Retrospective analysis of the clinical course for intubation vs. unspecified laryngeal granulomas

Intubation laryngeal granulomas (ILGs) are a well-known complication of endotracheal intubation. Cases other than ILGs can be categorized as unspecified laryngeal granulomas (ULGs) since their etiologies are often difficult to confirm. We intended to clarify clinical features of both ILGs and ULGs and that anticoagulant medication could cause the formation and delayed healing of ILGs in terms of wound-healing delay. We compared the results of our treatment of ILGs (n = 16) and ULGs (n = 47) treated between 1998 and 2009 to characterize these patients. The clinical course, treatment (medical vs. surgical), indications for surgical resection, treatment outcome, and use of anticoagulants for preexisting disease were reviewed and compared between these two groups. The resolution rate was significantly better in ILGs (p < .05). Five ILGs and seven ULGs were surgically resected. The main reason for resection was airway obstruction and the need for histological assessment, respectively. The use of anticoagulants was significantly higher in ILGs than ULGs (8/16 vs. 4/47, p < .01). The resolution period was significantly longer in the ILGs patients with anticoagulant medication compared to that in the ILGs patients without anticoagulant medication (152 ± 101 days vs. 76 ± 44 days, p < .05). ILGs may have different clinical course from ULGs, especially in terms of the resolution period. Moreover, administration of anticoagulants may deter healing of small injury due to intubation. Patients taking anticoagulants should be managed carefully during the perioperative period to prevent the occurrence of ILGs.     

Evaluation of new algorithm using TPLA as an initial syphilis screening test

We retrospectively compared the performance of an existing syphilis diagnostic algorithm with a new algorithm that analyzes the results of Treponema pallidum latex agglutination (TPLA) tests. Of the 100 clinical blood samples, 51 were classified as positive through both Mediace TPLA and ESPLINE TP; 2/51 were classified as negative by Architect Syphilis TP, whereas 1/51 was negative as per LUMIPULSE Presto TP. The false positive rate when the results of Mediace TPLA and ESPLINE TP were combined was 1.96% versus 0% for both Architect Syphilis TP and LUMIPULSE Presto TP. The sensitivity of Mediace TPLA (98%) was comparable to that of Architect Syphilis TP (98%) but lower than that of LUMIPULSE Presto TP (100%). The specificity of Mediace TPLA was 98.0% versus 100% for Architect Syphilis TP, and versus 100% for LUMIPULSE Presto TP. We conclude that the performance of Mediace TPLA in combination with a reverse algorithm is nearly equal to that of enzyme immunoassay (EIA) or chemiluminescence immunoassay (CIA). Because TPLA is low cost, highly sensitive method for IgM detection, and is easy to operate, we have recommended its adoption for initial syphilis screening tests.     

Network analysis of plasma and tissue amino acids and the generation of an amino index for potential diagnostic use

BACKGROUND: Few studies exist on the use of metabolic profiling of amino acids to examine underlying physiologic and disease states. OBJECTIVE: We aimed to introduce a new method for studying relations among amino acids and to generate a diagnostic index, or amino index, based on amino acid concentrations. DESIGN: For network analysis, 35 Fischer-344 rats were randomly divided into 7 groups and fed diets containing 5%, 10%, 15%, 20%, 30%, 50%, or 70% protein. Amino acid concentrations in plasma and various organs were used to derive correlation coefficients that were then used to construct correlation networks. To build a diagnostic index for diabetic rats, the plasma amino acid concentrations of diabetic and normal rats were analyzed by using a novel algorithm developed to generate amino acid-based indexes. Plasma amino acid concentrations from human growth hormone transgenic rats and insulin-treated diabetic rats were used to evaluate the index obtained for diabetes. Dimethylnitrosamine-treated Sprague-Dawley rats were used to generate an index for hepatic fibrosis. RESULTS: The scatter plots of plasma amino acid concentrations showed distinct patterns in different organs that were due to the different protein contents of the diets. Network analysis showed that data-driven networks for blood and tissue could be obtained. We derived a diagnostic index for the discrimination of diabetic rats with both sensitivity and specificity >97% and another surrogate index for liver hydroxyproline with a correlation of r2= 0.85. CONCLUSIONS: Correlation-based network analysis may help to uncover specific physiologic conditions or states. A novel approach using amino acid molar ratios was shown to generate indexes that can be used to separate animal disease models and monitor the progression of a disease parameter. Some of the methods described here may be applicable to the clinical setting.     

Treatment of primary central nervous system lymphoma with induction of complement-dependent cytotoxicity by intraventricular administration of autologous-serum-supplemented rituximab

We describe an immunocompetent 19-year-old man with CD20-positive primary central nervous system (CNS) lymphoma refractory to chemotherapy and irradiation. After intraventricular administration of rituximab, a chimeric anti-CD20 monoclonal antibody, supplemented with autologous serum, a remarkable response developed to the CNS parenchymal lymphoma. Cytotoxicity assays showed that untreated patient's serum with rituximab, but not that of heat-inactivated patient's serum with rituximab or rituximab alone, induced potent rituximab-mediated cytotoxicity against tumor cells in the patient's cerebrospinal fluid, suggesting induction of complement-dependent cytotoxicity against CNS lymphoma.     

Long-term results of primary closure for ventricular septal defects in the first year of life

The long-term results of primary closure for large ventricular septal defects (VSDs) in infants under 1 year of age with severe symptoms were studied over a period of more than 10 years. Between January, 1971 and March, 1982, 49 infants underwent primary closure of a VSD through a right ventriculotomy using complete cardiopulmonary bypass with mild hypothermia. There were four hospital deaths but no late deaths. Two of four infants with residual shunts had a left ventricular-right atrial shunt which necessitated reoperation. Surgical heart. block occurred in two infants who recovered sinus rhythm in the late period. The cardiothoracic ratio decreased from 60.5% preoperatively to 50.6% in the late postoperative period. Examination by cardiac catheterization revealed that the pulmonary-to-systemic pressure ratio (Pp/Ps) of 23 patients with a Pp/Ps of over 0.75 fell from 0.89 ± 0.09 preoperatively to 0.42 ± 0.12 by 1 month postoperatively, then to 0.27 ± 0.05 in the late postoperative period. The latest values for the cardiac index and left ventricular ejection fraction were 3.41 /min per m² and 64.4%, respectively. More than 10 years after their operation, all the survivors were growing normally and maintaining a good quality of life, which supports our recommendation that primary repair should be performed in the first year of life for infants with large VSDs.     

Physiologically based pharmacokinetic modeling as a tool for drug development

Since the pioneering work of Haggard and Teorell in the first half of the 20th century, and of Bischoff and Dedrick in the late 1960s, physiologically based pharmacokinetic (PBPK) modeling has gone through cycles of general acceptance, and of healthy skepticism. Recently, however, the trend in the pharmaceuticals industry has been away from PBPK models. This is understandable when one considers the time and effort necessary to develop, test, and implement a typical PBPK model, and the fact that in the present-day environment for drug development, efficacy and safety must be demonstrated and drugs brought to market more rapidly. Although there are many modeling tools available to the pharmacokineticist today, many of which are preferable to PBPK modeling in most circumstances, there are several situations in which PBPK modeling provides distinct benefits that outweigh the drawbacks of increased time and effort for implementation. In this Commentary, we draw on our experience with this modeling technique in an industry setting to provide guidelines on when PBPK modeling techniques could be applied in an industrial setting to satisfy the needs of regulatory customers. We hope these guidelines will assist researchers in deciding when to apply PBPK modeling techniques. It is our contention that PBPK modeling should be viewed as one of many modeling tools for drug development.     

Is the Dog a Useful Model for Accelerated Calcification Study of Cardiovascular Bioprostheses?

Abstract: Chitosan posttreatment has been shown to be effective in prevention of calcification of the glutaral-dehyde treated bovine pericardium when implanted sub-dermally in rats for 12 weeks. The efficacy of chitosan posttreatment in complete calcium mitigation of the glutaraldehyde treated porcine aortic valves implanted in the right side of the heart in dogs was well-documented in our previous study. In this study, an attempt has been made to evaluate the merit of the chitosan posttreatment in prevention of calcification of the glutaraldehyde (GA) treated porcine aortic valved conduits in the systemic circulation in dogs for a period of 5 months. Eleven mongrel dogs underwent left thoracotomy. Porcine aortic valved conduits treated with 0.625% GA (n = 5) and GA-chitosan (n = 6) were implanted in the descending thoracic aortas of the dogs for 5 months. Gross histological observations showed no calcification in either the 0.625% GA treated or in the GA-chitosan treated valved conduits at 5 months. This was confirmed by results of quantitative analyses for calcium in each explant. There was no significant difference in calcium content between the GA only (Ca, 0.43 ± 0.26 mg/g) and GA-chitosan treated (Ca, 0.51 ± 0.19 mg/g; p = 0.5959) valved conduits. This study suggests that the dog is not a suitable model for evaluating the efficacy of a calcium mitigating agent in bioprostheses implanted in systemic circulation.     

Site-specific drug delivery to the middle-to-lower region of the small intestine reduces food-drug interactions that are responsible for low drug absorption in the fed state

Food-drug interactions may reduce the bioavailability of drugs taken after meals (negative food effects). We designed enteric-coated tablets that start to disintegrate when they reach the middle-to-lower region of the small intestine, and examined whether they could reduce negative food effects in dogs. Tablets containing trientine as a model drug were coated with hypromellose acetate succinate (HPMCAS) with various values of succinoyl group content. The time lag of drug dissolution from these enteric-coated tablets in simulated intestinal fluid of pH 6.8 increased as the succinoyl group content was decreased. The AUC of trientine after oral administration of its aqueous solution to fed dogs was one-eighth of that in fasted dogs. The low drug absorption in fed dogs was improved when trientine was administered as enteric-coated tablets. The average ratio of AUC in the fed state to that in the fasted state increased with decreasing succinoyl group content of HPMCAS. Negative food effects completely disappeared after oral administration of tablets coated with HPMCAS having a succinoyl group content of 6.2% or less, which probably disintegrated in the middle-to-lower small intestine. Our results indicated that food-drug interactions were avoided by separating the main absorption site of drugs from that of food components.