Alpha 2-antiplasmin causes thrombi to resist fibrinolysis induced by tissue plasminogen activator in experimental pulmonary embolism

BACKGROUND: In patients with pulmonary embolism, thrombi resist fibrinolysis induced by plasminogen activators. Because the molecular basis of this thrombus resistance is poorly understood, we used a potent inhibitor to examine the potential role of alpha 2-antiplasmin (alpha 2AP) in experimental pulmonary embolism. METHODS AND RESULTS: Lysis of experimental pulmonary emboli was measured 4 hours after embolization in anesthetized ferrets. All animals received heparin (100 U/kg). Five experimental groups were studied: (1) no recombinant tissue plasminogen activator (rTPA); (2) rTPA at 1 mg/kg; (3) rTPA at 2 mg/kg; (4) rTPA at 1 mg/kg plus a control monoclonal antibody (MAb); and (5) rTPA at 1 mg/kg plus an alpha 2AP inhibitor (MAb 77A3). In comparison with ferrets receiving no rTPA (15.6 +/- 10.5% lysis, mean +/- SD), rTPA-treated groups showed significantly greater lysis (P < .01). Animals treated with rTPA and alpha 2AP inhibitor (56.2 +/- 4.7% lysis) showed significantly greater lysis than all other treatment groups, including ferrets treated with the same dose of rTPA alone (38.5 +/- 6.3%, P < .01), with twice the rTPA dose alone (45.0 +/- 6.5%, P < .05), or with a control MAb (35.2 +/- 4.6%, P < .01). The combination of rTPA treatment and alpha 2AP inhibition caused no consumption of fibrinogen. CONCLUSIONS: Inhibition of alpha 2AP significantly amplified the lysis of experimental pulmonary emboli by rTPA without increasing fibrinogen consumption. These results suggest that alpha 2AP may play an important role in thrombus resistance in patients with venous thromboembolism.     

Antibiotic optimization. An evaluation of patient safety and economic outcomes

BACKGROUND: Although numerous reports have described interventions designed to influence antibiotic utilization, to our knowledge none have been evaluated in a randomized study. METHODS: Adult inpatients receiving 1 or more of 10 designated parenteral antibiotics for 3 or more days during a 3-month period were randomized to an intervention (n = 141) and a control (n = 111) group using an unblocked, computer-generated random number table. Obstetric patients and those seen in infectious disease consultation were excluded. The intervention group received antibiotic-related suggestions from a team consisting of an infectious disease fellow and a clinical pharmacist. Both groups were evaluated for clinical and microbiological outcomes as well as antibiotic utilization via prospective chart reviews and analysis of the hospital's administrative database. RESULTS: Sixty-two (49%) of the intervention group patients received a total of 74 suggestions. Sixty-three (84%) of these suggestions were implemented; the majority involved changes in antibiotic choice, dosing regimen, or route of administration. Per patient antibiotic charges were nearly $400 less in the intervention group vs controls (P = .05). Almost all the savings were related to lower intravenous antibiotic charges. Clinical and microbiological response, antibiotic-associated toxic effects, in-hospital mortality, and readmission rates were similar for both groups. Multiple linear regression analysis identified randomization to the intervention group and female sex as the sole predictors of lower antibiotic charges. There was a trend toward a shorter length of stay for the intervention group (20 vs 24.7 days, P = .11). CONCLUSIONS: This is the first randomized study to evaluate whether antibiotic choices can be influenced in a cost-effective fashion without sacrificing patient safety. We demonstrate that 50% of patients initially treated with expensive parenteral antibiotics can have their regimens refined after 3 days of therapy and that these modifications result in good clinical outcomes with a substantial reduction in antibiotic expense.     

Targeted overexpression of protein kinase C beta2 isoform in myocardium causes cardiomyopathy

Increased cardiovascular mortality occurs in diabetic patients with or without coronary artery disease and is attributed to the presence of diabetic cardiomyopathy. One potential mechanism is hyperglycemia that has been reported to activate protein kinase C (PKC), preferentially the beta isoform, which has been associated with the development of micro- and macrovascular pathologies in diabetes mellitus. To establish that the activation of the PKCbeta isoform can cause cardiac dysfunctions, we have established lines of transgenic mice with the specific overexpression of PKCbeta2 isoform in the myocardium. These mice overexpressed the PKCbeta2 isoform transgene by 2- to 10-fold as measured by mRNA, and proteins exhibited left ventricular hypertrophy, cardiac myocyte necrosis, multifocal fibrosis, and decreased left ventricular performance without vascular lesions. The severity of the phenotypes exhibited gene dose-dependence. Up-regulation of mRNAs for fetal type myosin heavy chain, atrial natriuretic factor, c-fos, transforming growth factor, and collagens was also observed. Moreover, treatment with a PKCbeta-specific inhibitor resulted in functional and histological improvement. These findings have firmly established that the activation of the PKCbeta2 isoform can cause specific cardiac cellular and functional changes leading to cardiomyopathy of diabetic or nondiabetic etiology.     

Accuracy of duplex ultrasound in evaluating carotid artery anatomy before endarterectomy

PURPOSE: Anatomic features, such as a high carotid bifurcation (< 1.5 cm from the angle of the mandible), excessive distal extent of plaque (> 2.0 cm above the carotid bifurcation), or a small diameter (< or = 0.5 cm) redundant or kinked internal carotid artery can complicate carotid endarterectomy. In the past, arteriography was the only preoperative study capable of imaging these features. This study assessed the ability of duplex ultrasound to evaluate their presence before surgery. METHODS: A consecutive series of 20 patients who underwent 21 carotid endarterectomies had preoperative duplex ultrasound evaluations of these anatomic features. These evaluations were correlated with operative measurements from an observer blinded to the duplex findings. RESULTS: The mean difference between duplex and operative measurements for the distance between the carotid bifurcation and the angle of the mandible, the distal extent of plaque, and the internal carotid artery diameter was 0.9 cm, 0.3 cm, and 0.8 mm, respectively. The correlation coefficient between the two methods was 0.86, 0.75, and 0.59, respectively. Duplex ultrasound predicted a high carotid bifurcation, excessive distal extent of plaque, or a redundant or kinked internal carotid artery with 100% sensitivity (p < 0.05, p < 0.01, and p < 0.001, respectively). The sensitivity of duplex ultrasound in predicting a small internal carotid artery diameter was 80%. The specificity of duplex ultrasound for predicting excessive distal extent of plaque, small internal carotid artery diameter, high carotid bifurcation, and a coiled or kinked carotid artery was 92%, 56%, 100%, and 100%, respectively. CONCLUSION: Duplex ultrasound can predict the presence of anatomic features that may complicate carotid endarterectomy. Preoperative duplex imaging of these features may be helpful in patients who undergo carotid endarterectomy without preoperative arteriography.     

Solitary necrotic nodules of the liver

An experience is reported with solitary necrotic nodules of the liver, rare benign lesions described for the first time in 1983. Two patients were referred to our department because of the presence of hepatic lesions that radiology showed to be suspected secondary liver tumors. At laparotomy, both patients underwent liver resections because the lesions appeared to be malignant. Subsequent histological examination of the surgical specimens revealed that both were solitary necrotic nodules of the liver. These were the only solitary necrotic nodules found in a total of 840 operations carried out in our department since October 1981. Although they are completely benign, solitary necrotic nodules have a similar ultrasound pattern and radiological features to metastases and have been described in the literature during the follow-up of patients with other tumors. Uncertainty remains as to the etiology of these lesions, which still represent an occasional finding in liver surgery.     

Long-term effects of feeding high carbohydrate diet in pre-weaning period by gastrostomy: a new rat model for obesity

In the present study, we report the long-term metabolic consequences of feeding a milk substitute formula that is high in carbohydrate-derived calories during the suckling period. Male Sprague-Dawley rat pups were raised by gastrostomy on a high carbohydrate (HC) formula or a high fat (HF) formula (which mimicked rat milk composition in macronutrients) during the pre-weaning period (day 4 to 24). These rats were then weaned to a laboratory stock diet and subsequently challenged with a high sucrose diet to augment the development of obesity. The pups receiving the HC formula developed obesity in later life, even though there was no change in the body weight of this group compared to mother-fed (MF) controls or HF formula fed animals during the pre-weaning period. The HC rats were hyperinsulinemic and their growth rates were greater than MF rats starting at day 55. The lipogenic capacity of liver as well as adipose tissues (epididymal and omental) was higher in HC animals compared to MF control animals, as reflected by increases in two key lipogenic enzymes (fatty acid synthase and glucose-6-phosphate dehydrogenase) and in vitro synthesis of lipids. An analysis of adipose tissue morphology in adult rats showed an increase in cell size in epididymal adipose tissue of HC rats compared to the MF group. However, there was no significant difference in cell size in omental adipose tissue between the MF and HC rats. The HF group behaved similarly to the MF control group in growth pattern and measured metabolic parameters.