High-dose intravenous isosorbide-dinitrate is safer and better than Bi-PAP ventilation combined with conventional treatment for severe pulmonary edema.

OBJECTIVE: To determine the feasibility, safety and efficacy of bilevel positive airway ventilation (BiPAP) in the treatment of severe pulmonary edema compared to high dose nitrate therapy. BACKGROUND: Although noninvasive ventilation is increasingly used in the treatment of pulmonary edema, its efficacy has not been compared prospectively with newer treatment modalities. METHODS: We enrolled 40 consecutive patients with severe pulmonary edema (oxygen saturation <90% on room air prior to treatment). All patients received oxygen at a rate of 10 liter/min, intravenous (IV) furosemide 80 mg and IV morphine 3 mg. Thereafter patients were randomly allocated to receive 1) repeated boluses of IV isosorbide-dinitrate (ISDN) 4 mg every 4 min (n = 20), and 2) BiPAP ventilation and standard dose nitrate therapy (n = 20). Treatment was administered until oxygen saturation increased above 96% or systolic blood pressure decreased to below 110 mm Hg or by more than 30%. Patients whose conditions deteriorated despite therapy were intubated and mechanically ventilated. All treatment was delivered by mobile intensive care units prior to hospital arrival. RESULTS: Patients treated by BiPAP had significantly more adverse events. Two BiPAP treated patients died versus zero in the high dose ISDN group. Sixteen BiPAP treated patients (80%) required intubation and mechanical ventilation compared to four (20%) in the high dose ISDN group (p = 0.0004). Myocardial infarction (MI) occurred in 11 (55%) and 2 (10%) patients, respectively (p = 0.006). The combined primary end point (death, mechanical ventilation or MI) was observed in 17 (85%) versus 5 (25%) patients, respectively (p = 0.0003). After 1 h of treatment, oxygen saturation increased to 96 +/- 4% in the high dose ISDN group as compared to 89 +/- 7% in the BiPAP group (p = 0.017). Due to the significant deterioration observed in patients enrolled in the BiPAP arm, the study was prematurely terminated by the safety committee. CONCLUSIONS: High dose ISDN is safer and better than BiPAP ventilation combined with conventional therapy in patients with severe pulmonary edema.

Eaton-Lambert syndrome: acetylcholine and choline acetyltransferase in skeletal muscle.

In biopsied intercostal muscle from six patients with Eaton-Lambert syndrome, we measured acetylcholine content and release and choline acetyltransferase. Both the spontaneous and the KCl-evoked release of acetylcholine were abnormally low. On the other hand, the acetylcholine content and the level of choline acetyltransferase activity were within the range of values earlier found in healthy human intercostal muscle. These results are consistent with the view that the defect in this syndrome lies not in the synthesis or storage of the transmitter but in the mechanism of release itself.

The influence of drugs on the uptake of acetylcholine by slices of rat cerebral cortex.

1. The acetylcholine content of cortical slices from rat brain, was determined after incubation for 30 min in a medium containing acetylcholine (4 mug/ml.). The cholinesterase activity of the slices had been inhibited by pretreatment with 3,3-dimethyl-n-butyl 2-methylphosphonofluoridate (soman).2. Acetylcholine accumulated in the tissue slices, up to a concentration of about six times that in the medium.3. The uptake of acetylcholine was partly inhibited by potassium in high concentrations.4. Hemicholinium-3, O-ethyl S-diethylaminoethyl ethylphosphonothiolate, physostigmine, atropine and choline, in that order of potency, inhibited the accumulation of acetylcholine in the cortical slices, but soman and ethyl N,N-dimethyl phosphonoamidocyanate (tabun) had no effect on the uptake of acetylcholine.5. Substances interfering with energy metabolism, such as 2,4-dinitrophenol, oligomycin, sodium azide, amylobarbitone sodium and p-chloromercuribenzoate inhibited the uptake of acetylcholine. Ouabain had little inhibitory effect.6. In anaerobic conditions the accumulation of acetylcholine in the tissue slices was nearly blocked.7. The uptake of acetylcholine in the tissue slices was dependent on temperature. The Q(10) was about 2.8. Autoradiography of sections from slices in which (3)H-acetylcholine had accumulated showed a diffuse distribution of radioactivity in the cytoplasm of all cells. There was no visible preference for certain cells or cell structures.

Stimulating action of atropine on the release of acetylcholine by rat cerebral cortex in vitro.

1. In cortical slices from rat brain incubated in a medium containing the irreversible cholinesterase inhibitor, soman (0.005 mM) and a high concentration of KCl (25 mM), atropine exerts a stimulating action on the release of acetylcholine (ACh).2. Two possible explanations for this action were examined. Atropine might expel ACh from the nerve endings by occupying its storage sites or it might prevent an inhibitory action of the released ACh on its further release by occupying muscarinic receptors at the presynaptic endings; its action would then be a kind of ;disinhibition.'3. The stimulating action of atropine on ACh release persisted during prolonged incubation (up to 3.5 h) provided choline was added to the medium. This finding would be difficult to explain if atropine acted by expelling ACh from its storage sites.4. The stimulating action of atropine on ACh release was inhibited by oxotremorine and by methacholine, added to the medium in high concentrations. This finding is readily explained if atropine acts by ;disinhibition.'

Stimulation by atropine of acetylcholine release and synthesis in cortical slices from rat brain.

1. Cortical slices from rat brain were incubated in media containing the irreversible cholinesterase inhibitor soman and a high KCl concentration, and the release and synthesis of acetylcholine (ACh) were determined.2. Atropine enhanced the release and synthesis of ACh.3. Tetrodotoxin, a substance which blocks nervous conduction, did not influence the release and synthesis of ACh, in the absence or in the presence of atropine. Therefore the nerve endings are probably the site at which atropine acts when stimulating the release and synthesis of ACh.4. Pretreatment of the slices with botulinum type A toxin partially blocked the release and synthesis of ACh and reduced the extra amounts of ACh released and synthesized under the influence of atropine.5. Lowering the calcium or raising the magnesium concentration in the incubation medium reduced the release and synthesis of ACh and their enhancement by atropine.6. Physostigmine decreased the total extractable ACh content of the slices during incubation in a 25 mM KCl containing medium. This decrease was nearly prevented when the release and synthesis of ACh were inhibited by omission of the calcium ions from the medium, but was enhanced by atropine.7. The observations made with pretreatment by botulinum type A toxin, with changes in the calcium and magnesium concentration as well as with physostigmine, all support the theory that it is primarily the release of ACh which is enhanced by atropine and that its stimulating action on the synthesis results from the increased release.

Preferential release of newly synthesized 3 H-acetylcholine from rat cerebral cortex slices in vitro.

1. Slices of rat cerebral cortex after treatment with the irreversible cholinesterase inhibitor soman, were incubated for 5 min in a Krebs-Henseleit solution containing 25 mM KCl and (3)H-choline. Subsequently incubation was continued in a medium containing non-radioactive choline and this medium was replaced at 5 min intervals. The amounts of labelled and total acetylcholine (ACh) released into the medium and extracted from the slices were determined at intervals.2. After the initial 5 min contact with (3)H-choline, 44% of the newly synthesized ACh contained a choline moiety originating from the choline in the medium. During the initial 5 min and the subsequent incubation part of the labelled ACh was released. While the rate of total ACh release remained constant, that of the release of labelled ACh was highest in the 5 min period following the initial incubation with (3)H-choline and then declined exponentially.3. The ratio of labelled ACh/total ACh in the ACh released during the initial 5 min incubation with (3)H-choline and during the subsequent 5 min was about three times as high as that in the ACh extracted from the slices at the end of these incubation periods.4. The ratio of labelled ACh/total ACh in superficial layers of the slices was not higher than that in the total slices.5. The rates of release of labelled and unlabelled ACh decreased when calcium was omitted from the incubation medium and were restored when the calcium was added. This suggests that both labelled and unlabelled ACh were released from nerve endings. The efflux of (3)H-choline was not calcium dependent.6. It is concluded that labelled ACh newly synthesized from externally applied (3)H-choline does not exchange immediately with all other ACh in the tissue and has a greater chance of being released than unlabelled ACh.

Effect of potassium propionate on free and bound acetylcholine in frog muscle.

Frog sartorius muscles were homogenized under various conditions which allowed, by means of mass spectrometry, the measurement of total ACh, and different ACh compartments in the tissue: 'bound', 'free-1' and 'free-2' ACh. Bound ACh presumably corresponded to the vesicular compartment, and the free-1 and free-2 fractions to the cytoplasmic compartments of ACh. Stimulation of ACh release by La3+ ions for 60 min caused a decrease of both bound and free-2 ACh, but at 20 min bound ACh was reduced much more than free-2 ACh. Stimulation of ACh release by isotonic potassium propionate (KPr) solution for only 5 min caused a decrease of bound ACh, in contrast to free-1 and free-2 ACh which were not significantly changed. When muscles after 5 min stimulation in KPr were allowed to recover in normal Ringer, free-1 ACh did not change, but free-2 and bound ACh increased; after 180 min in Ringer bound ACh had recovered to control values. When ACh synthesis was prevented by hemicholinium-3 during recovery of the muscles in Ringer, bound ACh increased at the expense of free-2 ACh. In deuterium labeling experiments, in which the Ringer contained choline-d9, much more ACh-d9 was formed in stimulated than in unstimulated muscles. It appeared that almost all newly formed ACh was ACh-d9, since no significant synthesis of unlabeled ACh (ACh-d0) took place. Yet again, the amount of bound ACh-d0 significantly increased, apparently at the expense of preformed free-2 ACh-d0.(ABSTRACT TRUNCATED AT 250 WORDS)

Potassium propionate causes preferential loss of 'bound' acetylcholine in frog muscle.

Bound and free acetylcholine (ACh) were measured in frog sartorius muscles by mass fragmentography. Upon incubation of the muscles for 5 min with potassium propionate, which stimulated the release of ACh, there was a 2-fold reduction of bound ACh. In contrast, the amount of free ACh remained unchanged. After 65 min recovery from stimulation in normal Ringer solution containing deuterium-labelled choline, free ACh was labelled to a higher degree than bound ACh. The results are in agreement with the idea that ACh is synthesized in the cytoplasmic compartment of the motor nerve terminal, and subsequently transferred to the vesicles from which it is released upon stimulation.

Multireference CI calculation of nuclear quadrupole coupling constants of CN+ and CN-: rovibrational dependence.

The 14N quadrupole coupling constants of rovibrational levels of the X1sigma+ and c1sigma+ states of CN+, and the ground electronic state of CN- are calculated from molecular wavefunctions which explicitly describe nuclear displacement. From the electronic states considered, the excited 1sigma+ state of CN is predicted to exhibit the strongest N coupling, at least in the ground vibrational state. Compared to the vibrational dependence of the 14N QCC's, which is found to be significant in all cases, the rotational dependence is predicted to be unimportant. Special attention is paid to the assessment of adequacy of the expectation value approach to the evaluation of the electric field gradient tensor within the applied multireference configuration interaction formalism. Spectroscopic constants are derived from corresponding potential energy curves to testify to the quality of the correlated wave functions used.

Spurious hypokalaemia and hypophosphataemia due to extreme hyperleukocytosis in a patient with a haematological malignancy.

Serious hyperleukocytosis can strongly affect laboratory results of potassium, phosphate and arterial oxygen tension. A 40-year-old woman is presented with an acute myeloid leukaemia and a strongly elevated leukocyte count (310 x 10(9)/L). Apart from this hyperleukocytosis, initial blood tests showed hypokalaemia, hypophosphataemia and serious hypoxaemia without any corresponding complaints. Blood sampled and transported on ice or directly analysed showed no electrolyte abnormalities and hypoxaemia. The observed discrepancy in laboratory results is probably due to the metabolic activity of the leukocytes in vitro. Spurious laboratory results can be a reason for incorrect decisions concerning additional diagnostics and treatment. In conclusion, hyperleukocytosis can cause pseudohypokalaemia, pseudohypophosphataemia and pseudohypoxaemia, which can be prevented by correct sampling and immediate analysis.

Increasing resistance in community-acquired urinary tract infections in Latin America, five years after the implementation of national therapeutic guidelines.

BACKGROUND: The worldwide increasing resistance to antibiotics has complicated antimicrobial treatment of urinary tract infections (UTIs), especially in Latin America. This study aimed to report the present etiology and antimicrobial susceptibility of UTIs, and the effects of the national guidelines for UTIs introduced in 2003. METHODS: Urine samples were collected from 304 patients with a clinical suspicion of UTI at the university hospital and primary health centers of León, Nicaragua. When bacterial growth was reported, antimicrobial susceptibility tests for nine frequently used antibiotics were performed. RESULTS: Ninety-one (29.9%) patients had a positive urine culture. The most frequently isolated microorganisms were Escherichia coli (n=44), Serratia spp (n=11), and Escherichia fergusonii (n=10). High resistance rates were observed in E. coli to ampicillin (61.4%), cefalothin (45.5%), trimethoprim-sulfamethoxazole (38.6%), ciprofloxacin (31.8%), and ceftriaxone (20.5%). Amikacin and nitrofurantoin were the only drugs to which >90% of E. coli were susceptible. E. fergusonii and Serratia spp showed comparable high resistance patterns. Thirteen strains (29.5%) of E. coli were suspected to produce extended-spectrum beta-lactamase (ESBL). CONCLUSIONS: Resistance rates in community-acquired UTIs in Nicaragua are increasing. The introduction of therapeutic guidelines with ceftriaxone recommended for upper UTIs and nitrofurantoin for lower UTIs, has led to increasing resistance against both antibiotics. The emergence of ESBL-producing E. coli is worrisome, along with the appearance of Serratia spp in the population.

Acetylcholine synthesizing enzymes in frog skeletal muscle.

Acetylcholine synthesis in homogenates of frog sartorius muscle was measured by a radiometric method with a low blank. Choline acetyltransferase activity was very low (Vmax, 2nmol . g-1 . h-1, Km for choline, approx. 50 microM). The enzyme was found only in the endplate area and disappeared after denervation; it was inactivated by 4-(1-naphthylvinyl)pyridine. At high substrate concentrations its activity was overshadowed by the acetylcholine-synthesizing activity of a different enzyme not saturated by 10 mM-choline. The non-specific enzyme was present at and away from the endplate area, and it was not affected by denervation.