ability to rejoin either ssb or dsb, while the previously-described xrs-1 mutant showed the expected defect in rejoining dsb. The resistance of DNA synthesis to gamma-irradiation was measured in the 3 irs mutants and, for comparative purposes, in transformed human cell lines from normal and ataxia-telangiectasia (A-T) individuals. The irs2 mutant was found to be very similar in response to the A-T lines, showing a marked decrease in inhibition of DNA synthesis, compared to V79 cells, in both time-course and dose-response experiments. However, irs1 also had some decrease in inhibition at the higher doses used, while irs3 was similar to the wild-type V79 cells. Both irs1 and irs2 were found to be considerably more sensitive to the DNA topoisomerase I-inhibitor camptothecin, while irs3 was only slightly more sensitive than the parent V79 line. These data place the irs mutants in a similar category of radiosensitive phenotype to A-T cells, but we view this as only the beginning of a useful classification of this type of mutant. The irs2 mutant has the strongest links to A-T cells, through its sensitivity profile to DNA-damaging agents and radioresistant DNA synthesis, but irs1 in particular has other similarities to A-T.

Animals↗
PubMed2006

Evaluating anxiety sensitivity and other fundamental sensitivities predicting anxiety symptoms and fearful responding to a biological challenge.

Fear of arousal symptoms, often referred to as anxiety sensitivity (AS), appears to be associated with risk for anxiety pathology and other Axis I conditions. However, AS is only one of three fundamental components of Reiss' Expectancy Model proposed to account for the development of anxiety problems. Very little research has focused on the other two components of this model (Fear of Negative Evaluation, Illness/Injury Sensitivity) and the specificity of AS, relative to these other two components, has rarely been evaluated. This study evaluated general and unique associations among all three so-called fundamental sensitivities to fearful responding to a biological challenge in a nonclinical sample (N=404). Participants were administered a 20-s inhalation of 20% CO2/balance O2. Consistent with hypothesis, only AS uniquely contributed to increased subjective fear responding to the challenge. These findings are consistent with Expectancy Theory in suggesting that the AS component of the model is specific to amplification of fears to arousal cues.

Adolescent↗
PubMed2006

Differences in pharmacokinetic and electroencephalographic responses to caffeine in sleep-sensitive and non-sensitive subjects.

The present study investigated pharmacokinetic and electroencephalographic responses to caffeine (140 mg) in two groups of healthy volunteers reporting, or not, caffeine-related sleep disturbances. Significant differences in caffeine consumption and smoking habits were observed between the two groups. Plasma samples were taken from each subject before (T0) and after caffeine intake at 0.5, 1, 2, 4, 6 and 24 h. Three pharmacokinetic parameters: half-life (t1/2), maximum time (Tmax) and maximum plasma concentration (Cmax) were calculated from caffeine plasma concentration measurements determined by reversed phase HPLC analysis. Caffeine-sensitive subjects showed significantly greater half-life values when calculated on 24 h after the administration than tolerant subjects (p<0.05). Since the elimination kinetics were similar on the first 6 h after caffeine administration, the increased caffeine clearance observed overnight, when smoking was resumed in the control group, may indicate a short delay for the induction of hepatic cytochrome, reported here for the first time. Electrophysiological responses to caffeine, including vigilance and cortical activity, were assessed by ambulatory electroencephalographic (EEG) recorded during a period of 6 h before and after caffeine consumption. Following caffeine intake, the caffeine-intolerant subjects presented an increase in vigilance levels with faster peak alpha, beta frequency and lower delta and theta power when compared to tolerant subjects. Pharmacokinetic parameters and EEG data showed significant differences between sleep-sensitive and control subjects. These variations may be, in part, explained by cigarette smoking and the higher caffeine intake observed in the subjects of the control groups while caffeine sleep-sensitive subjects have a significantly lower caffeine intake, as already reported in previous studies on patients with sleep disturbances.

Adult↗
PubMed2006

Validation of a mouse model of chemical-induced asthma using trimellitic anhydride, a respiratory sensitizer, and dinitrochlorobenzene, a dermal sensitizer.

BACKGROUND: Occupational asthma can be caused by chemicals. Previously, we established a murine model of immunologically mediated chemical-induced asthma using toluene diisocyanate. OBJECTIVE: We sought to verify this model using trimellitic anhydride (TMA), a respiratory sensitizer, and 1-chloro-2,4-dinitrobenzene (DNCB), a dermal sensitizer. METHODS: BALB/c mice received dermal applications (vehicle or chemical) on days 1 and 7. On day 10, they received an intranasal instillation (vehicle or chemical). Whole-body plethysmography (enhanced pause) was used to monitor changes in ventilatory function and methacholine reactivity. Pulmonary inflammation was assessed by using bronchoalveolar lavage (cells, TNF-alpha levels, and macrophage inflammatory protein 2 levels). Immunologic parameters included total serum IgE levels, lymphocyte distribution in auricular and cervical lymph nodes, and IL-4 and IFN-gamma levels in supernatants of lymph node cells incubated with or without concanavalin A. RESULTS: Mice dermally treated and intranasally challenged with TMA experienced markedly increased enhanced pause immediately after intranasal challenge and increased methacholine reactivity (24 hours later). Mice similarly treated with DNCB did not show any ventilatory changes. Neutrophil influx and increased macrophage inflammatory protein 2 and TNF-alpha levels were found in bronchoalveolar lavage fluid in both TMA- and DNCB-treated mice. The proportion of CD19+ B cells was increased in auricular and cervical lymph nodes of TMA-treated mice. IL-4 and IFN-gamma levels were increased in supernatants of concanavalin A-stimulated auricular and cervical lymph node cells of TMA- or DNCB-treated mice; however, the relative proportions of IL-4 and IFN-gamma levels differed between TMA- and DNCB-treated mice. Serum total IgE levels were increased in TMA-treated mice only. CONCLUSION: Both compounds induce a mixed T(H)1-T(H)2 response, but only TMA induced ventilatory changes. CLINICAL IMPLICATIONS: In the workplace avoiding skin contact with chemical sensitizers might be advised to prevent chemical-induced asthma.

Allergens↗
PubMed2005

Evaluation of pressor sensitivity to norepinephrine infusion in dogs with iatrogenic hyperadrenocorticism. Pressor sensitivity in dogs with hyperadrenocorticism.

Hypertension is a common complication of canine hyperadrenocorticism. Increased pressor sensitivity to endogenous catecholamines is currently believed to be the main mechanism involved in the development of hypertension in human hyperadrenocorticism. The aim of this study was to evaluate pressor sensitivity to norepinephrine in dogs after induction of iatrogenic hyperadrenocorticism (I-HAC) by serial arterial blood pressure measurements during infusions of increasing dose rates of norepinephrine (0.1, 0.15, 0.2, 0.3, 0.4, 0.6, and 0.8 microg/kg/min) in eight dogs with I-HAC and eight control dogs. Systolic, diastolic, mean blood pressure and heart rate measurements were recorded. The changes in these parameters between the two groups of dogs were compared. Dogs in the I-HAC group had a more pronounced pressor response to norepinephrine infusions than control dogs since the infusions had to be stopped in seven of the dogs due to severe hypertension (>240 mmHg). The mean maximum tolerated dose rate in the control group was 0.6 microg/kg/min with a standard error of 0.0 and 0.34 microg/kg/min with a standard error of 0.08 in the I-HAC group. The study demonstrated the presence of increased pressor sensitivity to norepinephrine in dogs with I-HAC.

Adrenocortical Hyperfunction↗
PubMed1999

TTX-sensitive Na(+) and nifedipine-sensitive Ca(2+) channels in rat vas deferens smooth muscle cells.

The inward currents in single smooth muscle cells (SMC) isolated from epididymal part of rat vas deferens have been studied using whole-cell patch-clamp method. Depolarising steps from holding potential -90 mV evoked inward current with fast and slow components. The component with slow activation possessed voltage-dependent and pharmacological properties characteristic for Ca(2+) current carried through L-type calcium channels (I(Ca)). The fast component of inward current was activated at around -40 mV, reached its peak at 0 mV, and disappeared upon removal of Na ions from bath solution. This current was blocked in dose-dependent manner by tetrodotoxin (TTX) with an apparent dissociation constant of 6.7 nM. On the basis of voltage-dependent characteristics, TTX sensitivity of fast component of inward current and its disappearance in Na-free solution it is suggested that this current is TTX-sensitive depolarisation activated sodium current (I(Na)). Cell dialysis with a pipette solution containing no macroergic compounds resulted in significant inhibition of I(Ca) (depression of peak I(Ca) by about 81% was observed by 13 min of dialysis), while I(Na) remained unaffected during 50 min of dialysis. These data draw first evidence for the existence of TTX-sensitive Na(+) current in single SMC isolated from rat vas deferens. These Na(+) channels do not appear to be regulated by a phosphorylation process under resting conditions.

Animals↗
PubMed1976

The effect of intrauterinely injected lymphocytes prepared from sensitized or non-sensitized guinea-pigs on the ultrastructure of rat fetal membranes (visceral yolk sac).

The susceptibility of rat fetal membranes (visceral yolk sac) to cell-mediated immunity was studied electron microscopically at day 19 of pregnancy. For this purpose guinea-pigs were sensitized to rat placental antigens and the activated lymphocytes were injected intrauterinely. Simultaneously, the effect of lymphocytes from non-sensitized guinea-pigs was examined on the rat yolk sac. Lymphocytes from sensitized guinea-pigs revealed a clear cytotoxic effect on the visceral yolk sac, but the degree of cell destruction showed marked differences from one epithelial cell to the other. Furthermore, the yolk sac regionally displayed great differences in the intensity of immune cytolysis...

Animals↗
PubMed1989

Endothelin-sensitive intracellular Ca2+ store overlaps with caffeine-sensitive one in rat aortic smooth muscle cells in primary cultures.

We made use of quin2 microfluorometry to determine the effects of endothelin (ET) on cytosolic free Ca2+ concentrations [Ca2+]i) in rat aortic smooth muscle cells in primary culture. In Ca2+-containing medium, ET induced a rapid and sustained elevation of [Ca2+]i. In the latter component, in particular, the elevation of [Ca2+]i was inhibited by diltiazem. In Ca2+-free medium, ET induced a rapid and transient [Ca2+]i elevation, which was not inhibited by diltiazem. When the caffeine-sensitive intracellular Ca2+ store was practically depleted by repeated treatment with caffeine in Ca2+-free media, ET did not elevate [Ca2+]i. Thus, it was suggested that ET induces [Ca2+]i elevation not only by extracellular Ca2+-dependent, mechanisms but also by releasing Ca2+ from the intracellular store, and that the ET-sensitive Ca2+ store may overlap with the caffeine-sensitive one, in cultured vascular smooth muscle cells.

Aminoquinolines↗
PubMed1998

Differential sensitivity to ATP-sensitive potassium channel openers of norepinephrine-induced contraction of guinea pig and rat aorta.

Vasorelaxant effects of ATP-sensitive potassium (K(ATP)) channel openers were examined on the tonic phase of vascular contraction induced by norepinephrine (NE) in guinea pig and rat aorta. K(ATP) channel openers, NIP-121 and cromakalim, produced glibenclamide-sensitive and concentration-dependent relaxations in guinea pig and rat aorta preconstricted with NE. However, the vascular relaxations induced by both K(ATP) channel openers were less pronounced in guinea pig aorta than in rat aorta. D-cis-Diltiazem, at the concentration up to 10(-5) M, did not appreciably inhibit the NE-induced contraction of guinea pig aorta, whereas the compound almost completely inhibited the NE-induced contraction of rat aorta at the same concentration. By contrast, sodium nitroprusside relaxed the NE-induced contractions in both guinea pig and rat aorta with similar potencies. These findings suggest that vasorelaxant effects of K(ATP) channel openers on the NE-induced sustained contraction in guinea pig aorta is not attributable to the subsequent inhibition of Ca2+ influx through L-type voltage-gated Ca2+ channels. Lower sensitivity of guinea pig aortic smooth muscle to K(ATP) channel openers is most likely due to the low dependence of NE-induced contraction on the Ca2+ influx in this vascular smooth muscle.

Adenosine Triphosphate↗
PubMed1999

The spectral sensitivity of the human short-wavelength sensitive cones derived from thresholds and color matches.

We used two methods to estimate short-wave (S) cone spectral sensitivity. Firstly, we measured S-cone thresholds centrally and peripherally in five trichromats, and in three blue-cone monochromats, who lack functioning middle-wave (M) and long-wave (L) cones. Secondly, we analyzed standard color-matching data. Both methods yielded equivalent results, on the basis of which we propose new S-cone spectral sensitivity functions. At short and middle-wavelengths, our measurements are consistent with the color matching data of Stiles and Burch (1955, Optica Acta, 2, 168-181; 1959, Optica Acta, 6, 1-26), and other psychophysically measured functions, such as pi 3 (Stiles, 1953, Coloquio sobre problemas opticos de la vision, 1, 65-103). At longer wavelengths, S-cone sensitivity has previously been over-estimated.

Color Perception↗
PubMed1990

Salsalate cross-sensitivity in aspirin-sensitive patients with asthma.

Ten aspirin (ASA)-sensitive patients with asthma underwent double-blind, placebo-controlled oral challenges with salsalate followed by ASA-sensitive confirmatory challenges. All 10 patients sustained asthmatic reactions to ASA, but only two developed respiratory reactions to 2 gm of salsalate. In these two patients, repeat confirmatory challenges with 2 gm of salsalate reproduced the same asthmatic reactions. Both patients were desensitized to ASA, and cross-desensitization with 2 gm of salsalate was then achieved. We conclude that salsalate, a weak inhibitor of cyclooxygenase in vitro, is less likely than ASA to induce asthma in known ASA-sensitive patients with asthma but may occasionally cross-react in these patients. Such reactions were mild and easily treated with beta 2-agonists.

Acetaminophen↗
PubMed1999

IgE sensitivity and cross-reactivity to crude and purified mite allergens (Der f 1, Der f 2, Der p 1, Der p 2) in atopic dogs sensitive to Dermatophagoides mite allergens.

The present study investigates IgE-reactivity to crude and purified mite allergens by intradermal skin test (IDST), Immunodot method, and ELISA in atopic dogs sensitive to mite allergens, as well as the allergenic cross-reactivity between Dermatophgoides (D) farinae (DF) and D. pteronyssinus (DP) in dogs by IgE-ELISA inhibition. IDST and Immunodot method for crude mite allergens were performed for atopic dogs and 16 atopic dogs showed sensitivity to mite allergens. Of the 16 dogs, all dogs had anti-DF IgE and 11 had anti-DP IgE. We measured specific IgE to purified major allergens (Der f 1, Der f 2, Der p 1, Der p 2). Of the 16 atopic dogs, six had anti-Der f 1 IgE and seven had anti-Der f 2 IgE. Similarly, of the 16 dogs, six had anti-Der p 1 IgE and seven had anti-Der p 2 IgE. However, eight dogs had no specific IgE to these mite allergens. These dogs may be sensitive to other major mite allergens except Der 1 and Der 2. In the dogs that had both anti-DF and DP IgE, IgE binding to DF was greatly inhibited by DP, and reciprocal inhibition was observed. Based on these data, it appears that there is a strong cross-reactivity between DF and DP in dogs. Similarly, a cross-reactivity between DF and DP in purified allergens was also observed. IDST and Immunodot method are useful methods for the diagnosis of atopic diseases in dogs, and ELISA is a useful method for further investigation of IgE-reactivity for the allergens.

Allergens↗
PubMed2002

Insulin sensitivity in type 2 diabetes: univariate and multivariate techniques to derive estimates of insulin sensitivity from the insulin modified intravenous glucose tolerance test (FSIGT).

The use of univariate and multivariate techniques to derive estimates of insulin sensitivity from the insulin modified FSIGT were investigated in 12 Type 2 diabetic subjects aged (mean+/-S.D.) 59+/-9.5 years and BMI 28.1+/-2.2 kg m(-2), who underwent both a FSIGT and an isoglycemic hyperinsulinemic clamp. Reproducibility of the FSIGT was tested in four patients on three separate occasions. FSIGT data were assessed by both univariate and multivariate techniques. The sensitivity index for the FSIGT ranged from 0.162 to 3.292 (mean 1.378) x 10(-4) x l min(-1) mU(-1) for the univariate approach and from 0.163 to 2.727 (mean 1.378) x 10(-4) x l min(-1) mU(-1) for the multivariate method. Mean S(Iclamp) was 44.41 x 10(-4) x l(-2) min(-1) x mU(-1) (range 22.0-77.92). The correlation of the insulin sensitivity indices between the clamp and the FSIGT was 0.51 (P=0.056) for the univariate and 0.67 (P=0.017) for the multivariate analyses. Repeated FSIGTs showed a lower variability for the multivariate than for the standard approach.

Aged↗
PubMedDate not supplied

An influenza A live attenuated reassortant virus possessing three temperature-sensitive mutations in the PB2 polymerase gene rapidly loses temperature sensitivity following replication in hamsters.

The purpose of the present study was to produce an influenza A H2N2 donor virus from which an attenuating PB2 gene bearing three discrete temperature sensitive (ts) mutations could be readily transferred to currently epidemic influenza A H1N1 and H3N2 viruses via genetic reassortment. An influenza A transfectant virus was first produced that contained site-directed ts mutations at amino acids 112, 265, and 556 in the PB2 gene of influenza A/AA/60 virus origin in a background of the other seven RNA segments from the influenza A/LA/87 (H3N2) virus. The A/LA/87 PB2 ts transfectant virus (clone 22B1) was mated with the A/AA/60 (H2N2) wild type virus, and six H2N2 ts reassortants were obtained. One reassortant virus, clone 25A1, possessed the triple ts PB2 gene in the context of all seven other genes of homologous A/AA/60 origin. Isolation of this reassortant permitted an examination of the contribution of the ts mutations present in a triple ts PB2 transfectant virus to its attenuation and phenotypic stability independent from an effect of the A/AA/60-A/LA/87 gene constellation on attenuation. It was found that the A/AA/60 triple ts reassortant virus was less ts, less attenuated, and less phenotypically stable than the A/LA/87 triple ts transfectant virus from which it was derived. The A/AA/60 reassortant possessing the PB2 gene containing three introduced ts mutations underwent rapid and significant loss of its temperature sensitivity following replication in the lungs of immunocompetent hamsters. This indicated that the A/AA/60-A/LA/87 gene constellation contributed significantly to the overall level of temperature-sensitivity, attenuation, and stability of the A/LA/87 triple ts transfectant virus. It is likely that the instability of the ts phenotype exhibited by the A/AA/60 triple ts reassortant virus would not be acceptable for a vaccine to be used in humans. The implications of these findings for the usefulness of ts mutations as the sole attenuating mutation in influenza virus vaccines is discussed.

Animals↗