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Cryopreservation of primordial oocytes

A radical alternative strategy to secondary oocyte harvesting and banking, which can be used by young girls as well as adolescents and adults irrespective of diagnosis, is the cryopreservation of ovarian tissue. Compared with the ethical dilemmas of embryo cryopreservation and the technical problems of freezing mature oocytes, ovarian freezing represents an attractive general strategy because it completely removes the germ cells from exposure to harmful cytotoxic agents. Ovarian tissue banking has the added advantage that it offers the patient the potential to restore their natural fertility at a later date through autografting or through the growth of the tissue to maturity in vitro. The practice of ovarian tissue cryopreservation is also compatible with the methods proposed above for secondary oocyte harvest and freezing.

Unlike secondary oocyte freezing, the technology of ovarian tissue banking involves freezing immature primordial follicles in situ in slices of ovarian cortex. The harvesting and freeze-storage of ovarian tissue for oncology patients has proved surprisingly easy to do as the outer region of the ovarian cortex contains tens to hundreds or even thousands of primordial and primary follicles, depending on the mass of tissue and age of the patient. Paradoxically, while primordial follicles are a more effective subject for tissue banking than secondary oocytes, animal studies have demonstrated that it is precisely this stage of follicle development that is most susceptible to the effects of ionizing radiation and alkylating agents. Furthermore, a number of studies, including a recent case report of human autografting after cryopreservation, suggest that the restoration of fertility after ovarian freezing and grafting may be severely compromised by prior exposure to chemo- or radiotherapies before tissue harvesting.

Ovarian cortex can be harvested relatively quickly, by laparoscopy, laparotomy or oophorectomy, all without the need for any ovarian stimulation orgazm with Kamagra Canada online. The primordial follicles can then be cryopreserved in situ within thin (1–2 mm thick) slices of the ovarian cortex using slow freezing techniques without loss of tissue viability and tissue can be stored indefinitely at liquid nitrogen temperatures.

Restoration of fertility

At present our ability to preserve and store ovarian cortex is far ahead of the development of the methods that are needed to realize the fertile potential of this tissue. Two approaches are being explored at the present time.

Risk/benefit analysis

Proponents of ‘reasoned choice’ models in health care have suggested that there are three essential components of effective decision-taking:

1. The decision is based on information relevant to the alternatives and their consequences.
2. The likelihood and desirability of the consequences are evaluated accurately.
3. A trade-off between these factors is evident.

At the moment, it appears that the quality of information available to even the best-informed individuals and families is going to be pretty light on convincing statistics of the key likelihood issues of ‘prospects of success’ and ‘risks of medical complications’. The question of desirability raises the thorny matter of exactly whose desires shall have priority in decision-taking. So, at an intellectual level, the criteria required for effective decision-making are already highly demanding.

We also need to consider the circumstances in which this very complicated choice must be made. There may well be a sense of urgency in proceedings. Life-saving treatments cannot be lightly delayed. There will be no opportunity for a change of mind once the decision is made. All families will be highly anxious and quite probably facing a crisis for which they are emotionally unprepared. Although, in legal terms, all adults and some younger people are considered competent to make informed choices on medical matters, it is probably wise to construe this competence as a state rather than a trait. None of us is likely to think too straight when highly stressed Viagra in Australia and facing an overload of information. Under these circumstances we tend to take cognitive shortcuts (what the psychologists term ‘heuristics’) to reduce the challenge to a manageable size. A common heuristic employed when patients are confronted by complex medical decisions is to ask health care staff what they would do in the circumstances! Indeed, when decision-making aids have been introduced to enable patients to make more considered, autonomous and ‘rational’ treatment choices, they are not necessarily appreciated at the time.

In summary, therefore, the decision that we ask individuals and families to make concerning cryopreservation of reproductive tissue and gametes is both highly complex and informationally incomplete. We also ask them to take that decision rapidly and at a time when their collective cognitive functioning is likely to be impoverished. Under these circumstances, we should not be surprised if the choices that are made are heavily subject to external influence.

We also performed exploratory analyses to investigate treatment effects on sites of first recurrence. After a protocol amendment was approved before the first interim analysis in 2008, we added another secondary end point: invasive-disease–free survival, which was defined according to the Standardized Definitions for Efficacy and End Points in Adjuvant Breast Cancer Trials (STEEP) guidelines. The date of recurrence was defined as the date on which relapse was first suspected, rather than the date on which it was confirmed, to reduce the risk of ascertainment bias. On-site and telephone-based monitoring was performed to ensure that recurrence dates were backdated to the date on which the event was first suspected, when this date preceded clinical, histologic, or imaging confirmation. Viagra Australia website

Study Oversight

The study was sponsored by the University of Sheffield and approved as a United Kingdom national trial by the Clinical Trials Advisory Awards Committee. Grant support was provided by Novartis Pharmaceuticals and was supplemented in the United Kingdom by the infrastructure of the National Cancer Research Network. Novartis Pharmaceuticals donated study supplies of zoledronic acid. The authors developed the study concept, wrote the protocol, and performed and reviewed all analyses. The study was conducted in accordance with the protocol, with amendments to reduce the risk of osteonecrosis of the jaw and to inform both patients and dental practitioners of this risk. The first author wrote the first draft of the manuscript, and all authors were involved in revision and approval of the manuscript. Novartis Pharmaceuticals was given an opportunity to comment on the manuscript, but all decisions on submission of the manuscript for publication were made by the authors and the trial steering committee.

Statistical Analysis

A final analysis was planned after the primary end point (disease-free survival) had occurred in 940 patients, on the basis of the recruitment of 3300 patients during a 3-year period, an anticipated rate of disease-free survival of 75% at 3 years, and a 5% annual rate of loss to follow-up. It was estimated that these numbers would provide a power of 80% to detect a relative reduction of 17% in the rate of disease recurrence or death among patients receiving zoledronic acid, at a two-sided level of significance of 0.05, which would approximate an absolute benefit of 3.7 percentage points.

A single interim analysis was planned after the primary end point had been reached in 470 patients, with a two-sided alpha level of 0.005. After this analysis was performed, on the advice of the independent data and safety monitoring committee, no efficacy data were released. Because the rate of events contributing to the primary end point was lower than predicted (resulting in a combined rate of disease-free survival of 85% at 3 years), an independent statistician who was unaware of the findings and was not involved in the first interim analysis provided revised stopping boundaries for both efficacy and lack of benefit that would allow timely release of a clinically important result. A second interim analysis was planned after the primary end point had occurred in at least 705 patients, along with a 0.5% probability of declaring false positive results (one-sided) or a 5.0% probability of declaring negative results with the use of a group sequential-design method.13 The analysis was carried out on 752 events, resulting in an efficacy boundary for the hazard ratio of 0.833 (lower boundary) and a lack-of-efficacy boundary of 0.936 (upper boundary). At this interim analysis, the lack-of-efficacy boundary was crossed, and the committee recommended the release of results.

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Slowed relaxation was noted in early studies of experimental cardiac hypertrophy, but it was not until the past decade that the importance of lusitropic (relaxation) abnormalities was clearly demonstrated in patients with congestive heart failure. Although an impairment of the ion pumps that cause the myocardium to relax could be due in part to a chronic energy deficiency in the overloaded cells of the hypertrophied and failing heart (as described earlier), recent studies indicate that more complex molecular mechanisms contribute to the diastolic abnormalities. For example, relaxation is slowed in papillary muscles from cardiac-transplant recipients with dilated and hypertrophic cardiomyopathy, even after the tissue is isolated and studied in vitro.

Slowing of the active transport of calcium has been shown in several studies of sarcoplasmic-reticulum vesicles obtained from hypertrophied hearts. In keeping with the earlier emphasis on depressed contractility, this abnormality was initially interpreted as explaining the inotropic rather than the lusitropic abnormalities in heart failure. However, these observations have assumed new importance with the recognition of the clinical importance of relaxation abnormalities in the failing heart.

Impaired relaxation in the failing heart could be explained in part if the uptake of calcium by the sarcoplasmic reticulum was slowed by a chemical-energy deficit or altered membrane assembly. There are, however, other plausible explanations for this lusitropic abnormality; for example, diastolic stiffness may be increased by the spontaneous recycling of calcium in the sarcoplasmic reticulum during diastole. In addition, the energy-dependent reactions that cause the hypertrophied heart to relax appear to be abnormally sensitive to a fall in high-energy phosphate levels, such as occurs in hypoxia. This finding could be explained in part by the attenuation of an allosteric effect of ATP that accelerates the rate of the calcium pump of the sarcoplasmic reticulum. Reports that the calcium sensitivity of the sodium—calcium exchanger is reduced in hypertrophied rat hearts and that the activity of this important mechanism for the extrusion of calcium from the myocardial cell is depressed late in the course of heart failure in hamsters with cardiomyopathy suggest yet other causes for the lusitropic abnormalities in heart failure.

Clinical experience tells us that there is a wide spectrum in the individual hypertrophic response to overload. Most striking are the adolescents in whom massive ventricular hypertrophy develops in the absence of apparent hemodynamic overload; this is, of course, the condition recognized as hypertrophic cardiomyopathy. At the other end of the spectrum are the elderly patients with substantial overloading caused by severe and long-standing systemic hypertension who have relatively less severe left ventricular hypertrophy. In the middle of the spectrum are the hypertensive patients in whom there is no clear relation between the hypertrophic response of the ventricle and the severity and duration of overloading; however, there are reports that the prevalence of hypertensive heart disease for any given level of blood pressure is higher in men than women and in blacks than whites. A suggestion that the attenuation of the hypertrophic response to overload with advancing age may contribute to the high incidence of heart failure in the elderly has recently found support in studies showing a diminished capacity for left ventricular hypertrophy after experimentally induced aortic stenosis94 and insufficiency in aged rats.

Functional Abnormalities in the Hypertrophied and Failing Heart

The protein-isoform changes that have been described thus far probably represent but a small fraction of the molecular abnormalities that develop in chronically overloaded myocardial cells. Additional but as yet incompletely characterized changes in composition are suggested by important functional abnormalities in the hypertrophied and failing heart that may contribute to the arrhythmias and progressive pump dysfunction that lead to death in patients with congestive heart failure.

Electrophysiologic Abnormalities

Arrhythmias are among the most important determinants of prognosis in patients with congestive heart failure. Although these disorders arise in part from conduction inhomogeneities caused by the enlargement and fibrosis of the hypertrophied heart, there is growing evidence that abnormal isoforms of the ion channels responsible for the heart’s electrical activity may also be synthesized in the failing heart.

Prolongation of the action potential, among the most prominent electrophysiologic abnormalities in hypertrophied myocardial cells, may be due in part to an increase in the slow inward calcium current that maintains depolarization during the plateau of the cardiac action potential. Recent evidence suggests that such prolongation may be due in part to the delayed inactivation of L-type calcium channels. This abnormality may also be due to the attenuation of one or more of the outward potassium currents that cause repolarization, including the transient outward potassium current, the ATP-sensitive potassium current, and both inward and delayed rectifier currents.

A role for these molecular abnormalities in the pathogenesis of arrhythmias in patients with heart failure remains unproved; however, this is a rapidly developing field, and specific peptide regions in the large ion-channel proteins that regulate the opening, closing, and inactivation of the channel have recently been identified. The molecular mechanisms responsible for some of the electrophysiologic abnormalities in the failing heart may be elucidated by studies of single ion-channel molecules, which may uncover a molecular basis for some of the arrhythmias commonly seen in congestive heart failure.

Abnormalities in the sarcoplasmic reticulum of the failing heart, in which slowed calcium uptake may contribute to impaired relaxation (see “Relaxation Abnormalities”), appear to reflect a reduced concentration of calcium-pump ATPase molecules in this internal membrane, rather than the expression of an altered isoform of the large molecule.82 , 83 Another example of altered membrane assembly in the overloaded heart is suggested by a recent report that the density of voltage-sensitive calcium channels may be increased in the atria of patients with hypertrophic cardiomyopathy.84 This report extends to humans a genetic cardiomyopathy previously described in the Syrian hamster. However, since the density of calcium channels was not found to be altered in renal-hypertensive rats, the increased number of calcium channels described in the human and hamster cardio-myopathies may be related to underlying genetic abnormalities rather than to the hypertrophic response itself.

Role of Proto-oncogenes

Proto-oncogenes, which play a major part in regulating growth and differentiation, provide a remarkably complex control of the many steps between signal recognition and altered gene expression. By allowing protein synthesis to respond to a wide range of influences both outside and within the cells of the heart, the proto-oncogenes regulate the hypertrophic process and may have a pathogenetic role in the cardiomyopathy of overload.
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The proto-oncogenes exert their regulatory effects by encoding a variety of growth factors and their receptors, intracellular transducers, modulators, amplifiers, and DNA-binding factors involved in the control of RNA transcription. Although this field is still in its infancy, it is apparent that hemodynamic overloading increases the expression of c-fos and c-myc, proto-oncogenes that encode short-lived nuclear proteins that promote and regulate cell proliferation and differentiation. In the overloaded heart, the activation of these proto-oncogenes, along with the heat-shock protein gene HSP 70, resembles the early mitogenic responses to a variety of growth factors in other cell types and may be part of a general adaptive response to stress.

The induction of c-fos and c-myc, which occurs within an hour of acute pressure overload, is transient and precedes the expression of fetal isoforms of several contractile proteins and atrial natriuretic factor.76 Thus, in addition to stimulating the overall rate of protein synthesis, proto-oncogenes may control alterations in specific protein isoforms synthesized by the overloaded heart.

Although the roles of the proto-oncogenes in activating and reprogramming gene expression in the overloaded heart remain to be fully elucidated, rapid progress in this important field promises new insights into the pathogenesis of the cardiomyopathy of overload.

Adult myocardial cells respond to overload by accelerating protein synthesis, although at the same time they preferentially synthesize fetal isoforms of several proteins. Abnormal actin and tropomyosin, also synthesized by the overloaded heart, represent isoforms of the proteins that were predominant earlier in development, during fetal life.

This reversion to fetal isoforms may be related to the fact that the adult myocardium is a terminally differentiated tissue that, like mature peripheral-blood granulocytes, cannot divide and that normally synthesizes new protein at only a very slow rate. Unlike the granulocyte, which does not enlarge but is readily replenished by the proliferation and maturation of undifferentiated stem cells in the bone marrow, the adult heart can initiate rapid protein synthesis and so undergo hypertrophy. Thus, for adult myocardial cells to regain the capacity for rapid protein synthesis that they had during development, the pattern of protein synthesis may have to revert to that seen earlier in ontogeny. It is of interest, however, that the hypertrophy induced by hyperthyroidism does not increase the expression of fetal isoforms of myocardial proteins.

The functional consequences of the appearance of primitive isoforms of myocardial proteins in the overloaded heart are poorly understood. It is tempting to postulate that these changes may contribute to the cardiomyopathy of overload, but such speculation must await additional evidence.
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Heterogeneity of Protein Isoforms Synthesized in Response to Overload

It is now evident that the synthesis of new proteins in the overloaded heart is not due simply to the overall stimulation of muscle growth. Instead, the control of protein synthesis is complex, and the rates at which altered isoforms of several myofibrillar proteins appear are dissimilar. For example, new myosin and actin isoforms appear at different times during the initial response to overload. This complexity is highlighted by the recent finding that the localization of newly synthesized isoforms of myosin and actin in the overloaded rat heart also differs. New β-myosin heavy chains appear first in the subendocardial regions of the left ventricle and around blood vessels, whereas the fetal isoform of actin appears more uniformly throughout the myocardium. The heterogeneity in the appearance of the β-myosin may reflect the higher tension in the subendocardium and around blood vessels or, possibly, a local response to growth factors released by endothelial and endocardial cells.

Isoform changes in the hypertrophied heart have also been reported for lactate dehydrogenase,78 creatine kinase,79 , 80 and the sarcolemmal sodium pump.

Biochemical Changes

The pioneering work of Meerson,50 who first characterized the biochemical events that lead to myocardial deterioration and cell death in animals with acute aortic constriction, has provided an understanding of the cellular events in the overloaded heart that corresponds to the clinical observations made 75 years earlier by Osler. Meerson, like Osler, described three stages in the response of the heart to a sudden hemodynamic overload (Table 2). The first stage, which Meerson called transient breakdown, lasts several days and is characterized by acute heart failure with left ventricular dilatation, pulmonary congestion, and low cardiac output. The adaptive effects of cardiac hypertrophy then lead to a stage of stable hyperfunction, in which increased left ventricular mass raises cardiac output and alleviates the pulmonary congestion. However, in accord with Osler’s clinical observations, the compensation does not last but after several months is followed by progressive left ventricular failure. In this final stage, which Meerson called exhaustion and progressive cardiosclerosis, the hypertrophied heart undergoes progressive fibrosis and cell death, the circulatory manifestations of heart failure worsen, and the animals die.

Although the deterioration of the chronically overloaded heart, referred to here as the cardiomyopathy of overload, may be due in part to energy starvation (see above), there is growing evidence that molecular changes in the proteins synthesized in affected hearts also contribute to the downhill course usually seen in chronic congestive heart failure.

Abnormal Gene Expression in the Hypertrophied Myocardium

Since the pioneering work of Alpert and Gordon,53 who demonstrated that myosin ATPase activity is depressed in failing hearts, a growing number of molecular changes have been recognized in overloaded myocardial cells. This ability of the heart to alter its protein composition is a general process that can be viewed as a tonic control mechanism, which also adapts myocardial function to such long-term circulatory changes as aging and endocrine abnormalities.54 , 55 In addition, the remarkable ability of adjacent cells in the myocardium to express different genes gives rise to a “mosaicism” in which molecular heterogeneity in the proteins of the myocardium may help to achieve functional homogeneity, promoting efficient cardiac function.
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The appearance of abnormal isoforms of key myocardial proteins in the hypertrophic response to chronic overloading results from changes in gene expression that can arise from at least two different mechanisms. The first is the expression of different members of the multigene families that encode many important proteins of the heart. This mechanism is clearly seen in the rodent heart, in which the preferential synthesis of altered myosin isoforms adapts ventricular function to chronic abnormalities of the heart and circulation (see the next section). Variability in the proteins synthesized in the myocardium also results from alternative splicing, in which the exons of a single gene are assembled in different patterns as the nuclear RNA is processed to form messenger RNA. This mechanism allows the information contained in a single gene to encode the structures of several protein isoforms through variations in the manner by which the DNA sequence of the gene becomes transcribed into messenger RNA.

The complexity of cardiac hypertrophy was recognized almost a century ago by Osier, who observed that the heart’s first response to sudden hemodynamic overload, such as that caused by aortic-valve rupture, is a phase of “development” in which the myocardium begins to hypertrophy. The resulting augmentation of muscle mass, by distributing the excess load among an increased number of sarcomeres, alleviates the acute heart failure and so is clearly beneficial. Although the initial hypertrophic response leads to Osler’s second phase, compensation, and is thus adaptive, the hypertrophy that initially helped the heart to meet the overload does not end well. Instead, the chronically overloaded heart degenerates and weakens, leading to a final stage that Osier called broken compensation. Thus, like salt and water retention and vasoconstriction, myocardial hypertrophy provides effective compensation for only a limited time. Following a pattern similar to that of the circulatory adjustments to low cardiac output, cardiac hypertrophy appears to become deleterious when it becomes chronic. Unfortunately, in most patients who seek medical care for heart failure, the myocardium has probably already entered Osier’s final phase of broken compensation, the cardiomyopathy of overload.

Changing Composition of the Hypertrophied Heart

Central to an understanding of the cardiomyopathy of overload is a knowledge of the structural and functional abnormalities that initiate and perpetuate the deterioration of the hypertrophied, failing myocardium (Osler’s broken compensation). These abnormalities have been studied in depth from a morphologic standpoint and are now beginning to be understood at a molecular level in the light of the growing knowledge of changes in gene expression by the cells of the overloaded myocardium.

Morphologic Changes

Using traditional morphologic techniques, Linzbach noted that after initially thickening in response to overload, the walls of the heart become thinned in end-stage heart failure. Myocyte necrosis stimulates the proliferation of fibroblasts, replacing myocardial cells with connective tissue, and causes the late dilatation that increases the tension that must be developed by the muscular walls of the failing heart. The resulting progressive overload on the surviving cells of the hypertrophied heart, together with the relative decrease in capillary density and the number of mitochondria discussed earlier, probably contributes to a chronic energy deficit that sets up a vicious circle in the failing heart. Thus, although hypertrophy increases the number of sarcomeres and so is beneficial at first, this response represents an imperfect compensation because, when overloading is sustained, the hypertrophied myocardial cells ultimately deteriorate and die.

These considerations, which may explain reports of detrimental effects when inotropic drugs have been used to treat chronic heart failure, lack conclusive experimental support. Furthermore, they may not apply to the cardiac glycosides, which have only moderate inotropic effects and, by increasing baroreceptor sensitivity, may reduce afterload and slow the heart in patients with heart failure.
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Energetics in the Failing Heart

In heart failure, whether due to abnormal hemodynamic demands, as are produced by aortic stenosis, or to the loss of functional myocardial tissue, as occurs after myocardial infarction, the active myocardial cells become overloaded. The resulting increase in the rate of mechanical-energy expenditure by the overloaded heart not only is sustained from day to day, but persists when activity is curtailed by rest, and even during sleep.

Hypertrophy unloads the cells of the failing heart by adding new sarcomeres and thus has an energy-sparing effect because it decreases the rate of mechanical-energy expenditure by the overloaded sarcomeres. However, several changes in the architecture of the hypertrophied heart can exacerbate the imbalance between energy expenditure and energy production. Such changes include an increase in the distance between capillaries40 and a decrease in the density of transverse capillary profiles, which impair the diffusion of substrates, notably oxygen, essential for the production of energy by the hypertrophied heart. This imbalance is especially marked in the relatively underperfused subendocardial regions of the left ventricle and is reflected in a decrease in the coronary reserve. Cellular abnormalities also appear to contribute to energy starvation in the chronically overloaded failing heart; for example, long-standing hypertrophy increases the cell volume occupied by myofibrils, which increases the number of ATP-consuming myofibrils supplied by each ATP-generating mitochondrion, thus potentially exacerbating an energy deficit. Depressed contractility in the failing heart (see below) lessens energy demands and so may be compensatory in terms of the energetics of the individual myocardial cells. Viewed from the standpoint of the circulation, of course, depressed contractility is detrimental.

Hypertrophic Response of the Heart to Chronic Overload

It is now apparent that hypertrophy of the overloaded heart is a complex process that is both beneficial and detrimental. Like the short-term effects of salt and water retention and vasoconstriction, the effect of the benefit of an increased number of sarcomeres dominates the initial adaptation to overload. It is mainly when the overload is sustained, in chronic heart failure, that the deleterious effects of hypertrophy, referred to here as the cardiomyopathy of overload, become prominent. When hypertrophy is induced by exercise, however, its detrimental effects appear to be minimal or absent, possibly because of the intermittent rather than sustained stimulus to cell growth.