Over the last two decades, advanced molecular genetics technology has enabled analysis of complex microbial communities and the study of microbial genomics. Interest has grown in characterizing the microbiome, defined as a collective microbial community and its extensive genome, as a clue to disease mechanisms. “The Human Microbiome Project,” sponsored by the NIH Common Fund, was established to characterize the pathology-associated human microbiome in nasal passages, oral cavities, skin, the gastrointestinal tract, and the urogenital compartment. In particular, characterization of urogenital microbiota may elucidate etiologies of complex obstetrical syndromes and factors in fetal development that define risk for pathology in adulthood. This article summarizes recent findings defining the microbiome associated with the female urogenital compartment in child-bearing age women. We also describe our analysis of microbiome samples from the oral, vaginal, and rectal compartments in a cohort of pregnant women. Findings present technical considerations in the characterization of microbial diversity and composition associated with gestational diabetes as a model pregnancy-associated pathology.
The term sociotype has been introduced to describe the dynamic relationship of an individual with his/her social environment throughout life. The sociotype is a conceptual framework to highlight, in addition to bio-medical pathways, the psycho-social and environmental factors necessary to understand responses to life stresses and patient self-management for chronic illness. The sociotype interacts with genotype expression through mate selection and metabolic programming, and with the phenotype to determine adaptation throughout life from birth to old age. Following on the work of Antonovsky, Engel, and McEwen, and others in the life and social sciences, the sociotype details and expands the many factors generally included in the environmental influences on a person’s life identified here as the domains of health, relationships, and environment. Physiological mediators for sociotypic influences include: adrenal steroids and the sympathetic nervous system (allostatic load), and oxytocin (social neuroscience). The biological pathways are multiple through nutrition (essential dietary-derived amino- and fatty acids for neurotransmitter synthesis, caloric restriction, and diet–gene interactions), epigenesis, and metabolic programming. Nutrition influences growth and development, fertility and longevity, and also determines susceptibility to non-communicable diseases such as cardiovascular disease and cancer, and particularly diabetes and obesity, through in-utero effects, the development of intestinal flora (microbiome), and chronic stress. Thus the sociotype and nutrition are reciprocally related in both health and disease.
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.
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.
Late onset is a key unifying feature of human neurodegenerative maladies such as Alzheimer’s and Parkinson’s diseases and prion disorders. While sporadic cases typically emerge during the patient’s seventh decade of life or later, mutation-linked, familial cases manifest during the fifth or sixth decade. This common temporal emergence pattern raises the prospect that slowing aging may prevent the accumulation of toxic protein aggregates that lead to the development of these disorders, postpone the onset of these maladies, and alleviate their symptoms once emerged. Invertebrate-based studies indicated that reducing the activity of insulin/IGF signaling (IIS), a prominent aging regulatory pathway, protects from neurodegeneration-linked toxic protein aggregation. The validity of this approach has been tested and confirmed in mammals as reducing the activity of the IGF-1 signaling pathway protected Alzheimer’s model mice from the behavioral and biochemical impairments associated with the disease. Here I review the recent advances in the field, describe the known mechanistic links between toxic protein aggregation and the aging process, and delineate the future therapeutic potential of IIS reduction as a treatment for various neurodegenerative disorders.
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.
The immune system is critical for protection and health maintenance and is likely required for a long lifespan. Yet, despite its importance for health, the ability to assess its quality of function has been poor, nor is much known on its variation between individuals. Hence direct assessment of immune health has largely been missing from medicine, and metrics of immune health are not well defined, especially in non-extreme states. This is chiefly due to the high complexity of the immune system. Recently emerging technologies now enable broad surveying of many immune system components at high resolution, setting forth a transformation of immunology and, through it, medicine. Such technologies enable, for the first time, high resolution monitoring of an individual’s immune system. The resulting information can be used for diagnostic and prognostic purposes, as well as to provide a quantitative, global view of the immune system, i.e. ‘systems immunology.’ This is especially relevant in the context of aging, in which the immune system exhibits profound alterations in state and function.
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.
This paper examines the morality of schemes of payment to live donors/sellers of organs for transplantation. Following empirical and historical evidence it is argued that consent to sell organs is substantially different from consent to ordinary business transactions and that legalization of exchanges of organs with financial benefits deviates significantly from the scope of liberal toleration and human rights. Although altruistic giving is commendable, it is immoral for society to benefit from them without conferring to the donors benefits such as health and nursing insurance for life. Non-alienable and non-fungible benefits of this kind are moral as incentives to organ donation/giving
