Investigation of small fatigue cracks—I. Plastic deformation associated with small fatigue cracks

Small fatigue crack growth has been studied in two 7000 series aluminium alloys possessing different grain sizes. As it has been suggested that the relatively large plastic deformation associated with small fatigue cracks may explain thier fast growth rates compared to long cracks, the work focused on experimental measurement of the plastic zone size (PZS) accompanying small cracks. The characteristics of plastic zone development and the relationship between PZS and crack growth rate have been studied through periodic plastic zone size measurement of growing small fatigue cracks. It was found that small fatigue crack growth is indeed accompanied with comparatively large plastic zone sizes. It is suggested that this is mainly due to a near surface effect. It was also found that an exponential relation exists between small crack growth rates and their plastic zone sizes for a given material.     

Neuropathological sequelae of traumatic brain injury: relationship to neurochemical and biomechanical mechanisms

Brain injury is the leading cause of death among individuals under the age of 45 years in the United States and Europe. Recently, the neuropathologic classification of posttraumatic brain damage has provided insight into the specific mechanisms underlying traumatically induced neuronal damage and death. Studies regarding the biomechanics of brain trauma have also provided great insight into the pathophysiologic mechanisms underlying specific patterns of posttraumatic cellular death. Based upon recent clinical evaluations and biomechanical studies, laboratory models of human brain injury have been developed that faithfully reproduce a number of important features of clinical brain trauma. Biomechanical models have been used to study both the acute sequelae of brain injury and the role of neurochemical alterations in contributing to the development of secondary or delayed cellular death and damage. This report reviews and integrates the laboratory investigations linking experimental models of brain injury to clinical diagnosis and treatment.     

Role of programmed (apoptotic) cell death during the progression and therapy for prostate cancer

Cells possess within their epigenetic repertoire the ability to undergo an active process of cellular suicide termed programmed (or apoptotic) cell death. This programmed cell death process involves an epigenetic reprogramming of the cell that results in an energy-dependent cascade of biochemical and morphologic changes (also termed apoptosis) within the cell, resulting in its death and elimination. Although the final steps (i.e., DNA and cellular fragmentation) are common to cells undergoing programmed cell death, the activation of this death process is initiated either by sufficient injury to the cell induced by various exogenous damaging agents (e.g., radiation, chemicals, viruses) or by changes in the levels of a series of endogenous signals (e.g., hormones and growth/survival factors). Within the prostate, androgens are capable of both stimulating proliferation as well as inhibiting the rate of the glandular epithelial cell death. Androgen withdrawal triggers the programmed cell death pathway in both normal prostate glandular epithelia and androgen-dependent prostate cancer cells. Androgen-independent prostate cancer cells do not initiate the programmed cell death pathway upon androgen ablation; however, they do retain the cellular machinery necessary to activate the programmed cell death cascade when sufficiently damaged by exogenous agents. In the normal prostate epithelium, cell proliferation is balanced by a equal rate of programmed cell death, such that neither involution nor overgrowth normal occurs. In prostatic cancer, however, this balance is lost, such that there is greater proliferation than death producing continuous net growth. Thus, an imbalance in programmed cell death must occur during prostatic cancer progression. The goal of effective therapy for prostatic cancer, therefore, is to correct this imbalance. Unfortunately, this has not been achieved and metastatic prostatic cancer is still a lethal disease for which no curative therapy is currently available. In order to develop such effective therapy, an understanding of the programmed death pathway, and what controls it, is critical. Thus, a review of the present state of knowledge concerning programmed cell death of normal and malignant prostatic cells will be presented.     

The role of myocardial apoptosis in the development of heart failure

Heart failure can result from a variety of causes, including volume or pressure overload and contractile disturbances of the myocardium. Loss of myocytes is an important mechanism in the development of cardiac failure. In general, myocyte death resulting in progressive deterioration of myocardial function is attributed to necrosis, but recently the involvement of programmed cell death (mainly apoptosis) has been suggested. The authors review the possible role of myocardial apoptosis in developing of heart failure. Subcellular genetic regulatory processes as well as the pharmacological susceptibility of programmed cell death are also discussed. In heart failure, significant amount of cardiac myocytes undergoes apoptosis, that unlike necrosis can be prevented. Specific inhibition of this process could mean a considerable part of cardioprotection after thorough understanding of the underlying cellular mechanisms.     

Exogenous glutamate enhances glutamate receptor subunit expression during selective neuronal injury in the ventral arcuate nucleus of postnatal mice

Much attention has been paid to proteinases derived from not only neurons but also microglia in relation to neuronal death. There is accumulating evidence that intra- and extracellular proteinases in these cells are part of the basic machinery of neuronal death pathways. Some members of the ced-3/interleukin-1 beta converting enzyme (ICE) (caspase) family of cysteine proteinases have been thought to play a major role in apoptosis of not only non-neuronal cells but also neurons. Calpain has also been demonstrated to be a mediator of the neurodegenerative response. Recent studies have shown that excitotoxic and ischemic neuronal injury could be attenuated by inhibitors of caspases and calpain. Several recent studies have suggested the involvement of endosomal/lysosomal proteinases, including cathepsins B, D and E, in neuronal death induced by excitotoxins and ischemia. Furthermore, it has been reported that the extracellular tissue-type plasminogen activator/plasmin proteolytic cascade is involved in excitotoxic injury of the hippocampal neurons. In addition to such neuronal proteinases, microglial proteinases are believed to be important for the modification of neuronal functions positively or negatively. Cathepsins E and S derived from microglia have been suggested to contribute to neuronal survival through degradation and removal of beta-amyloid, damaged neurons and cellular debris. On the other hand, 6-hydroxydopamine-induced microglial cell death was inhibited by inhibitors of aspartic proteinases and caspases, suggesting the involvement of cathepsins E and D and caspases in microglial cell death. Therefore, identification of which proteinases play a causative role in neuronal death execution and clarification of the regulators and substrates for such proteinases is very important for understanding the molecular basis of the neuronal death pathways and to develop novel neuroprotective agents.     

Programmed cell death during the earliest stages of spinal cord development in the chick embryo: a possible means of early phenotypic selection

The spatiotemporal distribution of cell death in the chick embryo neural tube and spinal cord (brachial region) was examined between stage (St.) 12 and 22, in plastic semithin sections. Between St. 12 and 16, the total number of pycnotic cells per segment was low, whereas after St. 16 the number of pycnotic cells was substantially increased. Between St. 17 and 19 three cell death foci or regions could be recognized. One region, the dorsal pycnotic zone, was located in the most dorsal part of the spinal cord, including the neural crest, with the highest number of pycnotic cells observed at St. 18. The second region, or ventral pycnotic zone, was located between motoneurons and the floor plate and had the highest number of dying cells at St. 17. The third region, the floor plate pycnotic zone, was located in the midportion of the floor plate and had the greatest amount of cell death at St. 19. Although low numbers of pycnotic cells were also observed in other regions between St. 17 and 19, no pycnotic cells were found in the ventrolateral region that gives rise to motoneurons. Ultrastructural observations as well as data from in situ nick end labeling indicate that the pycnotic cells observed in the neural tube die by apoptosis and that the debris from the dead cells is phagocytized primarily by adjacent healthy neuroepithelial cells. Although the spatiotemporal distribution of pycnotic cells suggests that cell death at these early stages could play a role in establishing the pioneer axonal pathway for spinal commissural neurons, preliminary observations following perturbations of cell death do not support this notion. Alternatively, early cell death may be involved in the regulation of cellular patterning along the dorsoventral axis of the neural tube by a kind of negative selection of specific progenitor cells.     

The loss of driving force due to volume diffusion ahead of a migrating boundary in a cellular precipitation reaction

Experimental confirmation has been obtained of the existence of a solute diffusion zone ahead of a migrating cell boundary during the cellular precipitation of Cr₂N in a high nitrogen CrNi austenitic steel. The solute profile has been measured directly using analytical electron microscopy and indirectly by optical microscopy of potentiostatically etched specimens. The width of the diffusion zone was observed to increase with reaction time; this corresponded to the deceleration of the migration rate of the cell boundary with reaction time.     

Islamic views on organ donation

As medical technology continues its advance, the use of organ transplantation for the palliation and cure of chronic diseases is rising. However, many barriers to organ donation exist, including religious ones. It has long been known that Muslims in North America tend not to donate organs. In the past this tendency has been attributed to religious prohibitions even though cultural views may also play a strong role. The purpose of this article is to explore and define the Islamic religious opinion on organ donation and transplantation to enhance healthcare professionals' understanding of Islamic views concerning brain death and organ donation. It is hoped that this knowledge and understanding may benefit both patients and caregivers in the North American healthcare setting.     

Inositol 1,4,5-trisphosphate receptor expression in odontoblast cells

Although the exact pathogenesis of mustard gas-induced dermal toxicity remains elusive, morphopathological data gathered in controlled animal and in vitro investigations is providing important clues as to approximate mechanisms. Our laboratory has been studying dermal effects of the chemical warfare agent, sulfur mustard, in a variety of animal models, cultured isolated human cells, and in vitro organotypic skin models. Published anatomical, pathological, and ultrastructural results of these studies have documented consistent cellular and basement membrane zone effects irrespective of the model. Cellular effects include the early targeting of basal cells of the stratum basale to the exclusion of other epidermal cells, with nuclear and cytoplasmic indications of cell injury and cell death. Effects on the basement membrane zone include the formation of characteristic microvesicles in the lamina lucida of those models which possessed structural components of a true basement membrane. We are now investigating effects on proteins of the basement membrane microenvironment and correlate in the present paper the morphopathology of sulfur mustard dermal lesions with immunohistochemical study of bullous pemphigoid antigen, laminin, type IV collagen, and type VII collagen.     

Gap junction channels: new roles in disease

The importance of intercellular communication to complex cellular processes such as development, differentiation, growth, propagation of electrical impulses and diffusional feeding has long been appreciated. The realization that intercellular communication is mediated by gap junction channels, which are in turn comprised of a diverse family of proteins called the connexins, has provided new tools and avenues for studying the role of intercellular communication in these important cellular processes. The identification of different connexin isoforms has not only enabled the development of specific reagents to study connexin expression patterns, but has also allowed the functional properties of the different connexin isoforms and how they interact with each other, to be explored. Increasingly, the knowledge gained from studying connexin diversity is being used to investigate the role played by gap junction channels in a number of diseases. In this article we highlight selected cases where gap junction channels have been shown or are believed to be directly involved in the disease process.     

Nitric oxide: implication in excitotoxicity and cerebral ischemia

In the central nervous system, several cellular types are able to produce nitric oxide (NO). In particular in neuronal cells, the excitatory amino-acid receptor activation induces NO synthesis and release. Since excessive activation of these receptors is responsible of neuronal death in excitotoxicity or cerebral ischemia, the hypothesis of a NO role in neuronal damage has been proposed. The use of NO synthesis inhibitors in excitotoxicity or cerebral focal ischemia models has provided contradictory data. Here we attempt to present the main bibliographic data concerning this controversial research area in order to a better comprehension of NO role in neuronal death.     

Metabolic disarrangement in ischemic heart disease and its therapeutic control

The term myocardial ischaemia describes a condition which exists when fractional uptake of oxygen in the heart is not sufficient to maintain the rate of cellular oxidation. This leads to extremely complex situations which have been extensively studied in recent years. A large amount of experimental research has been directed to establish the precise sequence of biochemical events leading to myocyte necrosis as such knowledge could lead to rational treatments designed to delay myocardial cell death. At the present time there is no simple answer to the question of what determines cell death and no recovery on reperfusion. Problems arise because: (1) ischaemic damage is not homogeneous and many factors may combine to cause cell death; (2) severity of biochemical changes and development of necrosis are usually associated (both processes being dependent on the duration of the ischaemia) and it is impossible to establish a causal relationship; (3) the inevitability of necrosis can only be assessed by reperfusion of the ischaemic myocardium. Restoration of flow, however, might result in numerous further negative consequences, thus directly influencing the degree of recovery. From the clinical point of view, I have recently learned that there are several potential manifestations and outcomes associated with myocardial ischaemia and reperfusion. Without doubt ventricular dysfunction (either systolic or diastolic) of the ischaemic zone is the most reliable clinical sign of ischaemia, since ECG changes and symptoms are often absent. The ischaemia-induced ventricular dysfunction, at least initially, is reversible, as early reperfusion of the myocardium results in restoration of normal metabolism and contraction. In the ischaemic zone, recovery of contraction might occur instantaneously or, more frequently, with a considerable delay, thus yielding the condition recently recognized as the stunned myocardium. On the other hand, when ischaemia is severe and prolonged, cell death might occur. Reperfusion at this stage is associated with the release of intracellular enzymes, disruption of cell membranes, influx of calcium, persistent reduction of contractility, and eventual necrosis of at least a portion of the tissue. This entity has been called reperfusion damage by those who believe that much of the injury is the consequence of events occurring at the moment of reperfusion rather than as result of changes occurring during the period of ischaemia. The existence of reperfusion damage, however, has been questioned, and it has been argued that, with the exception of the induction of arrhythmias, it is difficult to be certain that reperfusion causes further injury. The existence of such an entity has clinical relevance, as it would imply the possibility of improving recovery with specific interventions applied at the time of reperfusion. In 1985 Rahimtoola described another possible out-come of myocardial ischaemia. He demonstrated that late reperfusion (after months or even years) of an ischaemic area showing ventricular wall-motion abnormalities might restore normal metabolism and function. He was the first to introduce the term hibernating myocardium, referring to ischaemic myocardium in which the myocytes remain viable but in which contraction is chronically depressed. Our data on metabolic changes occurring during ischaemia followed by reperfusion obtained either in the isolated and perfused rabbit hearts or in CAD patients undergoing intracoronary thrombolysis or aortocoronary by-pass grafting will be reviewed.     

Spondyloepiphyseal dysplasia, corneal clouding, normal intelligence and acid beta-galactosidase deficiency

The presence of fat in the fetal zone of the adrenal cortex in the stillborn macerated fetus is indicative of the mode of intrauterine death. Three basic patterns are recognized. In the type I pattern there is only a scant amount of fat, close to the medullary zone. In the type II pattern fat is more widespread and is present in many more cells of the fetal zone. The type III pattern reflects a massive fatty change of almost all cells throughout the fetal cortical zone. Correlation of the three fat patterns with the pathology of the placenta and clinical data relevant to the etiology of intrauterine death has led to the following conclusions. The type I fat pattern is indicative of an acute mode of death, the type II pattern is indicative of a more prolonged period of intrauterine deterioration prior to death, whereas the type III pattern is indicative of a chronic mode of death. Determination of the fat patterns in the fetal zone of the adrenal cortex can be helpful when the clinician is confronted with the problem of fetal death, especially when maceration may hamper more detailed pathologic studies.     

An Electron Microscope Study of the Featureless Zone Obtained during Rapid Solidification

The microstructure observed on the rapid solidification of dilute alloys of Cu in Al has been examined. A high intensity heat source, namely, a 6 kW CO₂ laser beam was passed over the surface of the alloy, and on regrowth a featureless zone is seen prior to a cellular morphology. Scanning transmission electron microscopy in conjunction with X-ray microanalysis was used to show that a concentration gradient exists across this region. The results support the theory that it is a plane front zone formed during the resolidification process. Formerly with the Department of Metallurgy, University of Illinois, is Scientist, Defence Metallurgical Research Laboratory, P. O. Kanchanbagh, Hyderabad, India 500258.     

Aggregate degradation by growth plate proteases

For long bone growth to occur, calcification of the matrix must begin in the lower hypertrophic zone of the growth plate. It generally is accepted that physeal proteoglycans help regulate mineralization, and that, at least in vitro, smaller proteoglycan fragments are less inhibitory of mineral formation. It also has been shown that proteoglycan degrading enzymes are concentrated in the hypertrophic zone, where calcification occurs. Thus, one can hypothesize that these enzymes are involved in the calcification process. Proteoglycans appear mainly as the aggregate form in the physis, and this study demonstrates the ability of the naturally occurring physeal enzymes to degrade proteoglycan aggregate, without first disaggregating it. Because the matrix constituents probably limit hypertrophic cell size and shape, this degradation may have some relationship to the rate of growth of the physis.     

Action of natural estrogens on the vessel wall: molecular mechanisms and clinical implications

Myocardial infarction is the major cause of death in the Western world. Men are more prone to develop coronary artery disease than women, who rarely develop coronary disease before menopause. Although epidemiological data has long been available showing a protective effect of estrogen on the vascular system, the underlying mechanisms have been investigated more thoroughly only in recent years. Meta-analysis studies have revealed that only half of the protective effect on estrogen replacement therapy is due to its positive effects on the lipid profile and that a large part of this protection is caused by mechanisms distinct from lipid metabolism. It is now known that estrogens also exert effects on vascular function and structure of the vessel wall involving numerous cellular and molecular mechanisms. Here we review actions of natural estrogens on human vascular cells and arteries. Estrogens can modulate vascular function by increasing nitric oxide production via stimulation of endothelial nitric oxide synthase (eNOS) and decreasing endothelin-1 levels in vivo. Furthermore, 17 beta-estradiol is an inhibitor of vascular smooth muscle cell proliferation and migration, phenomena that play a major role in atherosclerotic vascular disease and in the remodelling process. 17 beta-estradiol can also acutely affect vascular tone in human arteries and attenuates constriction induced by contractile agonists. Finally, clinical studies have shown that 17 beta-estradiol can acutely and chronically ameliorate vascular function in women with and without vascular disease. In conclusion, results from clinical and in vitro studies confirm the positive effects of natural estrogens on vascular function and protection from coronary heart disease. Thus, primary prevention of coronary heart disease by estrogen replacement therapy after the menopause appears to be a new and straightforward approach by which cardiovascular mortality in women can be reduced.