Inhibitor profiles of alkaline phosphatases in bovine preattachment embryos and adult tissues.

The alkaline phosphatases are a small family of isozymes. Bovine preattachment embryos transcribe mRNA for two tissue-specific alkaline phosphatases (TSAP2 and TSAP3) beginning at the 4- and 8-cell stages. Whereas no mRNA has been detected in oocytes, there is maternally inherited alkaline phosphatase activity. It is not known which isozyme(s) is responsible for the maternal activity or when TSAP2 and TSAP3 form functional protein. No antibodies are available that recognize the relevant bovine alkaline phosphatases. Therefore, sensitivity to heat and chemical inhibition was used to separate the different isozymes. By screening tissues, it was determined that the bovine tissue-nonspecific alkaline phosphatase (TNAP) is inactivated by low temperatures (65C) and low concentrations of levamisole (<1 mM), whereas bovine tissue-specific isozymes require higher temperatures (90C) and levamisole concentrations (>5 mM). Inhibition by L-homoarginine and L-phenylalanine was less informative. Cumulus cells transcribe two isozymes and the pattern of inhibition suggested heterodimer formation. Inhibition of alkaline phosphatase in bovine embryos before the 8-cell stage indicated the presence of only TNAP. At the 16-cell stage the pattern was consistent with TNAP plus TSAP2 or -3 activity, and in morulae and blastocysts the pattern indicated that the maternal TNAP is fully supplanted by TSAP2 or TSAP3.

Soluble adhesion molecules in infants and children undergoing cardiopulmonary bypass.

BACKGROUND: The vascular injury and tissue damage after cardiopulmonary bypass (CPB) involves leukocyte-endothelial interactions mediated by cell adhesion molecules. This study was designed to determine the time course of soluble adhesion molecule levels after CPB in infants and children and to determine whether these levels correlated with preoperative variables, intraoperative bypass management, or postoperative course. METHODS AND RESULTS: In 56 patients undergoing CPB (median age 1.0 year, range 2 days to 19 years), plasma concentrations of soluble E-, P-, and L-selection, soluble ICAM-1, and soluble VCAM-1 were measured using sandwich enzyme-linked immunosorbent assays at the following times: at induction of anesthesia, after 15 minutes of CPB, at the end of CPB, and 1, 6, 18, and 42 hours after CPB. Preoperative, intraoperative, and postoperative data were prospectively recorded. All soluble adhesion molecule levels fell markedly at the initiation of CPB as a result of a combination of dilution and bypass circuit uptake. The time course of soluble selectins (P, E, and L), normalized to end of bypass levels, all rose significantly (P<.001) in the initial 6 hours after CPB and then returned to end bypass levels at 42 hours. Soluble ICAM-1 and VCAM rose 63% and 89% in the first 6 hours and remained elevated throughout the 42 hours. Peak soluble P-selectin levels were associated with total support time (P=.04) and preoperative cyanosis (P=.003). Soluble L-selectin levels were inversely associated with longer total support time (P=.002), longer circulatory arrest time (P=.004), longer length of intubation (P=.0009), preoperative cyanosis (P=.002), and younger age at surgery (P=.01). CONCLUSIONS: Soluble adhesion molecules have a characteristic time course in infants and children undergoing CPB. The soluble adhesion molecule levels after CPB change most significantly in patients with the highest potential for vascular injury: younger, cyanotic patients with longer pump times and longer postoperative courses. These data may be useful in the assessment of new therapies.

Perioperative effects of alpha-stat versus pH-stat strategies for deep hypothermic cardiopulmonary bypass in infants.

OBJECTIVES: In a randomized, single-center trial, we compared perioperative outcomes in infants undergoing cardiac operations after use of the alpha-stat versus pH-stat strategy during deep hypothermic cardiopulmonary bypass. METHODS: Admission criteria included reparative cardiac surgery, age less than 9 months, birth weight 2.25 kg or more, and absence of associated congenital or acquired extracardiac disorders. RESULTS: Among the 182 infants in the study, diagnoses included D-transposition of the great arteries (n = 92), tetralogy of Fallot (n = 50), tetralogy of Fallot with pulmonary atresia (n = 6), ventricular septal defect (n = 20), truncus arteriosus (n = 8), complete atrioventricular canal (n = 4), and total anomalous pulmonary venous return (n = 2). Ninety patients were assigned to alpha-stat and 92 to pH-stat strategy. Early death occurred in four infants (2%), all in the alpha-stat group (p = 0.058). Postoperative electroencephalographic seizures occurred in five of 57 patients (9%) assigned to alpha-stat and one of 59 patients (2%) assigned to pH-stat strategy (p = 0.11). Clinical seizures occurred in four infants in the alpha-stat group (4%) and two infants in the pH-stat group (2%) (p = 0.44). First electroencephalographic activity returned sooner among infants randomized to pH-stat strategy (p = 0.03). Within the homogeneous D-transposition subgroup, those assigned to pH-stat tended to have a higher cardiac index despite a lower requirement for inotropic agents; less frequent postoperative acidosis (p = 0.02) and hypotension (p = 0.05); and shorter duration of mechanical ventilation (p = 0.01) and intensive care unit stay (p = 0.01). CONCLUSIONS: Use of the pH-stat strategy in infants undergoing deep hypothermic cardiopulmonary bypass was associated with lower postoperative morbidity, shorter recovery time to first electroencephalographic activity, and, in patients with D-transposition, shorter duration of intubation and intensive care unit stay. These data challenge the notion that alpha-stat management is a superior strategy for organ protection during reparative operations in infants using deep hypothermic cardiopulmonary bypass.

Famotidine as an adjunct treatment of resistant schizophrenia.

Some patients suffering from schizophrenia fail to respond to or tolerate adequate doses of available antipsychotic medications. Thus, innovative pharmacotherapeutic approaches, such as augmentation strategies, play an important role in the management of these treatment-resistant patients. A recent case report suggested that the administration of famotidine to a patient suffering from schizophrenia with peptic ulcer disease was associated with improvement in the deficit symptoms of schizophrenia. Famotidine is a potent highly selective H2 receptor antagonist which crosses the blood-brain barrier. Impressed by this finding, famotidine was prescribed to some of our treatment-resistant patients suffering from schizophrenia who demonstrated significant deficit symptoms of schizophrenia. The subjects were 12 (eight male, four female) treatment-resistant psychotic patients whose antipsychotic medications were augmented with famotidine in an open trial. They ranged in age from 21 to 48 years with a mean age of 32.75 years. Seven of the 12 subjects made significant improvement resulting in discharge from hospital. Paranoid disturbances as well as absence of comorbid substance use were predictors of good response to famotidine augmentation of the antipsychotic medications. The results implied that H2 receptor activity in the brain might play a role in the pathogenesis of deficit syndromes in schizophrenia. Further studies of this strategy are recommended, since it may open a window of understanding of the negative (deficit) syndrome and its treatment.