Characterization of apoptosis in intestinal ischaemia-reperfusion injury — a light and electron microscopic study.

Intestinal ischaemia-reperfusion (IR) injury has largely been attributed to cellular necrosis. Apoptosis, a distinct form of cell death has been observed following IR to the brain, heart, adrenals and the kidneys. In order to characterize the role of apoptosis in intestinal IR, small bowel grafts were stored in saline ( n  = 6) or modified University of Wisconsin solution ( n  = 6) at 4 °C for 12 h and reperfused for 6 h in syngeneic rats. Samples of normal, stored and reperfused intestines at 1, 3 and 6 h were analysed by light and electron microscopy. Following reperfusion, there was crypt and villous epithelial apoptosis, loss of crypt and villous structures, and an increase in mucosal inflammatory cell infiltration. Ongoing apoptosis was maximum at 1 h, its degree decreasing with increasing reperfusion intervals. Large numbers of apoptotic bodies dominated the picture from 3 h of reperfusion. This study has demonstrated the induction of apoptosis by intestinal IR injury, which begins within an hour of reperfusion and is probably responsible for the observed crypt and villous loss. This has potential therapeutic implications as, opposed to necrosis, apoptosis is an active process with genetic regulators and biochemical effectors, which can be specifically targeted to prevent or alleviate IR injury.     

Developmental Toxicity of CI-921, an Anilinoacridine Antitumor Agent

CI-921, an anilinoacridine compound active against leukemicand solid tumors, was evaluated for potential developmentaltoxicity. Intravenous injections of CI-921 in dextrose weregiven to female Sprague-Dawley rats (0.1, 0.5, and 1.0 mg/kg)on Gestation Days (GD) 6–15 and to female New ZealandWhite rabbits (0.1, 1.0 and 2.0 mg/kg) on GD 6–18. Appropriatevehicle and untreated controls were included. Maternal and fetalparameters, including external, visceral, and skeletal malformationsand variations, were assessed. Treatment of rats with 1.0 mg/kgresulted in maternal toxicity, manifested as reduced body weightgain and food consumption during and after treatment. Reducedfetal body weight, an increased incidence of stunted fetuses,malformations of the axial and appendicular skeleton, microphthalmia,and an increased number of anatomical variations (includinganomalies of the axial skeleton and apparent hydronephrosis)also occurred in rats at 1.0 mg/kg. Treatment of rabbits resultedin no apparent maternal toxicity. However, reduced fetal bodyweight, agenesis of the azygous lobe of the lung, and an increasedincidence of variations of the axial skeleton occurred at 2.0mg/kg in rabbits. These results indicate that CI-921, at thehighest dose tested in each species, produced developmentaltoxicity in the presence of maternal toxicity in rats, but inthe absence of maternal toxicity in rabbits.     

Use of Bromoergocryptine in the Validation of Protocols for the Assessment of Mechanisms of Early Pregnancy Loss in the Rat

Use of Bromoergocryptine in the Validation of Protocols forthe Assessment of Mechanisms of Early Pregnancy Loss in theRat. CUMMINGS, A. M., PERREAULT, S. D., AND HARRIS, S. T. (1991).Fundam. Appl. Toxicol 17, 563–574. Validated protocolsfor evaluating maternally mediated mechanisms of early pregnancyfailure in rodents are needed for use in the risk assessmentprocess. To supplement previous efforts in the validation ofa panel of protocols assembled for this purpose, bromoergocryptine(BEC) was used as a model compound because it is known to inhibitpituitary prolactin secretion. BEC was tested using the earlypregnancy protocol (EPP), the decidual cell response technique(DCR), the pre- vs postimplantation protocol (PPP), and embryotransport rate analysis (ETRA). These protocols evaluate theeffects of chemicals on multiple endpoints following exposureduring (a) the first 8 days of pregnancy, (b) early pseudopregnancyaccompanied by decidual induction, (c) the pre- and postimplantationintervals of early pregnancy, or (d) the period of embryo transport.In the EPP, dosing with BEC during Days 1–8 of pregnancyreduced the number of implantation sites found on Day 9 as wellas serum progesterone. The DCR technique revealed a dose-dependentinhibition of decidual growth concomitant with decreased serumprogesterone as a result of BEC treatment. A modified DCR techniqueusing hormone-supplemented ovariectomized rats demonstratedthat BEC did not impair decidual growth in the presence of adequateprogestogenic support. Pie- vs postimplantation dosing indicatedthat implantation is vulnerable to BEC effects at least throughDay 4. BEC had no effect on embryo transport rate. Data fromthese protocols identified BEC as having adverse maternal effectsduring early pregnancy. While the pituitary was not identifiedby these protocols as the site of BECs's primary action, theprotocols did identify a reduction in serum progesterone andimpaired uterine function as toxicological mechanisms mediatingthe reduced fertility seen following BEC exposure.     

Time course and mechanisms of decreased plasma volume during acute psychological stress and postural change in humans

In this study, we examined the effects of psychological stress on calculated plasma volume, the relationship of these changes to changes in hematologic factors, and the time course of plasma volume changes. Plasma volume changes were assessed using mass densitometry techniques, which measured changes in blood and plasma density. Hematologic and hemodynamic variables were assessed in 40 healthy men and women during a mental arithmetic (math) or benign reading task and during postural change (standing). Results indicated that math and posture change produced a significant decrease in plasma volume (ps < .001) and increases in blood pressure (ps < .001), blood and plasma density (ps < .001), and total plasma protein (p < .001). Correlations were observed between plasma volume changes and changes in systolic (r= .55, p < .0001), diastolic (r= .61, p < .0001), and mean (r= .65, p < .0001) arterial pressure during math; plasma volume and blood pressure returned to baseline within 12 min following the math task. These results suggest that an important mechanism for stress-induced decreases in plasma volume is increased blood pressure leading to increased fluid shifts from the vasculature into the interstitial spaces.     

Harlequin fetus successfully treated with etretinate

A harlequin fetus seen at birth was treated with etretinate and more general measures, including careful attention to fluid balance, calorie intake and temperature control. She improved, continued to develop, and had survived to 5 months at the time of this report.     

Adapting the Birthing Center Concept to a Traditional Hospital Setting

The author offers guidelines and examples of criteria which might be considered in establishing a birthing room facility in a traditional hospital setting.     

Teaching Mothers About Their Preterm Infants

The effects of a structured teaching program on 30 mothers' perceptions of and interaction with their premature (between 28 and 35 weeks' gestational age) infants was evaluated. Mothers who agreed to participate in the study were randomly assigned to one of three study groups: control, instruction, and attention. Mothers in the control group received routine care and support from the intensive care nursery staff. Mothers in the instruction group, in addition to the usual intensive care nursery procedures, received instruction about the unique physical and behavioral characteristics of premature infants. Mothers in the attention group were provided with the opportunity to discuss nonmedical concerns about their infants or their situations with the nurse researcher. Measures of maternal perceptions and behaviors were obtained by unbiased observers during home visits two, four, and eight weeks after the infants were discharged from the hospital. No significant differences were found among the groups on maternal perceptions or interaction behaviors.     

The role of endothelial cell apoptosis in inflammatory and immune diseases

The integrity of the endothelial lining of the vasculature is essential for vascular homeostasis and normal organ function. Endothelial injury or dysfunction has been implicated in the pathogenesis of diverse vascular diseases. Studies in vitro have demonstrated that a wide variety of stimuli can induce programmed cell death (apoptosis) of endothelial cells, and have suggested that apoptosis could be an important mechanism of vascular injury, resulting in vascular leak, inflammation, and coagulation. In this review, we focus on the potential role of endothelial apoptosis in the initiation and progression of inflammatory and immune disorders, reviewing human diseases and in vivo models in which endothelial cell apoptosis has been demonstrated. Although endothelial cell apoptosis is observed in many inflammatory and immune disorders, we find that there is, as yet, only limited experimental evidence demonstrating that it is critical to the pathogenesis of disease.     

Chronic Amiodarone Reduces Transmural Dispersion of Repolarization in the Canine Heart

Amiodarone Reduces Transmural Dispersion. Introduction: Amiodarone is a potent antiarrhythmic agent used in the management of both atrial and ventricular arrhythmias. In addition to its β-blocking properties, amiodarone is known lo block the sodium, potassium, and calcium channels in the heart. Its complex electropharmacology notwithstanding, the reasons for the high efficacy of the drug remain unclear. Also not well understood is the basis for the low incidence of proarrhythmia seen with amiodarone relative to other agents with Class III actions. The present study was designed to examine the effects of chronic amiodarone in epicardial, endocardial, and M cells of the canine left ventricle. Methods and Results: We used standard microelectrode techniques to record transmembrane activity from endocardial, epicardial, mid-myocardial, and transmural strips isolated from the canine left ventricle. Tissues were obtained from mongrel dogs receiving amiodarone orally (30 to 40 mg/kg per day) for 30 to 45 days or from untreated controls. Chronic amiodarone produced a greater prolongation of action potential duration in epicardium and endwardium, but less of an increase, or even a decrease at slow rates, in the M region, thereby reducing transmural dispersion of repolarization. In addition, chronic amiodarone therapy suppressed the ability of the I_kr, blocker, d-sotalol, to induce a marked dispersion of repolarization or early afterdepolarization activity. Conclusion: Our data demonstrate for the first time a direct effect of chronic amiodarone treatment to differentially alter the cellular electrophysiology of ventricular myocardium so as to produce an important decrease in transmural dispersion of repolarization, especially under conditions in which dispersion is exaggerated. These results may contribute to our understanding of the effectiveness of amiodarone in the treatment of life-threatening arrhythmias as well as to our understanding of the low incidence of proarrhythmia attending therapy with chronic amiodarone in comparison with other Class III agents.     

Epidemiology of low bone mineral density and fractures in children with severe cerebral palsy: a systematic review

Aim  Children with severe cerebral palsy (CP) are at risk for developing low bone mineral density (BMD) and low-impact fractures. The aim of this study was to provide a systematic literature review of the epidemiology of fractures and low BMD in children with severe CP, with an emphasis on risk factors. Gross Motor Function Classification System (GMFCS) levels IV and V were criteria for severe cerebral palsy.
Method  The literature (PubMed) was searched and eligible studies were given a level of evidence score using the Scottish Intercollegiate Guidelines Network criteria.
Results  Seven studies were found concerning epidemiology of fractures, 11 studies described epidemiology of low BMD, and 14 studies concerned risk factors. The methodological quality of most of these studies was poor. Five studies were considered well-conducted with low risk of confounding and bias. In these studies, the incidence of fractures in children with moderate to severe CP approached 4% per year, whereas the prevalence of low BMD in the femur was 77%. Limited ambulation, feeding difficulties, previous fractures, anticonvulsant use, and lower body fat mass were associated with low BMD z-scores.
Interpretation  There is only a limited amount of high-quality evidence on low BMD and fractures in children with severe CP.