Effects of phorbol myristate acetate and sivelestat on the lung injury caused by fat embolism in isolated lungs

Background  

Fat embolism syndrome (FES) associated with acute lung injury (ALI) is a clinical condition following long bone fracture. We have reported 14 victims due to ALI with FES. Our laboratory has developed an animal model that produced fat emboli (FE). The major purpose of this study was to test whether neutrophil activation with phorbol myristate acetate (PMA) and inhibition with sivelestat (SVT) exert protection on the lung.     

Fat embolism: a rational approach to treatment

Fat embolism following major trauma may be associated with a clinical syndrome with widespread pulmonary and systemic manifestations, the most serious being profound hypoxia with secondary atelectasis, pulmonary edema and pulmonary hypertension, and cerebral depression. Though the origin of the embolic fat is debated, there is evidence to support its origin from both the bone marrow and intravascular chylomicron coalescence.The clinical manifestations are largely explained by a prime assault upon the lung parenchyma and alteration in platelet characteristics.Early recognition and treatment of the condition is essential, adequate oxygenation being of prime importance. Steroids and heparin have been found to be of benefit.     

Cerebral fat embolism.

An unusual presentation of fat embolism is reported. Forty-eight hours after severe trauma to her legs the patient became stuporous and her right arm weak. A computerized tomography scan showed diffuse brain swelling. Although the petechiae, thrombocytopenia and lipuria characteristic of the fat embolism syndrome were present, at no time was there any evidence of pulmonary involvement.     

Nutritional deficiency anemias in nonhuman primates

The purpose of this report is to review past studies in which anemias, occurred spontaneously in nonhuman primates due to feeding inadequate diets or were induced by feeding diets deficient in a nutrient. Included is a review of anemias induced by deficiencies of iron, niacin, pyridoxine, pantothenic acid, protein, riboflavin, cyanocobalamin, folic acid, ascorbic acid and alpha-tocopherol. The anemia induced by deficiency of each nutrient is discussed with emphasis on the major clinical signs as well as peripheral blood and bone marrow pathology. Results of supplementation of the diet following induction of deficiency states are discussed also. Whenever applicable, a discussion is included of the use of nonhuman primates as animal models for studies simulating parallel nutritional deficiencies in man.     

Fat Embolism in Patients with Fractured Hips

Fat embolism was assessed at necropsy and correlated with clinical findings in the patients who died among 854 with fractured hips admitted to hospital between 1967 and August 1971. Sixteen cases of clinical importance were found, eight of which were judged to have been fatal or to have seriously contributed to death. Frequencies were as follows: 2·4 to 3·3% among 424 patients with subcapital fractures; 0·7 to 0·8% in the 405 with trochanteric fractures; 4·1 to 7% among subjects treated without operation, representing 30% of those who died within seven days; and 0·9 to 1·1% among patients treated by pinning, nailing, or nail-plating. The higher frequency in the conservatively treated group is probably related to selection of poor-risk subjects. Fat embolism was found in 6·8 to 8·0% of those with subcapital fractures treated by primary Thompson''s arthroplasty which utilizes acrylic cement, and in none of those given Moore''s prostheses for which cement is not used. Study of a larger group after Moore''s prosthesis is required to establish its lack of special risk. Fat embolism accounted for all the deaths within seven days of Thompson''s arthroplasty and for most within 14 days; it was clearly related to surgery in some cases.A possible explanation of the hazard of Thompson''s arthroplasty is that fat globule entry is enhanced by a rise of intramedullary pressure due to proximal occlusion of the reamed marrow cavity. A controlled trial of the effect of venting the marrow cavity on the frequency of fat embolism is warranted. It is possible that the acrylic monomer may also contribute to venous entry of medullary fat. The higher-age group of those with subcapital fractures and associated chronic cardiac and pulmonary disease might make them more susceptible to fat embolization than those in whom arthroplasty is also carried out for chronic hip disease.     

Comparative bone anatomy of commonly used laboratory animals: implications for drug discovery

To accommodate functional demands, the composition and organization of the skeleton differ among species. Microcomputed tomography has improved our ability markedly to assess structural parameters of cortical and cancellous bone. The current study describes differences in cortical and cancellous bone structure, bone mineral density, and morphology (geometry) at the proximal femur, proximal femoral diaphysis, lumbar vertebrae, and mandible in mice, rats, rabbits, dogs, and nonhuman primates. This work enhances our understanding of bone gross and microanatomy across lab animal species and likely will enable scientists to select the most appropriate species and relevant bone sites for research involving skeleton. We evaluated the gross and microanatomy of the femora head and neck, lumbar spine, and mandible and parameters of cancellous bone, including trabecular number, thickness, plate separation, and connectivity among species. The skeletal characteristics of rabbits, including a very short femoral neck and small amounts of cancellous bone at the femoral neck, vertebral body, and mandible, seem to make this species the least desirable for preclinical research of human bone physiology; in comparison, nonhuman primates seem the most applicable for extrapolation of data to humans. However, rodent (particularly rat) models are extremely useful for conducting basic research involving the skeleton and represent reliable and affordable alternatives to dogs and nonhuman primates. Radiology and microcomputed tomography allow for reliable evaluation of bone morphology, microarchitecture, and bone mineral density in preclinical and clinical environments.     

The three syndromes of fat embolism: pulmonary manifestations.

The clinical course and radiographs of 30 patients with fat embolism syndrome were reviewed. In all cases the classic triad of neurologic dysfunction, respiratory insufficiency, and petechiae were present. Three responses to embolized fat were noted. The hyperacute response was seen in two patients with paradoxical embolization of fat to the systemic circulation. A "classic response" was noted in 18 patients with transient respiratory compromise and variable radiographic findings. The two deaths in the group responding in the classical manner were attributed to massive pulmonary emboli. The third response, noted in ten patients, consisted of a chest radiograph compatible with pulmonary edema in the clinical setting of the adult respiratory distress syndrome. In this group the degree of respiratory dysfunction and pulmonary damage correlated with the development of disseminated intravascular coagulation. Pathologic correlations are presented and the mechanisms by which embolic fat produces tissue damage are discussed.     

Acute respiratory distress syndrome

Acute respiratory distress syndrome (ARDS) can be associated with various disorders. Among these, coronavirus infection may cause life-threatening severe acute respiratory syndrome (SARS). In this review, we present animal models and techniques for the study of ARDS, and discuss the roles and possible mechanisms of various chemical factors, including nitric oxide (NO). Our early work revealed that cerebral compression elicits severe hemorrhagic pulmonary edema (PE), leading to central sympathetic activation that results in systemic vasoconstriction. The consequence of systemic vasoconstriction is volume and pressure loading in the pulmonary circulation. Vasodilators, but not oxidant radical scavengers, are effective in the prevention of centrogenic PE. In isolated perfused lung, exogenous and endogenous NO enhances lung injury following air embolism and ischemia/reperfusion. In contrast, NO synthase (NOS) inhibitors reverse such lung injury. Although NO is important in maintaining vasodilator tone, hypoxia-induced pulmonary vasoconstriction is accompanied by an increase instead of a decrease in NO release. In animal and isolated lung studies, endotoxin produces acute lung injury that is associated with increases in cytokines and inducible NOS mRNA expression, suggesting that NO is toxic to the lung in endotoxin shock. Recently, we reported several rare cases that indicate that ARDS in patients with Japanese B encephalitis, lymphangitis with breast cancer and fat embolism is caused by different mechanisms. Our early and recent studies on ARDS and PE may provide information for clinical practice and the understanding of the pathogenesis of SARS.     

Endogenous colony formation in closed craniocerebral trauma in mice

The model of closed brain trauma in mice using stem hematopoietic cell cloning methods has shown inhibited endogenous spleen colony formation and reduced number of reticulocytes in blood circulation during early periods subsequent to traumatic procedure. Maximal inhibition of bone marrow function occurs 4 days after trauma and is accompanied by a dramatic reduction of thymus weight and cellularity. The observed changes in bone marrow function can be one of the important factors leading to lower resistance of the organism to infections during early periods after brain trauma.     

Biosafety in acquired immunodeficiency syndrome (AIDS) studies using nonhuman primates

The safety recommendations for studies on acquired immunodeficiency syndrome (AIDS) using nonhuman primates are based on knowledge about the epidemiology of the disease in humans, characteristics of the virus, and standard methods for handling nonhuman primates in the laboratory. Appropriate procedures avoid exposure to potentially infectious materials by skin puncture or to mucous membranes by using appropriate disinfecting agents, physical containment, protective clothing, and animal handling techniques.     

Vascular leak syndrome of Sprague-Dawley rats in a mandibular distraction osteogenesis study

Vascular leak syndrome (VLS) is a common and often fatal sequela of multiple bone traumas, and of infectious, toxic, and allergic insults in human patients. Although an animal model for VLS has not been fully established, rats have shown sensitivity to the syndrome that approximates that of the human population. We describe cases of VLS in three-month-old adult and one-month-old Sprague-Dawley rats in an osteogenesis study aimed at optimizing correction of bone hypoplasias and other craniofacial deformities in children, using a mandibular distraction device. In the study reported here, VLS was diagnosed in 40% of the rats that were necropsied after dying or being euthanized early, subsequent to mandibular osteotomy, a procedure that involves minimal bone trauma. The gross and histologic findings, as well as the clinical course of VLS in the rats of the osteogenesis study, were similar to those of documented human cases. Hence, the rat may be a useful animal model to h elp characterize the physiologic and molecular events that accompany this syndrome.     

Injections of leptin into rat ventromedial hypothalamus increase adipocyte apoptosis in peripheral fat and in bone marrow

The accumulation of fat cells (adipocytes) in bone marrow is now thought to be a factor contributing to age-related bone loss. Women with osteoporosis have higher numbers of marrow adipocytes than women with healthy bone, and bone formation rate is inversely correlated with adipocyte number in bone tissue biopsies from both men and women. Adipogenic differentiation of bone marrow stromal cells increases with age, but the factors regulating populations of mature adipocytes are not well understood. Leptin is thought to regulate adipose tissue mass via its receptors in the ventromedial hypothalamus (VMH). We have therefore tested the hypothesis that stimulation of leptin receptors in the VMH regulates adipocyte number in bone marrow. Results indicate that unilateral twice-daily injections of leptin into the rat VMH for only 4 or 5 days cause a significant reduction in the number of adipocytes in peripheral fat pads and bone marrow and indeed eliminate adipocytes almost entirely from bone marrow of the proximal tibia. Osteoblast surface is not affected with leptin treatment. Apoptosis assays performed on bone marrow samples from control and treated rats have revealed a significant increase in protein concentration of the apoptosis marker caspase-3 with leptin treatment. We conclude that stimulation of leptin receptors in the VMH significantly decreases the adipocyte population in bone marrow, primarily through apoptosis of marrow adipocytes. Elimination of marrow adipocytes via this central pathway may represent a useful strategy for the treatment and prevention of osteoporosis.     

Basic considerations in assessing and preventing occupational infections in personnel working with nonhuman primates

Transmission of zoonotic infections of nonhuman primates to human contacts is a documented occupational hazard. Although the list of naturally occurring and experimentally induced infections of nonhuman primates is extensive the risks of transmission may substantially be reduced by the use of good animal care practices, appropriate protective measures and devices, and suitable animal facilities. The essential elements of good animal care practices include high levels of personal hygiene; minimizing the creation of potentially infectious aerosols and droplets; use of personal protective clothing, devices, and vaccines; a system for reporting, evaluating, and treatment of occupational exposures and infections; and animal facilities appropriate for the species being used and the activities conducted. These essential elements are described and discussed in the context of published voluntary codes of practice--notably "Biosafety in Microbiological and Biomedical Laboratories."     

Preventing fat embolism syndrome (FES) in implantation of cemented hip endoprosthesis shafts with a trans-prosthetic drainage system (TDS)]

In vitro studies with the transprosthetic drainage system (TDS) have revealed a reduction in intrafemoral pressure in cemented total hip prosthesis. The aim of the present study was to establish whether the incidence of fat embolic syndrome (FES) is also reduced. Ten patients underwent standardized cemented total hip replacement using TDS under standardized general anaesthesia. The usual peri-operative monitoring measures were extended to include cardiopulmonary monitoring (pulmonary artery catheter, intra-arterial blood pressure) and two-dimensional transoesophageal echocardiography. Previous studies had reported an increased risk for fat embolic syndrome with conventional, and even with vacuum cementing techniques. Our recorded cardiopulmonary data and the data provided by two-dimensional transoesophageal echocardiography show a significant reduction in pulmonary embolism with TDS. This technique can be recommended in particular for high-risk patients (osteoporosis, elderly patients) and the implantation of long femoral stems. On the basis of the clinical data, a new femoral stem allowing the use of the TDS technique is being developed.     

Toward a science of welfare for animals in the zoo

Although the accredited institutions of the Association of Zoos and Aquariums have all committed to enhancing the welfare of nonhuman animals, acceptable standards and best practices are still under debate. Currently, experts from zoos and the field hold widely divergent opinions about exhibition and management standards for elephants. Standards and practices for managing nonhuman primates provide a model for other nonhuman creatures exhibited in zoos and aquariums. Examining the key issues for primates demonstrates the value of applying scientific data before promulgating standards. The field of applied behavior analysis provides a wealth of information to frame the debate. Animal behaviorists have contributed to an emerging science of animal welfare, which may provide a foundation for empirical zoo management, standards, and practices.     

Melioidosis in imported non-human primates

In 1969, five cases of melioidosis in three separate outbreaks were diagnosed in nonhuman primates in the United States. In the first outbreak, two stump-tailed macaque monkeys (Macaca arctoides) developed signs of the disease approximately 6 months after purchase. A third animal, a chimpanzee (Pan troglodytes), probably acquired its infection from one of these monkeys. Two other unrelated cases involving a pig-tailed monkey (Macaca nemestrina) and a rhesus monkey (Macaca mulatta) were diagnosed. These monkeys had been imported 3 years and 6 months, respectively, prior to the recognized onset of their disease. These cases represent the first known occurrences of spontaneous melioidosis in nonhuman primates in the United States.     

Prostaglandin E2 enhances human cord blood stem cell xenotransplants and shows long-term safety in preclinical nonhuman primate transplant models

Hematopoietic stem cells (HSCs) are used in transplantation therapy to reconstitute the hematopoietic system. Human cord blood (hCB) transplantation has emerged as an attractive alternative treatment option when traditional HSC sources are unavailable; however, the absolute number of hCB HSCs transplanted is significantly lower than bone marrow or mobilized peripheral blood stem cells (MPBSCs). We previously demonstrated that dimethyl-prostaglandin E2 (dmPGE2) increased HSCs in vertebrate models. Here, we describe preclinical analyses of the therapeutic potential of dmPGE2 treatment by using human and nonhuman primate HSCs. dmPGE2 significantly increased total human hematopoietic colony formation in?vitro and enhanced engraftment of unfractionated and CD34(+) hCB after xenotransplantation. In nonhuman primate autologous transplantation, dmPGE2-treated CD34(+) MPBSCs showed stable multilineage engraftment over 1 year postinfusion. Together, our analyses indicated that dmPGE2 mediates conserved responses in HSCs from human and nonhuman primates and provided sufficient preclinical information to support proceeding to an FDA-approved phase 1 clinical trial.     

A Tail of Two Monkeys: Social Housing for Nonhuman Primates in the Research Laboratory Setting

Despite great adaptability, most nonhuman primates require regular tactile contact with conspecifics for their psychological well being. By illustrating the inherent value of social contact and by providing clues to the best ways of satisfying this need, behavioral studies are useful in designing social enrichment programs. Although group housing is ideal for most gregarious primates, space constraints and protocol requirements may preclude such environments for macaques housed indoors. Pair housing is an effective and practical alternative. Furthermore, such social experience facilitates integration into future social groups, including those in postresearch retirement facilities. This article references common research protocols that accommodate pair housing and includes scientific recommendations for institutional animal care and use committees (IACUCs) to facilitate providing physical social contact for nonhuman primates in laboratories.     

A tail of two monkeys: social housing for nonhuman primates in the research laboratory setting

Despite great adaptability, most nonhuman primates require regular tactile contact with conspecifics for their psychological well being. By illustrating the inherent value of social contact and by providing clues to the best ways of satisfying this need, behavioral studies are useful in designing social enrichment programs. Although group housing is ideal for most gregarious primates, space constraints and protocol requirements may preclude such environments for macaques housed indoors. Pair housing is an effective and practical alternative. Furthermore, such social experience facilitates integration into future social groups, including those in postresearch retirement facilities. This article references common research protocols that accommodate pair housing and includes scientific recommendations for institutional animal care and use committees (IACUCs) to facilitate providing physical social contact for nonhuman primates in laboratories.     

The use of animal models for stroke research: a review

Stroke has been identified as the second leading cause of death worldwide. Stroke is a focal neurologic deficit caused by a change in cerebral circulation. The use of animal models in recent years has improved our understanding of the physiopathology of this disease. Rats and mice are the most commonly used stroke models, but the demand for larger models, such as rabbits and even nonhuman primates, is increasing so as to better understand the disease and its treatment. Although the basic mechanisms of stroke are nearly identical among mammals, we here discuss the differences between the human encephalon and various animals. In addition, we compare common surgical techniques used to induce animal models of stroke. A more complete anatomic knowledge of the cerebral vessels of various model species is needed to develop more reliable models for objective results that improve knowledge of the pathology of stroke in both human and veterinary medicine.