Research over the past 10 years in our laboratory has led to two major findings. The first is that haptoglobin (Hp) genotype can predict the risk of developing vascular complications in individuals with diabetes mellitus (DM), and the second, more far-reaching discovery, is that vitamin E treatment can significantly reduce vascular complications in individuals with DM and the Hp 2-2 genotype. The former finding has been well documented in numerous studies which included over 50,000 patients of diverse geographical and ethnic backgrounds. The latter discovery is more recent and less well accepted by the medical community due to confounding reports over the past 30 years regarding the efficacy of vitamin E treatment for vascular disease. We propose that the benefit of vitamin E treatment was not obvious in earlier studies due to the absence of any genetic basis for patient selection. Our studies dividing DM individuals into vitamin E treatment subgroups based on Hp genotype show a clear benefit for individuals of the Hp 2-2 genotype, while patients carrying the other two Hp genotypes are not affected or may be adversely affected by receiving vitamin E. These findings may explain the overall lack of benefit seen in previous vitamin E studies and emphasize the importance of carefully selecting which patients should receive vitamin E therapy. The pharmacogenomic paradigm discussed in this review potentially could result in a dramatic improvement in the health of millions of individuals worldwide using a treatment that is both accessible and affordable to all.
While Drs. Wolff, Parkinson, and White fully described the syndrome in 1930, prior case reports had described the essentials. Over the ensuing century this syndrome has captivated the interest of anatomists, clinical cardiologists, and cardiac surgeons. Stanley Kent described lateral muscular connections over the atrioventricular (AV) groove which he felt were the normal AV connections. The normal AV connections were, however, clearly described by His and Tawara. True right-sided AV connections were initially described by Wood et al., while Öhnell first described left free wall pathways. David Scherf is thought to be the first to describe our current understanding of the pathogenesis of the WPW syndrome in terms of a re-entrant circuit involving both the AV node–His axis as well as the accessory pathway. This hypothesis was not universally accepted, and many theories were applied to explain the clinical findings. The basics of our understanding were established by the brilliant work of Pick, Langendorf, and Katz who by using careful deductive analysis of ECGs were able to define the basic pathophysiological processes. Subsequently, Wellens and Durrer applied invasive electrical stimulation to the heart in order to confirm the pathophysiological processes.
Sealy and his colleagues at Duke University Medical Center were the first to successfully surgically divide an accessory pathway and ushered in the modern era of therapy for these patients. Morady and Scheinman were the first to successfully ablate an accessory pathway (posteroseptal) using high-energy direct-current shocks. Subsequently Jackman, Kuck, Morady, and a number of groups proved the remarkable safety and efficiency of catheter ablation for pathways in all locations using radiofrequency energy. More recently, Gollob et al. first described the gene responsible for a familial form of WPW. The current ability to cure patients with WPW is due to the splendid contributions of individuals from diverse disciplines throughout the world.
Evaluation of patients after penetrating neck injury has evolved over time. Previously, location of injury and symptoms were used to determine management. The contemporary management of penetrating neck injuries relies on physical examination. Patients with hard signs of vascular or aerodigestive tract injury require immediate operation, regardless of location of injury. Those with no signs can be observed. For the remainder with soft signs multidetector, computed tomographic angiography (MDCTA) is a highly sensitive and specific screening modality for evaluating the vasculature and aerodigestive structures in the neck. Utilizing MDCTA, the patient can be safely directed towards operative intervention, observation, or further investigation.
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.
Mitral valve regurgitation (MR) is the most prevalent valvular heart disease in the community, its prevalence increasing along with population aging and heart failure. While surgery remains the gold standard treatment in low-risk patients with degenerative MR, in high-risk patients and in those with functional MR, transcatheter procedures are emerging as an alternative therapeutic option. MitraClip is the device with the largest clinical experience to-date, as it offers sustained clinical benefit in selected patients. Further to MitraClip implantation, several additional approaches are developing, to better match with the extreme variability of mitral valve disease. Not only repair is evolving, initial steps towards percutaneous mitral valve implantation have already been undertaken and initial clinical experience has just started.
Four decades of innovations in the field of interventional cardiology are presented as an example for the great growth of high technology in medicine, sidebyside with the development of general technology and science. The field of percutaneous coronary intervention (PCI) was enabled by the development of X-ray systems,allowing us to view the pathology,and was critically dependent on courageous and imaginative physicians and scientists who developed percutaneous transluminal coronary angioplasty (PTCA), stents, and transarterial aortic valve replacement (TAVR). Today, outstanding research continues to progress, with stem cell research and IPC technologiespresenting new challenges and yet taller mountains to climb. The rapid development we have witnessed was due to tight collaborations between clinical and academic institutions and industry. The combination of all these elements, with a proper mechanism to handle conflict of interest,is an essential linkage for any progress in this field. We will continue to see exponential growth of innovations and must be prepared with appropriate bodies to encourage such developments and to provide early-stage funding and support for novel ideas.
The Cox maze III and Cox maze IV procedures are surgical solutions for the treatment of symptomatic stand-alone atrial fibrillation. Despite their proven efficacy, these procedures have not gained widespread acceptance because of the invasiveness, complexity, and technical difficulty. Endocardial pulmonary vein isolation is the cornerstone of percutaneous catheter ablation for atrial fibrillation. It is currently accepted as an invasive therapy, if rhythm control has failed using antiarrhythmic drugs or electrical cardioversions. Pulmonary vein isolation is reported to be effective in 60%–85% of patients with paroxysmal atrial fibrillation and in 30%–50% of patients with persistent atrial fibrillation. A second or third ablation is often necessary to achieve these results, and complications may occur in up to 6% of patients.
Surgical treatment of atrial fibrillation has seen important improvements in the last decade. New technologies have simplified creation of transmural lesions on the beating heart through a less-invasive, thoracoscopic procedure. This allows for pulmonary vein isolation, isolation of the posterior wall, and left atrial appendage exclusion—usually combined with ganglionic plexi evaluation and destruction. Nonethe¬less, it is still uncertain whether these procedures are effective in restoring permanent sinus rhythm since transmurality of a lesion set cannot be guaranteed with current ablation catheters on the beating heart.
In an attempt to limit the shortcomings of an endo- or an epicardial technique, a hybrid approach has recently been introduced. This approach is based on a close collaboration between the surgeon and the electrophysiologist, employing a patient-tailored procedure which is adapted to the origin of the patient’s atrial fibrillation and takes into consideration triggers and substrate. Using a mono- or bilateral energy source, a thoracoscopic epicardial approach is combined with a percutaneous endocardial ablation in a single-step or in a sequential-step procedure.
This article provides our experience and an overview of the current knowledge in the hybrid treatment of stand-alone atrial fibrillation.
Achievement of complete response (CR) to therapy in chronic lymphocytic leukemia (CLL) has become a feasible goal, directly correlating with prolonged survival. It has been established that the classic definition of CR actually encompasses a variety of disease loads, and more sensitive multiparameter flow cytometry and polymerase chain reaction methods can detect the disease burden with a much higher sensitivity. Detection of malignant cells with a sensitivity of 1 tumor cell in 10,000 cells (10–4), using the above-mentioned sophisticated techniques, is the current cutoff for minimal residual disease (MRD). Tumor burdens lower than 10–4 are defined as MRD-negative. Several studies in CLL have determined the achievement of MRD negativity as an independent favorable prognostic factor, leading to prolonged disease-free and overall survival, regardless of the treatment protocol or the presence of other pre-existing prognostic indicators. Minimal residual disease evaluation using flow cytometry is a sensitive and applicable approach which is expected to become an integral part of future prospective trials in CLL designed to assess the role of MRD surveillance in treatment tailoring.
