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PubMed1996

Calcium influx into human neuroblastoma cells induces ALZ-50 immunoreactivity: involvement of calpain-mediated hydrolysis of protein kinase C.

Calcium influx into SH-SY5Y human neuroblastoma cells after ionophore treatment or transient permeabilization in calcium-containing medium increased ALZ-50 immunoreactivity markedly. This increase was prevented by inhibitors active against calpain or against protein kinase C (PKC), suggesting that both of these enzymes were required to mediate the effect of calcium influx on ALZ-50 immunoreactivity. Treatment with PKC activator TPA increased ALZ-50 immunoreactivity in the absence of calcium influx or after intracellular delivery of the specific calpain inhibitor calpastatin, indicating that the influence of PKC was downstream from that of calpain. Calcium influx also resulted in mu-calpain autolysis (one index of calpain activation) and the transient appearance of PKM (i.e., free PKC catalytic subunits, generated by calpain-mediated cleavage of the regulatory and catalytic PKC domains). Inhibition of calpain within intact cells resulted in a dramatic increase in steady-state levels of total tau (migrating at 46-52 kDa) but resulted in a relatively minor increase in 68-kDa ALZ-50-immunoreactive tau isoforms. Although calcium influx into intact cells resulted in accumulation of ALZ-50 immunoreactivity, total tau levels were, by contrast, rapidly depleted. Incubation of isolated fractions with calpain in the presence of calcium indicated that ALZ-50-immunoreactive tau isoforms were more resistant to calpain-mediated proteolysis than were non-ALZ-50 reactive tau isoforms. These data therefore indicate that calpain may regulate tau levels directly via proteolysis and indirectly through PKC activation. A consequence of the latter action is altered tau phosphorylation, perhaps involving one or more kinase cascades, and the preferential accumulation of ALZ-50-immunoreactive tau isoforms due to their relative resistance to degradation. These findings provide a basis for the possibility that disregulation of calcium homeostasis may contribute to the pathological levels of conversion of tau to A68 by hyperactivation of the calpain/PKC system.

Antigens↗

PubMed2001

Electrophysiologic perturbations and arrhythmogenic activity caused by activation of the Fas receptor in murine ventricular myocytes: role of the inositol trisphosphate pathway.

INTRODUCTION: Experimental evidence suggests a major role for Fas receptor activation in a wide range of myocardial pathologies. Because clinical situations, which are likely to be associated with Fas activation, are accompanied by a variety of ventricular arrhythmias, the major goal of this study was to investigate the ionic mechanisms responsible for these phenomena. METHODS AND RESULTS: To delineate the origin of Fas-mediated electrophysiologic perturbations, the transient outward K+ current I(to) and the L-type Ca2+ current I(Ca,L) were studied in murine ventricular myocytes treated with the Fas-activating monoclonal antibody Jo2. Jo2 decreased I(to) (4.36 +/- 1.2 pA/pF vs 17.48 +/- 2.36 pA/pF in control, V(M) = +50 mV; P < 0.001) and increased I(Ca,L) (-13.17 +/- 1.38 pA/pF vs -3.94 +/- 0.78 pA/pF in control, V(M) = 0 mV; P < 0.001). Pretreatment of ventricular myocytes with ryanodine or thapsigargin prevented the electrophysiologic effects of Jo2, suggesting that [Ca2+]i elevation is important for Fas-mediated action. In agreement with our previous studies demonstrating dependence of Fas-based myocyte dysfunction on an intact inositol trisphosphate (1,4,5-IP3) pathway, the effects of Jo2 on I(to) and I(Ca,L) were prevented by the phospholipase C (generates 1,4,5-IP3) blocker U73122, and by xestospongin C (tested with I(to)), a specific blocker of IP3-operated sarcoplasmic reticulum Ca2+ release channels. Furthermore, intracellular perfusion with 1,4,5-IP3, but not with 1,3,4-IP3, caused electrophysiologic effects resembling those of Jo2. CONCLUSION: Decreased I(to) and increased I(Ca,L) underlie Fas-induced action potential alterations and arrhythmias in murine ventricular myocytes, effects that appear to be mediated by 1,4,5-IP3-induced intracellular calcium release.

Animals↗

PubMed1999

Cyclosporine A-induced prostacyclin release is maintained by extracellular calcium in rat aortic endothelial cells: role of protein kinase C.

Chronic treatment with the immunosuppressive drug Cyclosporine A (CsA) is associated with increased intracellular calcium in vascular smooth muscle cells, which may activate phospholipase A2. We used rat aortic endothelial cells to investigate the role of protein kinase C (PKC) in CsA-induced prostacyclin (PGI2) release. CsA (10(-9) M) produced a significant increase in PGI2 release. CsA-induced PGI2 release were inhibited 80-85% by 10(-9) M, and 99-100% by 10(-6) M pretreatment doses of any of three different PKC inhibitors, i.e. 1-(5-isoquinolinesulfonylmethyl)piperazine(H7), staurosporine or 1-(5-isoquinolinesulfonyl)piperazine. Pretreatment with (10(-9) M) of diltiazem (a voltage-sensitive L-type calcium channel blocker) completely inhibited both CsA-induced PGI2 release. Conversely, pretreatment with (10(-9) M) of thapsigargin (an intracellular calcium channel blocker) did not alter the action of CsA. These results strongly suggest that PKC, in association with an influx of extracellular calcium, mediates CsA-induced PGI2 release in rat aortic endothelial cells.

Animals↗

PubMedDate not supplied

Endocannabinoids in pain modulation.

Five major approaches have been employed to determine the role of endocannabinoids in pain modulation: (1) studies of various markers of endocannabinoid action aimed at determining whether the necessary cannabinoid biochemical machinery is present in those brain areas that control pain sensitivity; (2) administration of exogenous cannabinoids to determine whether endocannabinoid action at appropriate sites would lead to a loss of pain sensitivity; (3) administration of compounds that would affect endocannabinoid action such as antagonists and transport inhibitors to determine whether drug-induced preterbation of cannabinoid action would alter pain sensitivity; (4) studies of genetically altered animals aimed at determining whether pain responses or responses to cannabinergic drugs are altered; and (5) studies that measure the release of endocannabinoids. Converging evidence from each of these research areas indicates that endocannabinods function to control pain in parallel with endogenous opioids but via different mechanisms.

Animals↗

PubMed1991

Does estradiol treatment normalize the hypothalamic-pituitary-adrenal axis in streptozotocin-induced ovariectomized diabetic female rats?

We recently found circulating corticosterone (CS) levels to be significantly lower in diabetic female rats as compared with proestrous control animals. This reduction in CS was correlated with the hypoestrogenic state of the diabetic female. It was the purpose of this study to evaluate basal and corticotropin releasing hormone (CRH)-stimulated CS secretion in ovariectomized (OVX) control (C) and streptozotocin-induced diabetic (D) rats given blank, 5 mcg and 20 mcg estradiol (E2) implants to determine if adrenal CS secretion in the diabetic is normalized by E2 treatment. After 3 weeks of diabetes, pituitary-adrenal function was assessed in rats from each group with a CRH stimulation test. The remaining rats were sacrificed for determination of CS, E2, testosterone and fructosamine in serum. Suppressed CS secretion in OVX female diabetic rats was partially restored with E2 therapy. Basal CS levels were significantly higher in 20 mcg E2 treated C and D rats compared with OVX rats. However, C rats had significantly higher basal CS compared with D rats in similarly E2 treated groups. The CS response to CRH stimulation was not different between OVX female diabetic and control rats. Estrogen enhanced the CS response to CRH stimulation in control animals but not in diabetic animals suggesting altered estrogen action at the pituitary level in diabetic animals.

Adrenal Glands↗

PubMed1982

Propagation of satellite phage P4 as a plasmid.

Satellite phage P4 has two known options for propagation. In its lytic cycle, its regulatory functions can act in trans to alter the actions of a helper virus (P2), which then provides necessary gene products, including capsid proteins. P4 also can be propagated in the absence of a helper as a prophage, with distinct sites for integration within the Escherichia coli chromosome. We determined that a single spontaneous mutation (vir1) of phage P4 allows a third mode of propagation: as a plasmid (along with continued integration into the host chromosome). Hence, the P4 regulatory element is capable of (i) temperate; (ii) lytic, helper-dependent; and (iii) plasmid modes of development. These findings emphasize the close relationship between defective viruses and plasmids.

Cloning, Molecular↗

PubMed1982

Isolation of cloned cDNAs to auxin-responsive poly(A)RNAs of elongating soybean hypocotyl.

Auxin-responsive cDNA clones have been isolated from a cDNA library prepared from elongating soybean hypocotyl poly(A)(+)RNA. The expression of two such sequences has been assessed by RNA blot hybridization analyses during normal developmental transitions in the soybean hypocotyl and during incubation of sections excised from the region of cell elongation. The concentrations of these poly(A)(+)RNAs are higher in the elongating zone than in the apical and mature zones of the hypocotyl. Both poly(A)(+)RNAs are depleted during incubation of the sections in the absence of auxin. The loss of one of these sequences (pJCW1) is prevented by the addition of auxin to the incubation medium while the other sequence (pJCW2) increases above the initial level in the presence of auxin. The addition of auxin to auxin-depleted tissue in which the sequences are depleted results in rapid accumulation of these poly(A)(+)RNAs; pJCW1 accumulates to the control level while pJCW2 increases well above the control level. These data along with others [Baulcombe, D. C. & Key, J. L. (1980) J. Biol. Chem. 255, 8907-8913] demonstrate directly a highly selective effect of auxin on the expression of a small number of mRNAs in tissues undergoing both cell elongation and cell division in response to auxin. Although the data are suggestive of a close association betwen auxin action and altered gene expression, a causal relationship is not established. It seems highly unlikely, however, that such specific effects of auxin on gene expression are unimportant in auxin physiology.

Journal Article↗

PubMed1991

Evidence that somatostatin is localized and synthesized in lymphoid organs.

Because several peptides originally found in the pituitary as within the central nervous system have been localized in lymphoid tissues and because somatostatin (somatotropin-release-inhibiting hormone, SRIH) can act on cells of the immune system, we searched for this peptide in lymphoid organs. We demonstrated that SRIH mRNA exists in lymphoid tissue, albeit in smaller levels than in the periventricular region of the hypothalamus, the brain region that contains the highest level of this mRNA. SRIH mRNA was found in the spleen and thymus of male rats and in the spleen, thymus, and bursa of Fabricius of the chicken. Its localization in the bursa indicates that the peptide must be present in B lymphocytes since this is the site of origin of B lymphocytes in birds. The SRIH concentration in these lymphoid organs as determined by radioimmunoassay was greater in the thymus than in the spleen of the rat. These concentrations were 50 times less than those found in the periventricular region of the hypothalamus, the site of the perikarya of SRIH-containing neurons. In the chicken, as in the rat, the concentration of SRIH was greater in the thymus than in the spleen; it was present in the bursa of Fabricius, also in higher concentration than in the spleen. Fluorescence immunocytochemistry revealed the presence of SRIH-positive cells in clusters inside the white pulp and more dispersed within the red pulp of the spleen of both the rat and the chicken. The thymus from these species also contained SRIH-positive cells within the medulla and around the corticomedullary junction. In the chicken, there were large clusters of SRIH-positive cells in the medullary portion of each nodule of the bursa of Fabricius. Preabsorption of the primary antiserum or replacing this antiserum with normal rabbit serum verified the specificity of staining. Sequential immunostaining of the same sections from rat spleen using first SRIH antibody and subsequently a monoclonal antibody against a rat B-cell surface antigen revealed the presence of SRIH immunoreactivity in some, but not all, B cells. Other cell types in spleen not yet identified also stained positively with the SRIH antibody but were not reactive to monoclonal antibodies to rat Thy-1.1, a marker for all the thymic T lymphocytes. The possibility that SRIH is present in other populations of cells in the spleen cannot be ruled out. Sequential immunostaining of the same sections of rat thymus revealed the presence of SRIH immunoreactivity in a small population of T lymphocytes in the medulla, as revealed by the Thy-1.1 marker. The SRIH-positive cells were nonimmunoreactive when exposed to the B-cell marker; however, the possibility that SRIH is present in other cells was not investigated. Thus, our results indicate that SRIH is synthesized and stored in cells of the immune system. SRIH may be secreted from these cells to exert paracrine actions that alter the function of immune cells in spleen and thymus.

Animals↗

PubMed1999

Tumor necrosis factor-alpha mediates both apoptotic cell death and cell proliferation in a human hematopoietic cell line dependent on mitotic activity and receptor subtype expression.

The TF-1 human erythroleukemic cell line exhibits opposing physiological responses toward tumor necrosis factor-alpha (TNF) treatment, dependent upon the mitotic state of the cells. Mitotically active cells in log growth respond to TNF by rapidly undergoing apoptosis whereas TNF exposure stimulates cellular proliferation in mitotically quiescent cells. The concentration-dependent TNF-induced apoptosis was monitored by cellular metabolic activity and confirmed by both DNA epifluorescence and DNA fragmentation. Moreover, these responses could be detected by measuring extracellular acidification activity, enabling rapid prediction (within approximately 1.5 h of TNF treatment) of the fate of the cell in response to TNF. Growth factor resupplementation of quiescent cells, resulting in reactivation of cell cycling, altered TNF action from a proliferative stimulus to an apoptotic signal. Expression levels of the type II TNF receptor subtype (p75TNFR) were found to correlate with sensitivity to TNF-induced apoptosis. Pretreatment of log growth TF-1 cells with a neutralizing anti-p75TNFR monoclonal antibody inhibited TNF-induced apoptosis by greater than 80%. Studies utilizing TNF receptor subtype-specific TNF mutants and neutralizing antisera implicated p75TNFR in TNF-dependent apoptotic signaling. These data show a bifunctional physiological role for TNF in TF-1 cells that is dependent on mitotic activity and controlled by the p75TNFR.

Antigens, CD↗

PubMed2004

Direct stimulation of the lambdapaQ promoter by the transcription effector guanosine-3',5'-(bis)pyrophosphate in a defined in vitro system.

The bacterial response to nutritional deprivation, called the stringent response, results in the introduction of the specific nucleotide guanosine-3',5'-(bis) pyrophosphate (ppGpp). This nucleotide interacts with RNA polymerase and alters its action so that transcription from certain promoters is inhibited, whereas transcription from others seems to be activated. The exact mechanism of transcriptional stimulation by ppGpp in vivo remains unknown. A passive control model has been proposed according to which transcription inhibition during the stringent response at several very active promoters, like those for rRNA and tRNA genes, makes more free RNA polymerase (RNAP) molecules available for transcription at promoters with weak binding affinities for RNAP, thus leading to their passive activation. Among promoters whose transcription is activated by ppGpp in vivo is the histidine operon promoter (hisGp). However, in vitro it is only possible to demonstrate this effect in a coupled transcription-translation system. Here we demonstrate, using another in vivo ppGpp-stimulated promoter, the phage lambdapaQ promoter, that activation by ppGpp in a defined in vitro system is direct. A systematic study of ppGpp effects on the stimulation of paQ revealed that, as in the case of promoters inhibited by this nucleotide, ppGpp decreases the half-life of paQ open complexes. Our results also indicate that the equilibrium binding affinity of RNA polymerase to paQ seems not to be affected in the presence of ppGpp. Our data indicate that the mechanism underlying ppGpp stimulation of paQ is due to an increased rate of productive open complex formation.

DNA-Directed RNA Polymerases↗

PubMed2005

The tumor suppressor PTEN is necessary for human Sprouty 2-mediated inhibition of cell proliferation.

Sprouty family proteins are novel regulators of growth factor actions. Human Sprouty 2 (hSPRY2) inhibits the proliferation of a number of different cell types. However, the mechanisms involved in the anti-proliferative actions of hSPRY2 remain to be elucidated. Here we have demonstrated that hSPRY2 increases the amount of the tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and decreases its phosphorylation. The resultant increase in PTEN activity is reflected in decreased activation of Akt by epidermal growth factor and serum. Consistent with increased PTEN activity, in hSPRY2-expressing cells, the progression of cells from the G1 to S phase is decreased. By using PTEN null primary mouse embryonic fibroblasts and their isogenic controls as well as small interfering RNA against PTEN, we demonstrated that PTEN is necessary for hSPRY2 to inhibit Akt activation by epidermal growth factor as well as cell proliferation. Overall, we concluded that hSPRY2 mediates its anti-proliferative actions by altering PTEN content and activity.

Adaptor Proteins, Signal Transducing↗

PubMed2001

Neutrophils in lung inflammation: Which reactive oxygen species are being measured?

The oxidative burst in circulating polymorphonuclear leukocytes (PMN) plays a fundamental role in pulmonary defense and injury. Flow cytometric techniques have been developed for quantitation of oxidative burst activity at the single cell level using 2',7'-dichlorofluorescin (DCFH). However, the specific reactive oxidant species being measured using this method are not clearly defined. Isolated human PMN were loaded with DCFH diacetate, stimulated with phorbol myristate acetate (PMA) in the presence or absence of specific reagents, and analyzed using flow cytometry. Addition of PMA resulted in a 90-fold increase in the fluorescence intensity of DCFH-loaded neutrophils (p <.01). Inhibition of NADPH oxidase activity using a calmodulin antagonist (W-13) decreased PMA-induced DCFH oxidation by 70% (p <.05). Inhibition of nitric oxide synthase using N(G)-monomethyl-L-arginine (NMMA) did not significantly reduce DCFH oxidation, and did not alter the action of W-13. Addition of superoxide dismutase (SOD) had no effect, but catalase, with or without SOD, suppressed DCFH oxidation by 90% (p <.01). These data suggest that hydrogen peroxide, and not NO, is primarily responsible for the PMA-induced oxidation of DCFH in human PMN under these conditions.

Adolescent↗

PubMed2026

DESTINY-Lung06: trastuzumab deruxtecan and pembrolizumab as first-line treatment for HER2-overexpressing, PD-L1 TPS <50% NSCLC.

Non-small cell lung cancer (NSCLC) that overexpresses human epidermal growth factor receptor 2 (HER2) is associated with poor prognosis, and no HER2-targeting therapies for HER2-overexpressing NSCLC are currently approved in the first-line setting. Pembrolizumab plus pemetrexed and platinum-based chemotherapy is a recommended first-line treatment option for nonsquamous NSCLC with no actionable genomic alterations. However, improved outcomes with pembrolizumab-based therapies correlate with higher programmed death-ligand 1 (PD-L1) levels, underscoring the need for more targeted treatment options for patients with lower PD-L1 tumor proportion scores (TPS; <50%). DESTINY-Lung06 is a multicenter, open-label, randomized, phase III trial evaluating the efficacy and safety of trastuzumab deruxtecan (T-DXd) in combination with pembrolizumab in the first-line setting in patients with HER2-overexpressing (≥25% moderate/strong membrane staining), PD-L1 TPS <50% NSCLC. Planned enrollment will be approximately 686 patients randomly assigned to either T-DXd 5.4 mg/kg with pembrolizumab 200 mg intravenously every 3 weeks (Q3W) or pembrolizumab 200 mg plus pemetrexed 500 mg/m2 with platinum-based chemotherapy (cisplatin 75 mg/m2 or carboplatin under the concentration-time curve 5 mg min/mL) intravenously Q3W. Progression-free survival by blinded independent central review and overall survival are the primary and key secondary endpoints of the study, respectively.Clinical trial registration: www.ClinicalTrials.gov identifier is NCT06899126; EudraCT identifier is 2024-515658-26-00.

First-line↗

PubMed2026

Gut microbiota and metabolic alterations in participants with flatulence identify Faecalibacterium prausnitzii as a key microbial target for clinical intervention.

Flatulence is closely associated with gut dysbiosis, yet the characteristic microbial signatures, metabolic alterations, and actionable intervention targets remain unclear. This limited mechanistic understanding has hindered the development of precise microbiota-based strategies for managing flatulence. Here, we found that participants with flatulence exhibited marked shifts in gut microbial functions and fecal metabolic profiles compared with healthy controls, characterized by enhanced abnormal fermentation, enrichment of oxidative stress-related functions, elevated low-grade inflammatory signatures, and reduced anti-inflammatory and mucosal-protective metabolic features. Faecalibacterium prausnitzii was significantly negatively associated with the high-gas-producing phenotype. In vitro replenishment experiments further validated the role of F. prausnitzii in reducing gas production, promoting butyrate generation, and remodeling butyrate-associated microbial communities. Based on microbial interaction analysis, we identified Bifidobacterium longum CCFM1319 as a candidate strain for targeting F. prausnitzii. In a double-blind, randomized, placebo-controlled clinical trial, supplementation with B. longum CCFM1319 significantly increased intestinal F. prausnitzii abundance and improved flatulence-related symptoms. Collectively, these findings reveal the microbiota and metabolic dysbiosis underlying flatulence, highlight the key regulatory role of F. prausnitzii, and lays the foundation for targeted microbiota-based intervention strategies for flatulence.

Humans↗

PubMed1993

Lethal exacerbation of Pneumocystis carinii pneumonia in severe combined immunodeficiency mice after infection by pneumonia virus of mice.

Mice homozygous for the mutant allele scid (severe combined immunodeficiency) have been described as excellent models for Pneumocystis carinii (Pc) pneumonia (PCP), a major health problem in patients with acquired immune deficiency syndrome (AIDS) and other immunodeficiency states. Other microorganisms have been shown to infect AIDS patients simultaneously with Pc, but whether one opportunist is able to directly influence the pathogenicity of another has not been determined previously. We have deliberately coinfected scid mice (with extent Pc infection) with a variety of primarily pneumotropic viruses and bacteria and have identified pneumonia virus of mice as causing a dramatic increase in the density of Pc organisms and the morbidity due to PCP in immunodeficient scid mice. This finding has clinical significance in the management of PCP, in that the identification and treatment of coinfecting pneumotropic pathogens may be as important as treatment targeted at Pc. A search for other synergistic (or antagonistic) microorganisms and determination of their mechanism(s) of action in altering the progression of PCP is indicated.

Animals↗

PubMed1967

Effects of external calcium deprivation on single muscle fibers.

Deprivation of external calcium causes sudden potentiation of the twitch response of single muscle fibers. The potentiation was 64 +/- 8%. Potentiation is simultaneous with membrane depolarization occurring after Ca(++) removal. This depolarization amounted to 9 +/- 2 mv. Ca(++) removal also alters the action potential. 3 min after calcium withdrawal, action potential amplitude fell by 36 +/- 3 mv; maximum rates of rise and fall of the spike decreased by 55 +/- 5 and 63 +/- 5% respectively. Changes in shape of the A. P. differ from those seen with other potentiators of the twitch response, such as Zn(++). After short exposure to calcium-free media, potassium-induced contractures show potentiation of peak tension. The S-shaped curve relating potassium contracture tension to log [K](o) shifts to the left after such treatment. Calcium deprivation also increased the rate of relaxation of the contractures. This effect depends on the duration of calcium deprivation, and is probably related to the effect of calcium lack on the membrane. The change in relaxation occurred immediately after calcium deprivation, and was reversed by sudden readmission of calcium. Relaxation of twitch and tetanus responses also were affected by Ca lack, but not as rapidly as potassium contractures. The results suggest that external calcium is not directly involved in the process responsible for tension development, supporting the view that this process is mediated by translocation of intracellular calcium. The relaxation process, however, appears to be rapidly affected by deprivation of external calcium.

Action Potentials↗

PubMed2006

Improving the quality of self-monitoring blood glucose measurement: a study in reducing calibration errors.

BACKGROUND: Two independent studies reported that 16% of people who self-monitor blood glucose used incorrectly coded meters. The degree of analytical error, however, was not characterized. Our study objectives were to demonstrate that miscoding can cause analytical errors and to characterize the potential amount of bias that can occur. The impact of calibration error with three selfblood glucose monitoring systems (BGMSs), one of which has an autocoding feature, is reported. METHODS: Fresh capillary fingerstick blood from 50 subjects, 18 men and 32 women ranging in age from 23 to 82 years, was used to measure glucose with three BGMSs. Two BGMSs required manual coding and were purposely miscoded using numbers different from the one recommended for the reagent lot used. Two properly coded meters of each BGMS were included to assess within-system variability. Different reagent lots were used to challenge a third system that had autocoding capability and could not be miscoded. RESULTS: Some within-system comparisons showed deviations of greater than +/-30% when results obtained with miscoded meters were compared with data obtained with ones programmed using the correct code number. Similar erroneous results were found when the miscoded meter results were compared with those obtained with a glucose analyzer. For some miscoded meter and test strip combinations, error grid analysis showed that 90% of results fell into zones indicating altered clinical action. Such inaccuracies were not found with the BGMS having the autocoding feature. CONCLUSIONS: When certain meter code number settings of two BGMSs were used in conjunction with test strips having code numbers that did not match, statistically and clinically inaccurate results were obtained. Coding errors resulted in analytical errors of greater than +/-30% (-31.6 to +60.9%). These results confirm the value of a BGMS with an automatic coding feature.

Adult↗

PubMed1998

Aging decreases the sensitivity of the GABA carrier to propofol and etomidate.

The influence of aging on the pharmacodynamics of anaesthetic agents in the central nervous system remains poorly understood. As alpha-aminobutyric acid (GABA)-mediated neurotransmission appears to be an important target for anaesthetics in the brain, we hypothesized that aging could alter the sensitivity of the GABA carrier to anaesthetics. We have examined the effects of etomidate and propofol on the uptake of [3H]-GABA (5 min, 37 degrees C) into striatal synaptosomes of rats aged 2, 18 and 24 months. In 2-month-old rats, [3H]-GABA uptake was inhibited by nipecotic acid, a competitive inhibitor of the GABA carrier (IC50 = 3.6 SD 0.3 microM). Etomidate and propofol markedly reduced the activity of the GABA carrier, with IC50 values 58 (SD 3) and 46 (SD 3) mumol litre-1, respectively. Aging increased IC50 values for these anaesthetics. Nipecotic acid was unaffected. These data suggest that aging selectively alters the action of etomidate and propofol in the mammalian CNS.

Aging↗