A prospective randomized trial of ceftazidime versus cefazolin/tobramycin in the treatment of hospitalized patients with pneumonia

Ceftazidime and cefazolin/tobramycin were compared in the treatment of hospitalized patients with pneumonia. Iv doses 8-hourly were: ceftazidime--2 g, cefazolin--1.5 g, tobramycin--1.7 mg/kg. For patients with pseudomonas infection randomized to cefazolin/tobramycin, ticarcillin (3 g iv 4-hourly) was used instead of cefazolin. One hundred and ten of 129 patients were evaluable (ceftazidime = 52, cefazolin/tobramycin = 58). Seventy five cases (68%) had documented pathogens of which 81% were aerobic Gram-negative bacilli. Analysis of clinical response showed no difference in overall results (P = 0.77), or separate outcomes: cured (P = 0.85), improved (P = 0.62), failed (P = 0.53), or relapsed (P = 0.50). No differences in bacteriological response were noted either: eradication (P greater than 0.10), elimination with recurrence (P greater than 0.10), persistence (P greater than 0.10). The incidence of enterococcal and fungal colonization and superinfection was the same for both regimens. There was a greater incidence of Coombs' test positivity with ceftazidime (P less than 0.01) but greater nephrotoxicity with cefazolin/tobramycin (P less than 0.02). Ceftazidime appears to be as efficacious as cefazolin/tobramycin in the treatment of hospitalized patients with pneumonia, and is less nephrotoxic.     

Effects of pacing rate and timing of defibrillation shock on the relation between the defibrillation threshold and the upper limit of vulnerability in open chest dogs

To test the relation between the defibrillation threshold and the upper limit of vulnerability, the shock strength associated with 50% probability of successful defibrillation (DFT50) and that associated with 50% probability of reaching the upper limit of vulnerability (ULV50) were determined in 20 open chest dogs with use of the delayed up-down method, with pacing drive cycle lengths of 150 to 500 ms and either single 6-ms shocks (10 dogs) or 12-ms biphasic shocks (10 dogs) given at the mid-upslope, peak and mid-downslope of the T wave of electrocardiographic lead II. The shocks were given by means of a patch-patch configuration on the anterior and posterior surfaces of the heart, which was paced from a stimulating electrode attached to the left ventricular apex. Analysis of variance showed no statistically significant differences in ULV50 as determined with different pacing cycle lengths. For monophasic shocks, DFT50 (331 +/- 66 V or 5.8 +/- 2.7 J) was not significantly different from ULV50 determined at the mid-upslope of the T wave (318 +/- 64 V or 5 +/- 2 J). The correlation coefficients between the two values were 0.74 (p = 0.014) for voltage and 0.67 (p = 0.034) for energy. In contrast, DFT50 was significantly higher than ULV50 as determined at the peak of the T wave (219 +/- 43 V or 2.3 +/- 1 J) and mid-downslope of the T wave (200 +/- 38 V or 1.9 +/- 0.9 J). In three dogs, ventricular fibrillation could not be induced at the mid-downslope of the T wave with any baseline pacing (Si) cycle length.(ABSTRACT TRUNCATED AT 250 WORDS)     

Novel nonnucleoside inhibitor of hepatitis C virus RNA-dependent RNA polymerase

A novel nonnucleoside inhibitor of hepatitis C virus (HCV) RNA-dependent RNA polymerase (RdRp), [(1R)-5-cyano-8-methyl-1-propyl-1,3,4,9-tetrahydropyano[3,4-b]indol-1-yl] acetic acid (HCV-371), was discovered through high-throughput screening followed by chemical optimization. HCV-371 displayed broad inhibitory activities against the NS5B RdRp enzyme, with 50% inhibitory concentrations ranging from 0.3 to 1.8 microM for 90% of the isolates derived from HCV genotypes 1a, 1b, and 3a. HCV-371 showed no inhibitory activity against a panel of human polymerases, including mitochondrial DNA polymerase gamma, and other unrelated viral polymerases, demonstrating its specificity for the HCV polymerase. A single administration of HCV-371 to cells containing the HCV subgenomic replicon for 3 days resulted in a dose-dependent reduction of the steady-state levels of viral RNA and protein. Multiple treatments with HCV-371 for 16 days led to a >3-log10 reduction in the HCV RNA level. In comparison, multiple treatments with a similar inhibitory dose of alpha interferon resulted in a 2-log10 reduction of the viral RNA level. In addition, treatment of cells with a combination of HCV-371 and pegylated alpha interferon resulted in an additive antiviral activity. Within the effective antiviral concentrations of HCV-371, there was no effect on cell viability and metabolism. The intracellular antiviral specificity of HCV-371 was demonstrated by its lack of activity in cells infected with several DNA or RNA viruses. Fluorescence binding studies show that HCV-371 binds the NS5B with an apparent dissociation constant of 150 nM, leading to high selectivity and lack of cytotoxicity in the antiviral assays.     

Adnexal torsion: new clinical and imaging observations by sonography, computed tomography, and magnetic resonance imaging.

OBJECTIVE: The purpose of this study was to review the clinical, imaging, and pathologic findings associated with adnexal torsion. METHODS: A review of surgically proven cases of torsion between 1990 and 2006 included clinical, surgical, and pathologic data and preoperative sonographic, computed tomographic (CT), and magnetic resonance imaging (MRI) studies. Imaging reports were assessed to determine whether a correct preoperative diagnosis was made. Factors related to failure to make a correct diagnosis were evaluated. RESULTS: Fifty-eight cases of torsion were evaluated (patient ages, 12-85 years; 14 postmenopausal). There was a slight right-sided predominance (55%); in most cases (72%), both the ovary and fallopian tube were involved. Common symptoms/signs were pain (91%), leukocytosis (64%), nausea/vomiting (62%), and a palpable mass (41%). Twenty-eight patients (48%) had previous abdominal surgery; in 12 (46%) of these 28, pelvic adhesions were noted. At pathologic examination, underlying adnexal masses were found in 30 cases (52%); they were benign in 26 (87%) of 30 cases. Common imaging findings were an adnexal mass (65% on sonography, 87% on CT, and 75% on MRI), a displaced adnexal mass/enlarged ovary (53% on sonography, 87% on CT, and 75% on MRI), and ascites (53% on sonography, 73% on CT, and 50% on MRI). A correct preoperative diagnosis was made by initial sonography in 15 (71%) of 21 cases versus initial CT in 5 (38%) of 13. A correct imaging diagnosis was made more frequently in premenopausal than in menopausal patients (P = .02) and in patients without an underlying adnexal mass compared with those with a mass (P = .05). CONCLUSIONS: Although CT shows features suggestive of torsion, in our study, the diagnostic value of initial CT was less than that of initial sonography. A correct preoperative diagnosis was made less often with an underlying adnexal mass and in postmenopausal women. Previous surgery and adhesions may be predisposing factors for adnexal torsion.     

Pharmacology of Amikacin in Humans

Amikacin is a new aminoglycoside antibiotic which is active in vitro against most isolates of gram-negative bacilli. A dose of 300 mg/m(2) intramuscularly produced a highest mean serum concentration of 25.4 mug/ml with a mean serum concentration of 3.1 mug/ml at 8 h. The same dose intravenously produced a highest mean serum concentration of 52.4 mug/ml with a mean serum concentration of 2.1 mug/ml at 8 h. The mean urinary excretion during the first 6 h was 75 and 66%, respectively. When amikacin was administered at a dose of 150 mg/m(2) every 6 h, there was evidence of some drug accumulation. A loading dose of 150 mg/m(2) administered intravenously over 30 min followed by 200 mg/m(2) administered as a continuous infusion every 6 h maintained serum concentrations of 8 mug/ml. No major toxicity was observed with any of these drug regimens.     

Identification and analysis of bacterial protein secretion inhibitors utilizing a SecA-LacZ reporter fusion system

Protein secretion is an essential process for bacterial growth, yet there are few if any antimicrobial agents which inhibit secretion. An in vivo, high-throughput screen to detect secretion inhibitors was developed based on the translational autoregulation of one of the central protein components, SecA. The assay makes use of a SecA-LacZ fusion reporter construct in Escherichia coli which is induced when secretion is perturbed. Several compounds, including two natural product extracts, which had the ability to induce the reporter fusion were identified and the MICs of these compounds for Staphylococcus aureus strain MN8 were found to be < or =128 microg/ml. Enzyme-linked immunosorbent assay, Western blotting, and immunoprecipitation techniques were used to analyze the affects of these compounds on protein secretion. Six representative compounds presented here appear to be bona fide secretion inhibitors but were found to have deleterious effects on membranes. It was concluded that, while the method described here for identifying inhibitors of secretion is valid, screens such as this, which are directed against the membrane-bound portion of a pathway, may preferentially identify compounds which affect membrane integrity.     

The choleretic effect of iodipamide.

It is well established that a number of organic anions are excreted by the liver into bile in association with a marked increase in bile flow. Previous studies have shown that iodipamide (3,3'-(adipoyl-diimino)bis[2,4,6-triiodobenzoic acid]), the radiographic contrast material used for intravenous cholangiography, is a potent choleretic. Experiments were performed in unanesthetized dogs to determine if the increased bile flow produced by iodipamide is canalicular or ductular in origin, to quantitate the choleresis associated with iodipamide and taurocholate excretion, and to correlate these findings with the results of in vitro studies in which the osmotic activities of iodipamide and taurocholate in both isotonic saline and bile were determined. The plasma erythritol clearance increase linearly with the excretion of iodipamide, indicating that iodipamide stimulates canalicular bile flow. The choleretic potency of iodipamide (22 ml/mmol) is approximately 3 times that of taurocholate (7.8 ml/mmol), yet the osmotic activity of iodipamide in bile (1.5 mosmol/mmol) is only twice as great as that of taurocholate in bile (0.8 mosmol/mmol). It therefore appears that, per unit of effective osmotic solute secreted, iodipamide carries more water into the bile canaliculi than does taurocholate.     

Acute and Chronic Effects of Cryoablation of the Pulmonary Veins in the Dog as a Potential Treatment for Focal Atrial Fibrillation

Background: Atrial fibrillation (AF) may be triggered by premature atrial depolarizations originating in the pulmonary veins (PV). Radiofrequency catheter ablation of PV foci may prevent recurrence of AF, but may cause PV stenosis. Therefore, a safer method for ablation of PV foci is needed. This study evaluated the acute and chronic effects of PV ablation using a cryocatheter ablation (CCA) system, which may be less likely to cause PV stenosis. Methods: CCA was performed by freezing for 5 minutes or more in one or more PVs in 10 anesthetized dogs. Pacing threshold and vessel diameter were measured before and after PV cryoablation. All dogs were restudied at 4.0 ± 1.64 months (range 2–7) in a manner identical to baseline. Results: CCA was performed in 27 PVs (range 1–4/dog), with a mean freeze time of 8.62 ± 5.42 minutes per vein (range 5.23–22.06). Mean temperature for all freezes was –65 ± 5.3°C. Mean PV diameter was 6.49 ± 1.73 vs 6.24 ± 1.83 mm (p = NS) and mean pacing threshold 1.32 ± 0.75 vs 9.36 ± 5.93 mA (p < .01), before vs. acutely after ablation. At followup, at the ablation sites PV diameter (7.02 ± 1.88 mm) was unchanged from baseline, whereas pacing threshold remained elevated (2.54 ± 1.44 mA, p < .05 vs baseline). There were no acute or long-term complications. Conclusions: (1) CCA of PVs produced a significant rise in acute and chronic pacing threshold indicating loss of atrial conductivity. (2) CCA of PVs did not cause PV stenosis or other complications. (3) The data suggest that CCA of PVs may be a safe and effective method for treating focal AF.     

Preliminary results with percutaneous transcatheter microwave ablation of typical atrial flutter

Background: Linear microwave ablation has been shown to be effective for treatment of atrial fibrillation during open-heart surgery by producing transmural lesions in the atrium to isolate the pulmonary veins. However, the safety and efficacy of percutaneous, transcatheter, linear microwave ablation for atrial arrhythmias, while demonstrated in animal models, is unknown in humans. Therefore, we studied the safety and efficacy of linear microwave ablation of the cavotricuspid isthmus (CTI) in humans with typical atrial flutter, utilizing a 2-cm long microwave antenna mounted on a steerable 9-French catheter.
Methods and Results: In seven consecutive patients, multielectrode catheters were positioned at the His bundle (quadripolar) and around the TV annulus (duo-decapolar) for pacing and recording atrial activation sequence before and after ablation. The microwave antenna was withdrawn gradually from tricuspid annulus towards inferior vena cava to ablate the CTI. Intracardiac ultrasound was used to ensure adequate endocardial contact of the microwave ablation catheter with the CTI. Microwave energy was applied at a power of 18 to 21 W at each ablation point for 120 seconds. Ablation was repeated until bidirectional CTI block was confirmed by demonstrating a descending activation wavefront in the contralateral atrial wall during pacing from the coronary sinus ostium or low lateral right atrium, respectively. Bidirectional isthmus block was achieved in all patients, after a mean number of 27.4 ± 14.7 energy applications per patients. There were no acute procedural complications.
Conclusions: Percutaneous, transcatheter microwave ablation of CTI dependent atrial flutter was demonstrated to be safe and effective in this preliminary feasibility study.