Artificial oxygen carriers as red blood cell substitutes: a selected review and current status

Two distinct approaches are being explored in red blood cell substitute (RCS) development: hemoglobin-based oxygen carriers (HBOCs) and perfluorocarbon-based oxygen carriers (PFBOCs). HBOCs are based on intra- and/or intermolecularly "engineered" human or animal hemoglobins (Hbs), optimized for O2 delivery and longer intravascular circulation. Some are currently being evaluated in Phase II/III clinical studies. PFBOCs are aqueous emulsions of perfluorocarbon derivatives that dissolve relatively large amounts of O2. A PFBOC based on a 60% (wt/vol) emulsion of perfluorooctyl bromide has been evaluated in Phase II/III clinical trials. Although current PFBOC products generally require patients to breathe O2 enriched air, they render certain advantages since they are totally synthetic. This article provides a short review of the basic principles, approaches, and current status of RCS development. Results of preclinical and clinical studies including recent Phase II/III clinical studies are discussed.     

Civilian uses of hemoglobin-based oxygen carriers

This article briefly discusses a few key issues related to transfusion, the concept of hemoglobin-based red blood cell substitutes (HBOCs), and some parameters useful in evaluating the current properties of solutions. Potential uses of HBOCs in civilian applications are identified and listed. Use of HBOCs as a hemodiluent for intraoperative autologous blood donation (IAD) is a particular application that has relevance in many surgical settings and this is discussed in some detail. Data from a Phase III clinical trial is presented to show the potential for avoiding the use of allogeneic blood and blood products in a clinical model of large volume red cell use. Extrapolation to a general use model, primarily based in the potential for surgery, will be noted. Some general parametric values of HBOCs are presented. These values are by no means considered optimal for all HBOCs and are subject to exploration, fine tuning, correction, or even rejection.     

Increased risk of preterm birth in singleton pregnancies resulting from in vitro fertilization-embryo transfer or gamete intrafallopian transfer: a meta-analysis

OBJECTIVE: To perform a systematic review of the literature to determine whether singleton pregnancies resulting from IVF-ET/GIFT are at higher risk for preterm birth (<37 weeks). DESIGN: Literature search and systematic review. SETTING: Medical school. INTERVENTION(S): A MEDLINE search (1965-2000) was performed using the terms "premature labor," "infertility," "pregnancy complications," "gonadotropins," "pregnancy outcome," "preterm delivery," and "in vitro fertilization." Criteria for inclusion were English language, original research article, study patients conceived using IVF-ET (with or without intracytoplasmic sperm injection) or GIFT, pregnancy outcome reported compared with a control group (e.g., naturally conceived singletons at their hospital or a national reference), and prematurity clearly defined. Incomplete articles (e.g., abstracts), reports of other studies, and studies that failed to separate multiple from singleton gestations were excluded. MAIN OUTCOME MEASURE(S): Summary of relative risks of preterm birth. RESULT(S): Twenty-seven articles met all inclusion/exclusion criteria and were analyzed by meta-analysis. The random-effects summary relative risk of preterm birth in singleton pregnancies resulting from IVF-ET/GIFT was 1.98 (95% confidence interval, 1.77-2.22). CONCLUSION(S): The risk of preterm birth in singleton pregnancies resulting from IVF-ET/GIFT is twice that of natural conceived pregnancies.     

Nomograms including nuclear matrix protein 22 for prediction of disease recurrence and progression in patients with Ta, T1 or CIS transitional cell carcinoma of the bladder

PURPOSE: We developed and validated nomograms that accurately predict disease recurrence and progression in patients with Ta, T1, or CIS transitional cell carcinoma (TCC) of the bladder using a large international cohort. METHODS: Univariate and multivariate logistic regression models targeted histologically confirmed disease recurrence, and focused on 2,542 patients with bladder TCC from 10 participating centers. Variables consisted of pre-cystoscopy voided urine Nuclear Matrix Protein 22 (NMP22) assay, urine cytology, age and gender. Resulting nomograms were internally validated with bootstrapping. Nomogram performance was explored graphically with Loess smoothing plots. RESULTS: Overall 957 patients had recurrent TCC. Tumor grade and stage was available for 898 patients, including 24% grade I, 43% grade II, and 33% grade III; 45% stage Ta, 32% T1 and/or CIS, and 23% T2 or greater. Bootstrap corrected predictive accuracy for any TCC recurrence was 0.842; grade III Ta/T1 or CIS was 0.869; and T2 or higher stage TCC of any grade was 0.858. Virtually perfect performance characteristics were observed for the nomograms predicting any TCC recurrence or grade III Ta/T1 or CIS. The nomogram predicting T2 or higher stage TCC overestimated the observed probability for predicted values greater than 45%. CONCLUSIONS: We developed and internally validated nomograms that incorporate urinary NMP22, cytology, age and gender to predict with high accuracy the probability of disease recurrence and progression in patients with Ta, T1, and/or CIS bladder TCC. These nomograms could provide a means for individualizing followup in patients with Ta, T1, CIS bladder TCC.     

Proton pump inhibitors and their drug interactions: an evidence-based approach

The proton pump inhibitors (PPIs) are the most effective antisecretory agents used to treat acid-related disorders. As such, they are frequently prescribed for patients who are concurrently using other medications. PPIs may interact with other drugs through numerous mechanisms. The most important include competitive inhibition of hepatic cytochrome P (CYP) 450 enzymes involved in drug metabolism, and alteration of the absorption of other drugs via changes in gastric pH levels. Poor metabolizers, who lack CYP2C19, may be particularly predisposed to drug interactions. Although the potential for drug interactions is high, few clinically significant interactions have been reported for the PPIs. Nevertheless, caution is indicated when certain drugs are co-prescribed with these agents. The incidence of clinically significant drug interactions increases proportionately with the number of drugs taken and with the age of the patient. The drug interaction with the greatest clinical importance is the reduction in benzodiazepine clearance by omeprazole.     

2,3-diphosphoglycerate, nucleotide phosophate, and organic and inorganic phosphate levels during the early phases of diabetic ketoacidosis.

The relation between serum and red blood cell (RBC) inorganic phosphate levels, RBC 2,3-diphosphoglycerate (2,3-DPG) levels, RBC nucleotide phosphate (Pn), and RBC total phosphate (Pt) levels were studied during the early phases of treatment and recovery from diabetic ketoacidosis (DKA). A steady drop in serum inorganic phosphate was found during the first 24 hours of insulin treatment and was most profound at 24 hours. No statistically significant changes (P less than 0.05) were found in red cell inorganic phosphate or nucleotide phosphate levels during the 24-hour study period. The levels of total red cell phosphate were lower in this group of patients than in nonacidotic diabetic subjects and decreased slightly after 24 hours of treatment. The red cell 2,3-DPG levels were low at the initiation of therapy and remained low during the 24-hour study period. Glucose, bicarbonate, lactate, and ketone levels fell in linear patterns with treatment. In view of the current evidence for the effects of low 2,3-DPG on oxygen delivery and the relation of low serum phosphate levels to RBC glycolysis and 2,3-DPG formation, this study reemphasizes the need for phosphate replacement during the early phases of treatment of DKA.     

Durability testing of a completely implantable electric total artificial heart

In vitro durability testing was conducted on the Penn State/3M electric total artificial heart (ETAH) to determine device durability and to evaluate device failures. A specialized mock circulatory loop was developed for this testing. Customized software continuously acquired data during the test period, and failures were analyzed using FMEA (failure modes and effects analysis) and FMECA (failure modes, effects, and criticality analysis) principles. Redesigns were implemented when appropriate. Reliability growth principles were then applied to calculate the 1 and 2 year reliability. The 1 and 2 year reliability of the Penn State/3M ETAH was shown to be 96.1% and 59.9%, respectively, at 80% confidence.