Transient global amnesia associated with cardiac arrhythmia and digitalis intoxication.
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A 54-year-old woman with transient global amnesia (TGA) was found to have digitalis-induced bradyarrhythmia with atrioventricular dissociation. The amnesia cleared only upon resolution of the arrhythmia. Cardiac arrhythmia has been postulated as a cause, but TGA in the setting of cardiac arrhythmia has not been documented previously. Cardiac arrhythmia should be excluded in patients with TGA, and TGA, a syndrome diagnosed on clinical grounds alone, must be recognized as one possible manifestation of treatable, potentially serious cardiac or cerebrovascular disease. (+info)
Conditions that may affect the results of susceptibility testing of Mycobacterium tuberculosis to pyrazinamide.
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Pyrazinamide (PZA) is an important front-line anti-tuberculosis drug that is active only at acid pH. However, acid pH causes significant difficulty for PZA susceptibility testing. A common problem in PZA testing is false resistance caused by large bacterial inocula. This study investigated the relationship of false resistance to numbers of bacilli, pH and other factors that potentially affect susceptibility to PZA. Large inocula (10(7-8) bacilli/ml) of M. tuberculosis H37Ra caused significant increase in medium pH from 5.5 towards neutrality, and thus produced false resistance results. The increase in medium pH was determined to be a function of live bacilli; heat-killed bacilli had little or no effect. Susceptibility to PZA and its active derivative pyrazinoic acid (POA) was comparable on 7H11 agar medium, but POA was less active than PZA in liquid medium containing bovine serum albumin (BSA), suggesting that susceptibility to PZA or POA was reduced in the presence of BSA, because of its neutralising effect on medium pH and significant POA binding. A 3-month-old H37Ra culture was shown to be more susceptible to PZA exposure than a 4-day log-phase culture, suggesting that PZA is more active for non-growing bacilli. Finally, reserpine, an inhibitor of POA efflux pump, increased susceptibility to PZA even near neutral pH 6.8, with an MIC of 400 mg/L compared with 1,000 mg/L without reserpine. These findings should have implications for understanding the mode of action of PZA and for PZA susceptibility testing. (+info)
The action of 5-hydroxytryptamine on chemoreceptor discharges of the cat's carotid body.
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1 Chemoreceptor discharges were recorded in vivo from fine filaments of the carotid sinus nerve containing a single or several active units; their frequency was used as an index of receptor activity. The effects of 5-hydroxytryptamine (5-HT) on chemoreceptors were studied in 26 adult cats. At times, sinus baroreceptor discharges were recorded from the carotid nerve and the effect of 5-HT on the discharges was examined. 2 Intra-carotid injections of 5-HT (2-20 mug) induced a sharp and brief increase in chemoreceptor discharges, followed by depression or block which lasted for several seconds. Repeated injections at short intervals, and a small dose after a large dose of 5-HT resulted in depressed or blocked response to 5-HT. 3 5-HT in high doses (10-20 mug, i.a.) slightly depressed the chemoreceptor discharges induced by either acetylcholine (ACh) or NaCN, when these substances were applied within 20 s after 5-HT. 5-HT (5-20 mug, i.a.) applied during asphyxia induced a further increase in chemoreceptor discharges, soon followed by block of the discharges lasting for several seconds. 4 Atropine or hexamethonium in high doses did not change the chemoreceptor response to 5-HT, while that to ACh was markedly depressed. 5 (+)-Lysergic diethylamide (LSD), methysergide or gramine did not alter the response to 5-HT, while LSD in low doses produced a marked increase in chemoreceptor discharges. 6 Acute and chronic treatment with reserpine (5-10 mg/kg, i.v.) of the animals did not change the sensitivity and the reactivity of the chemoreceptor to ACh and NaCN, while the chemoreceptor response to 5-HT was augmented, indicating an increase in the sensitivity of chemoreceptors to 5-HT. 7 5-HT in small doses (2-10 mug, i.a.) induced a marked increase in sinus baroreceptor discharges; subsequently discharges were depressed or blocked for several seconds. 8 The results are discussed in relation to possible mechanism of action of 5-HT on the chemoreceptors. It is concluded that the exogenous 5-HT probably acts directly on the chemosensory nerve endings and depolarizes them, but 5-HT contained in the carotid body does not play a significant role in the generation of chemoreceptor discharges. (+info)
Topoisomerase II and IV quinolone resistance-determining regions in Stenotrophomonas maltophilia clinical isolates with different levels of quinolone susceptibility.
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The quinolone resistance-determining regions (QRDRs) of topoisomerase II and IV genes from Stenotrophomonas maltophilia ATCC 13637 were sequenced and compared with the corresponding regions of 32 unrelated S. maltophilia clinical strains for which ciprofloxacin MICs ranged from 0.1 to 64 microg/ml. GyrA (Leu-55 to Gln-155, Escherichia coli numbering), GyrB (Met-391 to Phe-513), ParC (Ile-34 to Arg-124), and ParE (Leu-396 to Leu-567) fragments from strain ATCC 13637 showed high degrees of identity to the corresponding regions from the phytopathogen Xylella fastidiosa, with the degrees of identity ranging from 85.0 to 93.5%. Lower degrees of identity to the corresponding regions from Pseudomonas aeruginosa (70.9 to 88.6%) and E. coli (73.0 to 88.6%) were observed. Amino acid changes were present in GyrA fragments from 9 of the 32 strains at positions 70, 85, 90, 103, 112, 113, 119, and 124; but there was no consistent relation to higher ciprofloxacin MICs. The absence of changes at positions 83 and 87, commonly involved in quinolone resistance in gram-negative bacteria, was unexpected. The GyrB sequences were identical in all strains, and only one strain (ciprofloxacin MIC, 16 microg/ml) showed a ParC amino acid change (Ser-80-->Arg). In contrast, a high frequency (16 of 32 strains) of amino acid replacements was present in ParE. The frequencies of alterations at positions 437, 465, 477, and 485 were higher (P < 0.05) in strains from cystic fibrosis patients, but these changes were not linked with high ciprofloxacin MICs. An efflux phenotype, screened by the detection of decreases of at least twofold doubling dilutions of the ciprofloxacin MIC in the presence of carbonyl cyanide m-chlorophenylhydrazone (0.5 microg/ml) or reserpine (10 microg/ml), was suspected in seven strains. These results suggest that topoisomerases II and IV may not be the primary targets involved in quinolone resistance in S. maltophilia. (+info)
Fluoroquinolone resistance in Streptococcus pneumoniae in United States since 1994-1995.
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The in vitro activities of ciprofloxacin, levofloxacin, gatifloxacin, and moxifloxacin against a large collection of clinical isolates of Streptococcus pneumoniae (n = 4,650) obtained over a 5-year period, 1994-1995 through 1999-2000, were assessed as part of a longitudinal multicenter U.S. surveillance study of antimicrobial resistance. Three sampling periods were used during this investigation, the winter seasons of 1994-1995, 1997-1998, and 1999-2000; and 1,523, 1,596 and 1,531 isolates were collected during these three periods, respectively. The overall rank order of activity of the four fluoroquinolones examined in this study was moxifloxacin > gatifloxacin > levofloxacin = ciprofloxacin, in which moxifloxacin (MIC at which 90% of isolates are inhibited [MIC(90)], 0.25 microg/ml; modal MIC, 0.12 microg/ml) was twofold more active than gatifloxacin (MIC(90), 0.5 microg/ml; modal MIC, 0.25 microg/ml), which in turn was fourfold more active than either levofloxacin (MIC(90), 1 microg/ml; modal MIC, 1 microg/ml) or ciprofloxacin (MIC(90), 2 microg/ml; modal MIC, 1 microg/ml). Changes in the in vitro activities of fluoroquinolones against S. pneumoniae strains in the United States over the 5-year period of the survey were assessed by comparing the MIC frequency distributions of the study drugs against the isolates obtained during the three sampling periods encompassing this investigation. These comparisons revealed no evidence of changes in the in vitro activities of the fluoroquinolones. In addition, the percentages of isolates in the three sampling periods for which MICs were above the resistance breakpoints were compared. Low percentages of resistant strains were detected, and there was no evidence of resistance rate changes over time. For example, by use of a ciprofloxacin MIC of > or = 4 microg/ml to define resistance, the proportions of isolates from the three sampling periods for which MICs were at or above this breakpoint were 1.2, 1.6, and 1.4%, respectively. A total of 164 unique isolates (n = 58 from 1994-1995, 65 from 1997-1998, and 42 from 1999-2000) were examined for evidence of mutations in the quinolone resistance-determining regions (QRDRs) of the parC and the gyrA genes. Forty-nine isolates harbored at least one mutation in the QRDRs of one or both genes (1994-1995, n = 15; 1997-1998, n = 19; 1999-2000, n = 15). Among the 4,650 isolates of S. pneumoniae examined in the study, we estimated that 0.3% had mutations in both the parC and gyrA loci. The majority of mutations (67.3% of the mutations in 49 isolates with mutations) were amino acid substitutions in the parC locus only. Four isolates had a mutation in the gyrA locus only, and 12 isolates had mutations in both genes (8.2 and 24.5% of isolates with mutations, respectively). There was no significant difference in the number of isolates with parC and/or gyrA mutations detected during each study period. Finally, because of the magnitude of the study, we had reasonably large numbers of pneumococcal isolates with genotypically defined mechanisms of fluoroquinolone resistance and were thus able to determine the effects of specific resistance mutations on the activities of different fluoroquinolones. In general, isolates with mutations in parC only were resistant to ciprofloxacin but remained susceptible to levofloxacin, gatifloxacin, and moxifloxacin, whereas isolates with mutations in gyrA only and isolates with mutations in both parC and gyrA were resistant to all four fluoroquinolones tested. (+info)
Accumulation of 10 fluoroquinolones by wild-type or efflux mutant Streptococcus pneumoniae.
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A method for measuring fluoroquinolone accumulation by Streptococcus pneumoniae was rigorously examined. The accumulation of ciprofloxacin, clinafloxacin, gatifloxacin, grepafloxacin, levofloxacin, moxifloxacin, norfloxacin, ofloxacin, sitafloxacin, and trovafloxacin in the presence and absence of either carbonyl cyanide m-chlorophenyl-hydrazone (CCCP) or reserpine was determined for two wild-type fluoroquinolone-susceptible capsulated S. pneumoniae strains (M3 and M4) and the noncapsulated strain R6. Two efflux mutants, R6N (which overexpresses PmrA) and a mutant of M4, M22 (no expression of PmrA), were also examined. Essentially, the fluoroquinolones fell into two groups. (i) One group consisting of ciprofloxacin, grepafloxacin, and norfloxacin accumulated to 72 to 92 ng/mg (dry weight) of cells in all strains. (ii) The remainder of the agents accumulated to 3 to 30 ng/mg (dry weight) of cells. With a decrease in hydrophobicity, there was a decrease in the concentration accumulated. With an increase in the molecular weight of the free form of each agent, there was also a decrease in the concentration accumulated. The strains differed in their responses to reserpine and CCCP. For the three fluoroquinolone-susceptible strains, only reserpine had a significant effect upon accumulation of moxifloxacin and clinafloxacin by M3 and showed no effect for the other agents and strains. For M3 and M4, CCCP enhanced the concentration of ciprofloxacin and norfloxacin accumulated, whereas for R6, the effect was only statistically significant for ofloxacin. Efflux mutant M22 accumulated less ciprofloxacin, gatifloxacin, and ofloxacin than M4 did. M22 accumulated more norfloxacin than M4 did. Reserpine and CCCP had variable effects as for the other strains. Differences in the accumulation of fluoroquinolones by R6 and R6N were highly dependent upon growth phase, and only for norfloxacin was there a significant difference between two strains. (+info)
Trends in antihypertensive drug use among orally treated diabetic patients, in France between 1981 and 1992. Impact of guidelines and new drugs.
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OBJECTIVE: To compare antihypertensive drug use between diabetics and non-diabetics and to analyse the change between the two last decennial national surveys on health and medical care in France, in 1981 and 1992. MATERIAL AND METHODS: These surveys included respectively 12,725 and 13,887 adults over 25 years. Use of all antihypertensive drugs marketed in France was compared between orally treated diabetics and non-diabetics who were non-insulin and non-oral anti-diabetic treated population. RESULTS: In 1981, while diuretics were the first treatment in both populations (53% in diabetics vs 60% in non-diabetics, non significant), central inhibitors (31 vs 16% respectively, p<0.001) were the second agent among diabetic patients instead of beta blockers in non-diabetic patients (13 vs 22% respectively, p<0.05). In 1992, beta blockers were also less used in diabetics (21 versus 33%, p=0.001). In contrast, ACE inhibitors were more used (43 versus 35%, p=0.06). In both surveys and populations, other classes (reserpin, vasodilator and alpha blockers) had minor place in the strategy. The frequency of combinations of antihypertensive drugs was similar in both surveys and populations. The preferred combination treatment was in both populations reserpin with diuretics in 1981 (7 vs 9%, non significant) and ACE inhibitors with diuretics in 1992 (18 vs 18%). CONCLUSION: Independently of guidelines, our data suggest that the strategy of hypertension treatment has changed last years and that prescriptions were more targeted for diabetic patients. (+info)
Vascular reactions to in vivo electroporation: characterization and consequences for drug and gene delivery.
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In vivo electroporation (EP) is gaining momentum for drug and gene delivery. In particular, DNA transfer by EP to muscle tissue can lead to highly efficient long-term gene expression. We characterized a vascular effect of in vivo EP and its consequences for drug and gene delivery. Pulses of 10-20,000 micros and 0.1-1.6 kV/cm were applied over hind- and forelimb of mice and perfusion was examined by dye injection. The role of a sympathetically mediated vasoconstrictory reflex was investigated by pretreatment with reserpine. Expression of a transferred gene (luciferase), permeabilization (determined using (51)Cr-EDTA), membrane resealing and effects on perfusion were compared to assess the significance of the vascular effects. Above the permeabilization threshold, a sympathetically mediated Raynaud-like phenomenon with perfusion delays of 1-2 min was observed. Resolution of this phase followed kinetics of membrane resealing. Above a second threshold, irreversible permeabilization led to long perfusion delays. These vascular reactions (1) affect kinetics of drug delivery, (2) predict efficient DNA transfer, which is optimal during short perfusion delays, and (3) might explain electrocardiographic ST segment depressions after defibrillation as being caused by vascular effects of EP of cardiac muscle. (+info)