Heparanase that was cloned from and is abundant in the placenta is implicated in cell invasion, tumor metastasis, and angiogenesis. Recently we have demonstrated that heparanase may also affect the hemostatic system in a non-enzymatic manner. Heparanase was shown to up-regulate tissue factor (TF) expression and interact with tissue factor pathway inhibitor (TFPI) on the cell surface, leading to dissociation of TFPI from the cell membrane of endothelial and tumor cells, resulting in increased cell surface coagulation activity. More recently, we have shown that heparanase directly enhances TF activity, resulting in increased factor Xa production and activation of the coagulation system. Data indicate increased levels and possible involvement of heparanase in vascular complications in pregnancy. Taking into account the prometastatic and proangiogenic functions of heparanase, overexpression in human malignancies, and abundance in platelets and placenta, its involvement in the coagulation machinery is an intriguing novel arena for further research.
Although Maimonides stated that perfection in the medical art, both in theoretical and in practical expertise, is very difficult to achieve, he did not accept Galen's opinion, i.e. that perfection is beyond human capability.
Any person seeking intellectual perfection should, according to Maimonides' view, be fully trained in logic, in the natural sciences, and in theology.
A physician is moreover requested to study and memorize basic medical literature; he must consider each patient as a sick individual, without neglecting the patient's psychological disposition; and he should aim at inspiring confidence and trust, not only to his patient, but also to the latter's environment.
Even when feeling competent and trustworthy, the physician should not be conceited; here Maimonides insists on offering his personal experience, in a quite impressive way.
This approach of Maimonides to the practice of medicine should be considered, even today, as a valuable incentive for patient-oriented medical education, as already expressed in the late eleventh century.
Heart failure is a leading cause of morbidity and mortality with a prevalence that is rising throughout the world. Currently the pharmaceutical therapy of heart failure is mainly based on inhibition of the neurohumoral pathways that are activated secondary to the deterioration of cardiac function, and diuretics to alleviate the salt and water overload. With our increasing understanding of the pathophysiology of heart failure, it is now clear that the macroscopic and functional changes in the failing heart result from remodeling at the cellular, interstitial, and molecular levels. Therefore, emerging therapies propose to intervene directly in the remodeling process at the cellular and the molecular levels. Here, several experimental strategies that aim to correct the abnormalities in receptor and post-receptor-function, calcium handling, excitation and contraction coupling, signaling, and changes in the extra-cellular matrix in the failing heart will be discussed. These novel approaches, aiming to reverse the remodeling process at multiple levels, may appear on the clinical arena in the coming years.
A very troubling issue for health care systems today is that of life-sustaining treatment for patients who have permanently lost their cognitive capacities. These include patients in persistent vegetative state (PVS), or minimally conscious state (MCS), as well as a growing population of patients at the very end stage of dementia. These patients are totally dependent on life-sustaining treatments and are, actually, kept alive “artificially.” This phenomenon raises doubts as to the ethics of sustaining the life of patients who have lost their consciousness and cognitive capacities, and whether there is a moral obligation to do so. The problem is that the main facts concerning the experiences and well-being of such patients and their wishes are unknown. Hence the framework of the four principles—beneficence, non-maleficence, autonomy, and justice—is not applicable in these cases; therefore we examined solidarity as another moral value to which we may resort in dealing with this dilemma.
This article shows that the source of the dilemma is the social attitudes towards loss of cognitive capacities, and the perception of this state as loss of personhood. Consequently, it is suggested that the principle of solidarity—which both sets an obligation to care for the worst-off, and can be used to identify obligations that appeal to an ethos of behavior—can serve as a guiding principle for resolving the dilemma. The value of solidarity can lead society to care for these patients and not deny them basic care and life-sustaining treatment when appropriate.
The randomized controlled trial is the fundamental study design to evaluate the effectiveness of medications and receive regulatory approval. Observational studies, on the other hand, are essential to address post-marketing drug safety issues but have also been used to uncover new indications or new benefits for already marketed drugs. For example, hormone replacement therapy (HRT), effective for menopausal symptoms, was reported in several observational studies during the 1980s and 1990s to also significantly reduce the incidence of coronary heart disease. This hypothesis was disproved in 2002 by the large-scale Women’s Health Initiative randomized trial. An example of a new indication for an old drug is that of metformin, an anti-diabetic medication, which is being hailed as a potential anti-cancer agent, primarily on the basis of several recent observational studies that reported impressive reductions in cancer incidence and mortality. These observational studies have also sparked the conduct of large-scale randomized controlled trials in cancer. We show in this paper that the spectacular effects on new indications or new outcomes reported in many observational studies in chronic obstructive pulmonary disease (COPD), HRT, and cancer are the result of time-related biases, such as immortal time bias, that tend to seriously exaggerate the benefits of a drug and that eventually disappear with the proper statistical analysis.
In all, while observational studies are central to assess the effects of drugs, their proper design and analysis are essential to avoid bias. The scientific evidence on the potential beneficial effects in new indications of existing drugs will need to be more carefully assessed before embarking on long and expensive unsubstantiated trials.
The sirtuins are highly conserved enzyme homologues of the yeast Sir2, with activities of NAD+ dependent deacetylase and/or mono ADP ribosyltransferase. A long line of evidence has implicated sirtuins in regulating the aging process of yeast, worms, flies, and rodents. Moreover, much work has been published on the important role of sirtuins in several age-related diseases such as diabetes type II, cancer, cardio¬vascular diseases, and dyslipidemia. However, despite the many publications supporting a pro-longevity role for sirtuins, there has been emerging debate about the direct role of Caenorhabditis elegans and Drosophila melanogaster sirtuins in aging and in lifespan extension in response to dietary restriction. In addition, until recently, the role of the seven mammalian sirtuins, SIRT1 to SIRT7, in regulating lifespan was unclear. Here, we review the history of the scientific debate on the role of sirtuins in regulating lifespan, especially in light of a recent publication showing a direct regulation of mammalian lifespan by a sirtuin family member, SIRT6.
Genetic determinants of sex in placental mammals developed by the evolution of primordial autosomes into the male and female sex chromosomes. The Y chromosome determines maleness by the action of the gene SRY, which encodes a protein that initiates a sequence of events prompting the embryonic gonads to develop into testes. The X chromosome in the absence of a Y chromosome results in a female by permitting the conversion of the embryonic gonads into ovaries. We trace the historical progress that resulted in the discovery that one X chromosome in the female is randomly inactivated in early embryogenesis, accomplishing approximate equivalency of X chromosome gene dosage in both sexes. This event results in half of the somatic cells in a tissue containing proteins encoded by the genes of the maternal X chromosome and half having proteins encoded by the genes of the paternal X chromosome, on average, accounting for the phenotype of a female heterozygote with an X chromosome mutation. The hypothesis of X chromosome inactivation as a random event early in embryogenesis was first described as a result of studies of variegated coat color in female mice. Similar results were found in women using the X chromosome-linked gene, glucose-6-phosphate dehydrogenase, studied in red cells. The random inactivation of the X chromosome-bearing genes for isoenzyme types A and B of glucose-6-phosphate dehydrogenase was used to establish the clonal origin of neoplasms in informative women with leiomyomas. Behind these discoveries are the stories of the men and women scientists whose research enlightened these aspects of X chromosome function and their implication for medicine.
Successful deceased organ donation requires a reproducible—consistent (scientific) system that eva-luates the potential for organ donation and determines objectively whether the national system is achieving its goals. The science of organ donation also pertains to the determination of death. We are a common humanity that dies similarly— a humanity whose ultimate criterion of life resides in the function of the human brain. The recent brain death law of Israel encouragingly enables a determination of death by the loss of neurologic function but it has become complicated by a practice that may perpetuate societal misperceptions. As a result opportunities for deceased organ donation --to provide for Israelis in need of organ transplants are being lost. A statured task force of society could be assembled to convey its support for deceased donation to influence society and resolve these misperceptions.
The World Health Organization is now calling for each member state to achieve a self-sufficiency in organ donation and transplantation "equitably meeting the transplantation needs of a given population using resources from within that population". Patients should not be compelled to go to foreign countries for their organs. Israel has been a leader in the development of a model program intended to address transplant tourism. Insurance companies are no longer permitted to provide resources for Israelis to undergo illegal transplants in foreign destinations. The social necessity of a scientifically and medically applied system of deceased organ donation is now evident so that a sufficient number of organs can be available for patients from within the country they reside.
The effects of genomic medicine on child health promise to be profound. Medical applications will eventually include characterizing patients’ genomes to detect predictive mutations for pre-symptomatic counseling where treatment exists; to search for causes of diseases of unknown etiology, and to detect carriers for prenatal counseling; to define cancer and other disease-based genomes to design individualized therapy; and to understand our microbiomes to modify these in health and disease. Rapid advances in technology and bioinformatics has reduced the cost and the time and increased the accuracy necessary to sequence whole genomes or whole exomes. However, complete understanding of disease will also require correlation of genomic information with high-quality phenotypic data. In addition, several critical ethical, psycho-social, and public policy issues will require clarity in the coming years. Ultimately these advances will improve the effectiveness of health care for children and for society.
Hereditary, environmental, and stochastic factors determine a child’s growth in his unique environ-ment, but their relative contribution to the phenotypic outcome and the extent of stochastic pro-gramming that is required to alter human phenotypes is not known because few data are available. This is an attempt to use evolutionary life-history theory in understanding child growth in a broad evolutionary perspective, using the data and theory of evolutionary predictive adaptive growth-related strategies. Transitions from one life-history phase to the next have inherent adaptive plasticity in their timing. Humans evolved to withstand energy crises by decreasing their body size, and evolutionary short-term adaptations to energy crises utilize a plasticity that modifies the timing of transition from infancy into childhood, culminating in short stature in times of energy crisis. Transition to juvenility is part of a strategy of conversion from a period of total dependence on the family and tribe for provision and security to self-supply, and a degree of adaptive plasticity is provided and determines body composition. Transition to adolescence entails plasticity in adapting to energy resources, other environmental cues, and the social needs of the maturing adolescent to determine life-span and the period of fecundity and fertility. Fundamental questions are raised by a life-history approach to the unique growth pattern of each child in his given genetic background and current environment.
