Showing papers in "Annals of the New York Academy of Sciences in 2006"
TL;DR: The technique of disc electrophoresis has been presented, including a discussion of the technical variables with special reference to the separation of protein fractions of normal human serum.
Abstract: Summary
The technique of disc electrophoresis has been presented, including a discussion of the technical variables with special reference to the separation of protein fractions of normal human serum.
17,771 citations
TL;DR: Some mechanisms that provide a rationale for the resolution afforded by zone electrophoresis in many gels will be detailed; the theory of some new modifications of zone electophoresis that have been designed to take maximum advantage of these mechanisms will be developed.
Abstract: Although electrophoresis is one of the most effective methods for the separation of ionic components of a mixture, the resolving power of different electrophoretic methods is quite variable. To separate two component ions, it is necessary to permit migration to continue until one of the kinds of ions has traveled at least one thickness of the volumes that it initially occupied (the starting zone) further than the other. However, the sharpness, and therefore the resolution, of the zones occupied by each ion diminishes with time because of the spreading of the zones as a result of diffusion. Remarkable resolution has been achieved when advantage is taken of the frictional properties of gels to aid separation by seiving at the molecular level (see Smithies’). A new method, disc electrophoresis, t has been designed that takes advantage of the adjustability of the pore size of a synthetic gel and that automatically produces starting zones of the order of 10 microns thickness from initial volumes with thicknesses of the order of centimeters. High resolution is thus achieved in very brief runs. With this technique, over 20 serum proteins are routinely separated from a sample of whole human serum as small as one microliter in a 20-minute run (see FIGURE 1) . Direct analysis of even very dilute samples becomes routine because the various ions are automatically concentrated to fixed high values at the beginning of the run just prior to separation. Preliminary laboratory studies and theoretic considerations provide evidence of the applicability of this technique to a wide range of ionic species for both analytic and large-scale preparative purposes. Theory has also provided the basis for a simple application of disc electrophoresis to the simultaneous determination of both the free mobility and the aqueous diffusion constant of a protein. This report will detail some mechanisms that provide a rationale for the resolution afforded by zone electrophoresis in many gels; will develop the theory of some new modifications of zone electrophoresis that have been designed to take maximum advantage of these mechanisms; and will provide some examples of the results that disc electrophoresis has produced.
4,255 citations
TL;DR: The beneficial effects of inflammation devoted to the neutralization of dangerous/harmful agents early in life and in adulthood become detrimental late in life in a period largely not foreseen by evolution, according to the antagonistic pleiotropy theory of aging.
Abstract: In this paper we extend the “network theory of aging,” and we argue that a global reduction in the capacity to cope with a variety of stressors and a concomitant progressive increase in proinflammatory status are major characteristics of the aging process. This phenomenon, which we will refer to as “inflamm-aging,” is provoked by a continuous antigenic load and stress. On the basis of evolutionary studies, we also argue that the immune and the stress responses are equivalent and that antigens are nothing other than particular types of stressors. We also propose to return macrophage to its rightful place as central actor not only in the inflammatory response and immunity, but also in the stress response. The rate of reaching the threshold of proinflammatory status over which diseases/disabilities ensue and the individual capacity to cope with and adapt to stressors are assumed to be complex traits with a genetic component. Finally, we argue that the persistence of inflammatory stimuli over time represents the biologic background (first hit) favoring the susceptibility to age-related diseases/disabilities. A second hit (absence of robust gene variants and/or presence of frail gene variants) is likely necessary to develop overt organ-specific age-related diseases having an inflammatory pathogenesis, such as atherosclerosis, Alzheimer's disease, osteoporosis, and diabetes. Following this perspective, several paradoxes of healthy centenarians (increase of plasma levels of inflammatory cytokines, acute phase proteins, and coagulation factors) are illustrated and explained. In conclusion, the beneficial effects of inflammation devoted to the neutralization of dangerous/harmful agents early in life and in adulthood become detrimental late in life in a period largely not foreseen by evolution, according to the antagonistic pleiotropy theory of aging.
3,763 citations
TL;DR: Improvement in the design and construction of electrode systems and their associated electronic instrumentation, together with the commercial development and availability of stable amplifiers and recorders, has now provided entirely satisfactory systems for the rapid and accurate measurement of blood pH, pCO2, and pOz.
Abstract: Instruments capable of continuously indicating the chemical composition of blood have proved to be useful in controlling heart-lung machines, in regulating operative and postoperative management of patients, and in teaching and research. At first, such instruments were used with sensors mounted directly in the extracorporeal blood circuit that is used for perfusion of open-heart surgery patients.] Later, continuous monitoring of both machine and patients was conducted by means of continuous withdrawal of blood pumped into external cuvettes equipped with appropriate sensors. Improvement in the design and construction of electrode systems and their associated electronic instrumentation, together with the commercial development and availability of stable amplifiers and recorders, has now provided entirely satisfactory systems for the rapid and accurate measurement of blood pH, pCO2, and pOz. Electrodes for measurement of blood p 0 2 and $ 0 2 can also be used for recording these tensions in gases. By mixing blood with certain reagents, these electrodes can be used to record blood gas contents as well as tensions. Intravascular electrodes are being used to time hydrogen appearance, to detect changes in oxygen tension, and to record ascorbate indicator dilution curves. Such electrodes are proving valuable in cardiac catheterization and in evaluation of the effectiveness of corrective endocardiac surgical procedures. Speed of response, ease of use, autoclavability, smallness of size, and the practicability of using multiple electrodes simultaneously is often sufficient advantage to overcome the present lack of quantitative response of these relatively simple electrodes. By withdrawing blood through microcatheters, continuous recording of blood composition for many hours, even days, is possible, using only about 10 cc. of blood per hr. Continued development of electrode systems may extend their usefulness to the measurement of blood ions, sugar, and urea and finally result in instruments with which analyses can be performed with a minimum of reagents and with but little delay. Electrode systems readily lend themseIves to either intermittent, semiautomatic, or continuous analytical processes. Blood oxygen tension. Electrodes available at present, mounted in thermostated cuvettes, have proved very satisfactory for the measurement of p 0 2 in blood samples. Thousands of analyses have been performed with the several units available here. We have evaluated several means of utilizing electrodes to follow blood pO2 under conditions encountered in cardiovascular operating rooms and have found that analysis of individual samples, withdrawn in plastic syringes, is the least troublesome and most
3,207 citations
TL;DR: It is shown that in a system consisting of two additive components which are mixed but the densities of which are known, the determination of the density of the system allows one to calculate the proportional masses of the two components.
Abstract: One can trace to Archimedes the idea that in a system consisting of two additive components which are mixed but the densities of which are known ( d l , d 2 ) , the determination of the density of the system ( D ) allows one to calculate the proportional masses of the two components. Let’s denote these components as W1 and W2.S Then, in a system with total weight W = W1 + Wz, the general equation for calculating component W1 expressed as a fraction (w1) of the total body weight is:
2,221 citations
TL;DR: Special consideration is given to the extent to which these divergencies are due to diflerences in experimental findings brought about by dserences in Experimental conditions and procedures, and are due, on the other hand, to differences in interpretation and calculation.
Abstract: Whether insulin acts immediately on the liver to reduce its rate of glucose output is a matter of great current interest. From the theoretical aspect, the answer given to this question has serious implications with respect to hypotheses concerning the mechanism of insulin action. In particular, an increase in permeability to glucose of the hepatic cell membrane should increase rather than decrease its rate of glucose output. In the hepatic cell, in contrast to the muscle cell, the net flow of glucose is from inside to outside the cell, and an increased facility for glucose transport across the cell membrane of the kind postulated for insulin action on the muscle cell could serve only to increase this flow and not to decrease it. Several investigative groups have used C14 glucose in attempts to supply the answer to this question, and the divergent findings that have resulted have been summarized and evaluated in a recent article.' In the present communication special consideration is given to the extent to which these divergencies are due, on the one hand, to diflerences in experimental findings brought about by dserences in experimental conditions and procedures, and are due, on the other hand, to differences in interpretation and calculation.
1,796 citations
TL;DR: Since its etiology and pathogenesis have eluded detection, it is not surprising that therapeutic attempts have been empiric and often unscientific.
Abstract: Multiple sclerosis has become a focus of growing interest to neurologists, general physicians, and the public. The disorder has an uneven but worldwide distribution and is present in approximately 30 to 60 people per 100,000 in the temperate zones of the world. Though some of these individuals remain unaffected by serious disability, in the majority the disease leads to crippling and ultimately premature death. To the public a special appeal lies in the frequent occurrence of multiple sclerosis in the young adult, often with disruption of early family life. To date no satisfactory treatment for the amelioration or cure of the disease has been discovered. Since its etiology and pathogenesis have eluded detection, it is not surprising that therapeutic attempts have been empiric and often unscientific. Reports of benefit from various types of therapy based on uncontrolled observations have led to unwarranted and occasionally widespread application of methods whose value remained unsubstantiated. In recent years criticisms have been made of the lack of adequate controls in trials of therapy. The difficulties inherent in judging the effects of therapy have been stressed.', * These are: (1) Lack of precision in diagnosis. (2) The erratic and unpredictable course of the disease with periods of spontaneous remission of symptoms. (3) Lack of a direct method for investigating activity of the disease. (4) The existence of only crude parameters for quantitating and recording the clinical course of the disease. (5) The irreversibility of gliosis and its masking effect on disease activity elsewhere in the nervous system. (6) Psychological disturbances, including hysterical tendencies, in some patients. (7) Problems of keeping large groups of patients under standard conditions of therapy or control for long periods (necessary because of the chronicity and erratic nature of the disease). Attempts to apply some degree of scientific control to therapeutic investigations in multiple sclerosis, however, have been made r e ~ e n t l y . ~ ~ Because of the prevalence of poorly controlled therapy reports, the National Institute of Neurological Diseases and Blindness provided financial support for a Symposium on the Evaluation of Drug Therapy in Neurologic and Sensory Diseases* which was held at the University of Wisconsin in May, 1960. Ten panels composed of investigators, clinicians, and statisticians met to consider the problem of experimental trials of therapy in various areas of nervous system disease. The results of the discussions were subsequently published.6 The conclusions reached by the Panel on Multiple Sclerosis comprised essentially a statement of the problems that needed study and solution to permit the design of a protocol for sound experimental trials of therapy. Thus, they formed merely a point of departure for future study. As an outgrowth of the initial considerations of the Panel on Multiple Sclerosis, a continuing panel was formed which held a series of workshops on the problem.
1,444 citations
TL;DR: Five main implications stem from the research to date: resistance to hazards may derive from controlled exposure to risk (rather than its avoidance), and resilience may be constrained by biological programming or damaging effects of stress/adversity on neural structures.
Abstract: Resilience is an interactive concept that refers to a relative resistance to environmental risk experiences, or the overcoming of stress or adversity. As such, it differs from both social competence positive mental health. Resilience differs from traditional concepts of risk and protection in its focus on individual variations in response to comparable experiences. Accordingly, the research focus needs to be on those indi- vidual differences and the causal processes that they reflect, rather than on resilience as a general quality. Because resilience in relation to child- hood adversities may stem from positive adult experiences, a life-span trajectory approach is needed. Also, because of the crucial importance of gene-environment interactions in relation to resilience, a wide range of research strategies spanning psychosocial and biological methods is needed. Five main implications stem from the research to date: (1) resis- tance to hazards may derive from controlled exposure to risk (rather than its avoidance); (2) resistance may derive from traits or circumstances that are without major effects in the absence of the relevant environmental hazards; (3) resistance may derive from physiological or psychological coping processes rather than external risk or protective factors; (4) de- layed recovery may derive from "turning point" experiences in adult life; and (5) resilience may be constrained by biological programming or damaging effects of stress/adversity on neural structures.
1,339 citations
TL;DR: The composition and synthesis of hydrogels, the character of their absorbed water, and permeation of solutes within their swollen matrices are reviewed to identify the most important properties relevant to their biomedical applications.
Abstract: This paper reviews the composition and synthesis of hydrogels, the character of their absorbed water, and permeation of solutes within their swollen matrices The most important properties of hydrogels relevant to their biomedical applications are also identified, in particular for use of hydrogels as drug and cell carriers, and as tissue engineering matrices
1,229 citations
TL;DR: Neuroimaging research reveals heightened amygdala responsivity in PTSD during symptomatic states and during the processing of trauma‐unrelated affective information and suggests diminished volumes, neuronal integrity, and functional integrity of the hippocampus in PTSD.
Abstract: The last decade of neuroimaging research has yielded important information concerning the structure, neurochemistry, and function of the amygdala, medial prefrontal cortex, and hippocampus in posttraumatic stress disorder (PTSD). Neuroimaging research reviewed in this article reveals heightened amygdala responsivity in PTSD during symptomatic states and during the processing of trauma-unrelated affective information. Importantly, amygdala responsivity is positively associated with symptom severity in PTSD. In contrast, medial prefrontal cortex appears to be volumetrically smaller and is hyporesponsive during symptomatic states and the performance of emotional cognitive tasks in PTSD. Medial prefrontal cortex responsivity is inversely associated with PTSD symptom severity. Lastly, the reviewed research suggests diminished volumes, neuronal integrity, and functional integrity of the hippocampus in PTSD. Remaining research questions and related future directions are presented.
1,058 citations
TL;DR: If reactive oxygen species are intimately involved with the redox regulation of cell functions, as seems likely from current evidence, it may be easier to understand why attempts to change antioxidant balance in aging experiments have failed.
Abstract: In the late 1950's free radicals and antioxidants were almost unheard of in the clinical and biological sciences but chemists had known about them for years in the context of radiation, polymer and combustion technology. Daniel Gilbert, Rebeca Gerschman and their colleagues related the toxic effects of elevated oxygen levels on aerobes to those of ionizing radiation, and proposed that oxygen toxicity is due to free radical formation, in a pioneering paper in 1956. Biochemistry owes much of its early expansion to the development and application of chromatographic and electrophoretic techniques, especially as applied to the study of proteins. Thus, superoxide dismutase (SOD) enzymes (MnSOD, CuZnSOD, FeSOD) were quickly identified. By the 1980's Molecular Biology had evolved from within biochemistry and microbiology to become a dominant new discipline, with DNA sequencing, recombinant DNA technology, cloning, and the development of PCR representing milestones in its advance. As a biological tool to explore reaction mechanisms, SOD was a unique and valuable asset. Its ability to inhibit radical reactions leading to oxidative damage in vitro often turned out to be due to its ability to prevent reduction of iron ions by superoxide. Nitric oxide (NO.) provided the next clue as to how SOD might be playing a critical biological role. Although NO. is sluggish in its reactions with most biomolecules it is astoundingly reactive with free radicals, including superoxide. Overall, this high reactivity of NO. with radicals may be beneficial in vivo, e.g. by scavenging peroxyl radicals and inhibiting lipid peroxidation. If reactive oxygen species are intimately involved with the redox regulation of cell functions, as seems likely from current evidence, it may be easier to understand why attempts to change antioxidant balance in aging experiments have failed. The cell will adapt to maintain its redox balance. Indeed, transgenic animals over-expressing antioxidants show some abnormalities of function. There must therefore be a highly complex interrelationship between dietary, constitutive, and inducible antioxidants with the body, under genetic control. The challenge for the new century is to be able to understand these relationships, and how to manipulate them to our advantage to prevent and treat disease.
TL;DR: It is proposed that the anterior cingulate cortex is a specialization of neocortex rather than a more primitive stage of cortical evolution, and thus are a recent evolutionary specialization probably related to these functions central to intelligent behavior.
Abstract: We propose that the anterior cingulate cortex is a specialization of neocortex rather than a more primitive stage of cortical evolution. Functions central to intelligent behavior, that is, emotional self-control, focused problem solving, error recognition, and adaptive response to changing conditions, are juxtaposed with the emotions in this structure. Evidence of an important role for the anterior cingulate cortex in these functions has accumulated through single-neuron recording, electrical stimulation, EEG, PET, fMRI, and lesion studies. The anterior cingulate cortex contains a class of spindle-shaped neurons that are found only in humans and the great apes, and thus are a recent evolutionary specialization probably related to these functions. The spindle cells appear to be widely connected with diverse parts of the brain and may have a role in the coordination that would be essential in developing the capacity to focus on difficult problems. Furthermore, they emerge postnatally and their survival may be enhanced or reduced by environmental conditions of enrichment or stress, thus potentially influencing adult competence or dysfunction in emotional self-control and problem-solving capacity.
TL;DR: Health risks in elderly people cannot be evaluated simply in conventional terms of body fatness or fat distribution, and Elders at greatest risk are those who are simultaneously sarcopenic and obese.
Abstract: Health risks in elderly people cannot be evaluated simply in conventional terms of body fatness or fat distribution. Elderly people have less muscle and bone mass, expanded extracellular fluid volumes, and reduced body cell mass compared to younger adults. These nonfat components of body composition play critical roles, influencing cognitive and physical functional status, nutritional and endocrine status, quality of life, and comorbidity in elderly people. Different patterns of "disordered body composition" have different relationships to these outcomes and may require different, tailored approaches to treatment that combine various exercise regimens and dietary supplements with hormone replacement or appetite-stimulating drugs. Skeletal muscle atrophy, or "sarcopenia," is highly prevalent in the elderly population, increases with age, and is strongly associated with disability, independent of morbidity. Elders at greatest risk are those who are simultaneously sarcopenic and obese. The accurate identification of sarcopenic obesity requires precise methods of simultaneously measuring fat and lean components, such as dual-energy X-ray absorptiometry.
TL;DR: The heaviest projections from the amygdala to the hippocampal formation and the parahippocampal areas originate in the lateral, basal, accessory basal, and posterior cortical nuclei, and the underlying principles of organization of these projections are discussed.
Abstract: Recent anterograde and retrograde studies in the rat have provided detailed information on the origin and termination of the interconnections between the amygdaloid complex and the hippocampal formation and parahippocampal areas (including areas 35 and 36 of the perirhinal cortex and the postrhinal cortex). The most substantial inputs to the amygdala originate in the rostral half of the entorhinal cortex, the temporal end of the CA1 subfield and subiculum, and areas 35 and 36 of the perirhinal cortex. The amygdaloid nuclei receiving the heaviest inputs are the lateral, basal, accessory basal, and central nuclei as well as the amygdalohippocampal area. The heaviest projections from the amygdala to the hippocampal formation and the parahippocampal areas originate in the lateral, basal, accessory basal, and posterior cortical nuclei. These pathways terminate in the rostral half of the entorhinal cortex, the temporal end of the CA3 and CA1 subfields or the subiculum, the parasubiculum, areas 35 and 36 of the perirhinal cortex, and the postrhinal cortex. The connectional data are summarized and the underlying principles of organization of these projections are discussed.
TL;DR: Clinical fluctuations and dyskinesias are frequent complications of levodopa therapy; these, as well as some motor features of PD, improve by resetting the abnormal brain physiology towards normal by surgical therapy.
Abstract: Parkinsonism is a clinical syndrome comprising combinations of motor problems-namely, bradykinesia, resting tremor, rigidity, flexed posture, "freezing," and loss of postural reflexes. Parkinson's disease (PD) is the major cause of parkinsonism. PD is a slowly progressive parkinsonian syndrome that begins insidiously and usually affects one side of the body before spreading to involve the other side. Pathology shows loss of neuromelanin-containing monoamine neurons, particularly dopamine (DA) neurons in the substantia nigra pars compacta. A pathologic hallmark is the presence of cytoplasmic eosinophilic inclusions (Lewy bodies) in monoamine neurons. The loss of DA content in the nigrostriatal neurons accounts for many of the motor symptoms, which can be ameliorated by DA replacement therapy-that is, levodopa. Most cases are sporadic, of unknown etiology; but rare cases of monogenic mutations (10 genes at present count) show that there are multiple causes for the neuronal degeneration. The pathogenesis of PD remains unknown. Clinical fluctuations and dyskinesias are frequent complications of levodopa therapy; these, as well as some motor features of PD, improve by resetting the abnormal brain physiology towards normal by surgical therapy. Nonmotor symptoms (depression, lack of motivation, passivity, and dementia) are common. As the disease progresses, even motor symptoms become intractable to therapy. No proven means of slowing progression have yet been found.
TL;DR: There is evidence that the sickness motivational state can interact with other motivational states and respond to nonimmune stimuli probably by way of sensitization and/or classical conditioning, however, the mechanisms that are involved in plasticity of the Sickness motivational state are not yet understood.
Abstract: Sickness behavior refers to a coordinated set of behavioral changes that develop in sick individuals during the course of an infection. At the molecular level, these changes are due to the brain effects of proinflammatory cytokines such as interleukin-1 (IL-1) and tumor necrosis factor alpha (TNFalpha). Peripherally released cytokines act on the brain via a fast transmission pathway involving primary afferent nerves innervating the bodily site of inflammation and a slow transmission pathway involving cytokines originating from the choroid plexus and circumventricular organs and diffusing into the brain parenchyma by volume transmission. At the behavioral level, sickness behavior appears to be the expression of a central motivational state that reorganizes the organism priorities to cope with infectious pathogens. There is evidence that the sickness motivational state can interact with other motivational states and respond to nonimmune stimuli probably by way of sensitization and/or classical conditioning. However, the mechanisms that are involved in plasticity of the sickness motivational state are not yet understood.
TL;DR: It is hypothesized that the selective and sustained expression of certain transcription factors and related “atheroprotective genes” in the endothelial lining of lesion‐protected areas represents a mechanism whereby hemodynamic forces can influence lesion formation and progression.
Abstract: Phenotypic modulation of endothelium to a dysfunctional state contributes to the pathogenesis of cardiovascular diseases such as atherosclerosis. The localization of atherosclerotic lesions to arterial geometries associated with disturbed flow patterns suggests an important role for local hemodynamic forces in atherogenesis. There is increasing evidence that the vascular endothelium, which is directly exposed to various fluid mechanical forces generated by pulsatile blood flow, can discriminate among these stimuli and transduce them into genetic regulatory events. At the level of individual genes, this regulation is accomplished via the binding of certain transcription factors, such as NF kappa B and Egr-1, to shear-stress response elements (SSREs) that are present in the promoters of biomechanically inducible genes. At the level of multiple genes, distinct patterns of up- and downregulation appear to be elicited by exposure to steady laminar shear stresses versus comparable levels of non-laminar (e.g., turbulent) shear stresses or cytokine stimulation (e.g., IL-1 beta). Certain genes upregulated by steady laminar shear stress stimulation (such as eNOS, COX-2, and Mn-SOD) support vasoprotective (i.e., anti-inflammatory, anti-thrombotic, anti-oxidant) functions in the endothelium. We hypothesize that the selective and sustained expression of these and related "atheroprotective genes" in the endothelial lining of lesion-protected areas represents a mechanism whereby hemodynamic forces can influence lesion formation and progression.
TL;DR: The working hypothesis is that structural plasticity in response to repeated stress starts out as an adaptive and protective response, but ends up as damage if the imbalance in the regulation of the key mediators is not resolved.
Abstract: The hippocampus is an important structure for declarative, spatial, and contextual memory and is implicated in the perception of chronic pain. The hippocampal formation is vulnerable to damage from seizures, ischemia, and head trauma and is particularly sensitive to the effects of adrenal glucocorticoids secreted during the diurnal rhythm and chronic stress. Adrenal steroids typically have adaptive effects in the short run, but promote pathophysiology when there is either repeated stress or dysregulation of the HPA axis. The damaging actions of glucocorticoids under such conditions have been termed “allostatic load”, referring to the cost to the body of adaptation to adverse conditions. Adrenal steroids display both protective and damaging effects in the hippocampus. They biphasically modulate excitability of hippocampal neurons, and high glucocorticoid levels and severe acute stress impair declarative memory in a reversible manner. The hippocampus also displays structural plasticity, involving ongoing neurogenesis of the dentate gyrus, synaptogenesis under control of estrogens in the CA1 region, and dendritic remodeling caused by repeated stress or elevated levels of exogenous glucocorticoids in the CA3 region. In all three forms of structural plasticity, excitatory amino acids participate along with circulating steroid hormones. Glucocorticoids and stressors suppress neurogenesis in the dentate gyrus. They also potentiate the damage produced by ischemia and seizures. Moreover, the aging rat hippocampus displays elevated and prolonged levels of excitatory amino acids released during acute stress. Our working hypothesis is that structural plasticity in response to repeated stress starts out as an adaptive and protective response, but ends up as damage if the imbalance in the regulation of the key mediators is not resolved. It is likely that morphological rearrangements in the hippocampus brought on by various types of allostatic load alter the manner in which the hippocampus participates in memory functions and it is conceivable that these may also have a role in chronic pain perception.
TL;DR: These findings implicate fundamental adaptive systems, which in turn suggest hot spots for the rising fourth wave of integrative research on resilience in children, focused on processes studied at multiple levels of analysis and across species.
Abstract: The first three waves of research on resilience in development, largely behavioral in focus, contributed a compelling set of concepts and methods, a surprisingly consistent body of findings, provocative issues and controversies, and clues to promising areas for the next wave of resilience research linking biology and neuroscience to behavioral adaptation in development. Behavioral investigators honed the definitions and assessments of risk, adversity, competence, developmental tasks, protective factors, and other key aspects of resilience, as they sought to understand how some children overcome adversity to do well in life. Their findings implicate fundamental adaptive systems, which in turn suggest hot spots for the rising fourth wave of integrative research on resilience in children, focused on processes studied at multiple levels of analysis and across species.
TL;DR: In humans, the leptin signaling system appears to be mainly involved in maintenance of adequate energy stores for survival during periods of energy deficit, and its role in the etiology of human obesity is only demonstrated in the very rare situations of absence of the leptin signal.
Abstract: A chronic minor imbalance between energy intake and energy expenditure may lead to obesity. Both lean and obese subjects eventually reach energy balance and their body weight regulation implies that the adipose tissue mass is "sensed", leading to appropriate responses of energy intake and energy expenditure. The cloning of the ob gene and the identification of its encoded protein, leptin, have provided a system signaling the amount of adipose energy stores to the brain. Leptin, a hormone secreted by fat cells, acts in rodents via hypothalamic receptors to inhibit feeding and increase thermogenesis. A feedback regulatory loop with three distinct steps has been identified: (1) a sensor (leptin production by adipose cells) monitors the size of the adipose tissue mass; (2) hypothalamic centers receive and integrate the intensity of the leptin signal through leptin receptors (LRb); (3) effector systems, including the sympathetic nervous system, control the two main determinants of energy balance-energy intake and energy expenditure. While this feedback regulatory loop is well established in rodents, there are many unsolved questions about its applicability to body weight regulation in humans. The rate of leptin production is related to adiposity, but a large portion of the interindividual variability in plasma leptin concentration is independent of body fatness. Gender is an important factor determining plasma leptin, with women having markedly higher leptin concentrations than men for any given degree of fat mass. The ob mRNA expression is also upregulated by glucocorticoids, whereas stimulation of the sympathetic nervous system results in its inhibition. Furthermore, leptin is not a satiety factor in humans because changes in food intake do not induce short-term increases in plasma leptin levels. After its binding to LRb in the hypothalamus, leptin stimulates a specific signaling cascade that results in the inhibition of several orexigenic neuropeptides, while stimulating several anorexigenic peptides. The orexigenic neuropeptides that are downregulated by leptin are NPY (neuropeptide Y), MCH (melanin-concentrating hormone), orexins, and AGRP (agouti-related peptide). The anorexigenic neuropeptides that are upregulated by leptin are alpha-MSH (alpha-melanocyte-stimulating hormone), which acts on MC4R (melanocortin-4 receptor); CART (cocaine and amphetamine-regulated transcript); and CRH (corticotropin-releasing-hormone). Obese humans have high plasma leptin concentrations related to the size of adipose tissue, but this elevated leptin signal does not induce the expected responses (i.e., a reduction in food intake and an increase in energy expenditure). This suggests that obese humans are resistant to the effects of endogenous leptin. This resistance is also shown by the lack of effect of exogenous leptin administration to induce weight loss in obese patients. The mechanisms that may account for leptin resistance in human obesity include a limitation of the blood-brain-barrier transport system for leptin and an inhibition of the leptin signaling pathways in leptin-responsive hypothalamic neurons. During periods of energy deficit, the fall in leptin plasma levels exceeds the rate at which fat stores are decreased. Reduction of the leptin signal induces several neuroendocrine responses that tend to limit weight loss, such as hunger, food-seeking behavior, and suppression of plasma thyroid hormone levels. Conversely, it is unlikely that leptin has evolved to prevent obesity when plenty of palatable foods are available because the elevated plasma leptin levels resulting from the increased adipose tissue mass do not prevent the development of obesity. In conclusion, in humans, the leptin signaling system appears to be mainly involved in maintenance of adequate energy stores for survival during periods of energy deficit. Its role in the etiology of human obesity is only demonstrated in the very rare situations of absence of the leptin signal (mutations of the leptin gene or of the leptin receptor gene), which produces an internal perception of starvation and results in a chronic stimulation of excessive food intake.
TL;DR: A system with three basic components: 1) a sensor which rigorously and effectively scans microscopic fields and converts the optical information into digital form; 2) human analysts who contribute heuristics, devise image processing methods and 3) quantitative methods which fully utilize measurements of light intensity of optical density.
Abstract: Automation of the acquisition and interpretation of data in microscopy has been a focus of biomedical research for almost a decade. In spite of many serious mechanical perception of microscopic fields with a reliability that would inspire routine application still eludes us. Many facets of the problem appear to be well within the grasp of presentday technology. Thus, available histochemical techniques make it possible to prepare biological materials so that morphological integrity is preserved, key constituents are stained stoichiometrically, and the specimens are favorably dispersed for effective imaging one by one. Scanning microscopes now have the requisite sensitivity, resolution, and stability to sample such objects and make photometric measurements over a wide range of magnifications and wavelengths within the visible and near-visible spectrum. Furthermore, modern large capacity, high speed data facilities at last provide the ability to manipulate the hitherto unmanageable quantities of optical information contained within all but the simplest images. With the basic materials for achieving automation via mensuration finally a t hand, attention has been turned toward generating and evaluating methods for extracting meaning from quantitative optical information. Definitive concepts for image structuring and image characterization have yet to be realized, to be given satisfactory operational definitions, and to be assembled within a machine-oriented perceptual framework.6 Criteria for effective and efficient discrimination and interpretation of images must be evolved. It would be a serious mistake to presuppose that mechanical perception must mimic the human’s perceptual apparatus in organizing images as complexes of picture eIements. Likewise i t would be serious to ignore traditional descriptive morphology and established taxonomies. In steering a middle course, the exploration of many complementary approaches and the introduction of numeric methods which fully utilize measurements of light intensity of optical density seemed to us to hold the most promise for augmenting and explicating the existing, largely verbal tradition of microscopic morphology. To realize these objectives, we have designed a system with three basic components: 1) a sensor which rigorously and effectively scans microscopic fields and converts the optical information into digital form; 2) human analysts who contribute heuristics, devise image processing methods and en-
TL;DR: Mounting evidence from many laboratories supports an Aβ accumulation in limbic and association cortices as the fundamental initiator of the disease, with attendant therapeutic implications.
Abstract: A central challenge of research on Alzheimer's disease (AD) is to assemble the enormous body of scientific observations about the disorder, some of them seemingly in conflict with others, into a coherent and credible mechanism of pathogenesis. In this article, I attempt to synthesize the disparate findings on AD into a unified sequence that essentially begins with alterations in the production or clearance of the amyloid beta-protein (A beta). Mounting evidence from many laboratories supports an A beta accumulation in limbic and association cortices as the fundamental initiator of the disease, with attendant therapeutic implications.
TL;DR: The purpose of this paper is to present a strategy that is useful in extending disc electrophoresis to new conditions of pH and constituent with considerably greater convenience than by using the rather complex calculations from the theory presented by Ornstein.
Abstract: Disc electrophoresis was developed by Ornstein and Davis' for the analytical separation of protein mixtures. By this method proteins are concentrated into thin starting zones and then separated by the combined action of electrophoresis and molecular sieving. Available however, are limited to a few pH values and to a few constituents.+ The purpose of this paper is to review the procedures and principles of disc electrophoresis and to present a strategy that is useful in extending it to new conditions of pH and constituent with considerably greater convenience than by using the rather complex calculations from the theory presented by Ornstein.'
TL;DR: The chemistry of reactive oxygen species‐mediated protein modification will be discussed and the accumulation of oxidatively modified proteins may reflect deficiencies in one or more parameters of a complex function that maintains a delicate balance between the presence of a multiplicity of prooxidants, antioxidants, and repair, replacement, or elimination of biologically damaged proteins.
Abstract: Although different theories have been proposed to explain the aging process, it is generally agreed that there is a correlation between aging and the accumulation of oxidatively damaged proteins, lipids, and nucleic acids. Oxidatively modified proteins have been shown to increase as a function of age. Studies reveal an age-related increase in the level of protein carbonyl content, oxidized methionine, protein hydrophobicity, and cross-linked and glycated proteins as well as the accumulation of less active enzymes that are more susceptible to heat inactivation and proteolytic degredation. Factors that decelerate protein oxidation also increase the life span of animals and vice versa. Furthermore, a number of age-related diseases have been shown to be associated with elevated levels of oxidatively modified proteins. The chemistry of reactive oxygen species-mediated protein modification will be discussed. The accumulation of oxidatively modified proteins may reflect deficiencies in one or more parameters of a complex function that maintains a delicate balance between the presence of a multiplicity of prooxidants, antioxidants, and repair, replacement, or elimination of biologically damaged proteins.
TL;DR: Vagal activity appears to play an inhibitory function in the regulation of allostatic systems associated with glucose regulation, hypothalamic‐pituitary‐adrenal (HPA) axis function, and inflammatory processes.
Abstract: The autonomic nervous system (ANS) plays a role in a wide range of somatic and mental diseases. Whereas the role of the ANS in the regulation of the cardiovascular system seems evident, its role in the regulation of other systems associated with allostasis is less clear. Using a model of neurovisceral integration we describe how the ANS and parasympathetic tone in particular may be associated with the regulation of allostatic systems associated with glucose regulation, hypothalamic-pituitary-adrenal (HPA) axis function, and inflammatory processes. Decreased vagal function and heart rate variability (HRV) were shown to be associated with increased fasting glucose and hemoglobin A1c levels, increased overnight urinary cortisol, and increased proinflammatory cytokines and acute-phase proteins. All of these factors have been associated with increased allostatic load and poor health. Thus, vagal activity appears to play an inhibitory function in the regulation of allostatic systems. The prefrontal cortex and the amygdala are important central nervous system structures linked to the regulation of these allostatic systems via the vagus nerve. Finally, the identification of this neurovisceral regulatory system may help to illuminate the pathway via which psychosocial factors may influence health and disease.
TL;DR: The stability constants for various desferrioxamine-metal complexes compared with the constants for other chelating agents are listed in TABLE l.596 The higher the constant, the more stable the complex.
Abstract: For several years now, the metabolites of Actinomycetes have been under study in the research laboratories of the Swiss Federal Institute of Technology in Zurich and of CIBA Limited in Basle. In the course of these studies, numerous compounds have been isolated which contain complexbound trivalent iron and which are brownish-red in color. By reference to the effects they exert, these naturally occurring substances can be subdivided into two groups : the sideromycins and the sideramines.' The sideromycins are antibiotics, whereas the sideramines specifically antagonize the antibacterial properties of the sideromycins. The sideramines also possess growth-promoting properties and appear to exert an important function in the iron metabolism of microorganisms, possibly acting as iron donors in the incorporation of iron in the porphyrin systems. Among the various sideramines obtained from Streptomyces pilosus, the principal product is the so-called ferrioxamine B.?.$ The complex-bound trivalent iron contained in ferrioxamine B can be removed by chemical means, thus yielding the colorless, crystalline substance to be discussed here: desferrioxamine B.' Desferrioxamine is composed of one molecule of acetic acid, two molecules of succinic acid, and three molecules of 1-amino-5-hydroxylaminopentane. The organic units of which desferrioxamine is built up are interlinked to form a chain, in which there are three hydroxamic acid groups inside, and one free amino group a t the end. The free amino group accounts for the basic character of the compound, which enables i t to form salts with organic and inorganic acids (FIGURE 1). When a ferric ion comes into contact with desferrioxamine, the straightchained molecule twines itself around the ion, becoming attached to the latter by means of its three hydroxamic acid groups (FIGURE 2 ) . The iron is thus surrounded by a shell of organic material, which results in an iron complex of very great stability. The stability constants for various desferrioxamine-metal complexes compared with the constants for other chelating agents are listed in TABLE l.596 The higher the constant, the more stable the complex. The highest figure here, lo:{', is for the iron complex of desferrioxamine. All the other constants for this compound are lower by at least 10.' This means that desferrioxamine is not only the most potent, but also by far the most spe-
TL;DR: Fibrinogen and fibrin play important, overlapping roles in blood clotting, fibrinolysis, cellular and matrix interactions, inflammation, wound healing, and neoplasia, and crosslinks form mainly between complementary sites on γ chains (forming γ‐polymers), and even more slowly among γ dimers to create higher order crosslinked γ trimers and tetramers, to complete the mature network structure.
Abstract: Fibrinogen and fibrin play important, overlapping roles in blood clotting, fibrinolysis, cellular and matrix interactions, inflammation, wound healing, and neoplasia. These events are regulated to a large extent by fibrin formation itself and by complementary interactions between specific binding sites on fibrin(ogen) and extrinsic molecules including proenzymes, clotting factors, enzyme inhibitors, and cell receptors. Fibrinogen is comprised of two sets of three polypeptide chains termed A alpha, B beta, and gamma, that are joined by disulfide bridging within the N-terminal E domain. The molecules are elongated 45-nm structures consisting of two outer D domains, each connected to a central E domain by a coiled-coil segment. These domains contain constitutive binding sites that participate in fibrinogen conversion to fibrin, fibrin assembly, crosslinking, and platelet interactions (e.g., thrombin substrate, Da, Db, gamma XL, D:D, alpha C, gamma A chain platelet receptor) as well as sites that are available after fibrinopeptide cleavage (e.g., E domain low affinity non-substrate thrombin binding site); or that become exposed as a consequence of the polymerization process (e.g., tPA-dependent plasminogen activation). A constitutive plasma factor XIII binding site and a high affinity non-substrate thrombin binding site are located on variant gamma' chains that comprise a minor proportion of the gamma chain population. Initiation of fibrin assembly by thrombin-mediated cleavage of fibrinopeptide A from A alpha chains exposes two EA polymerization sites, and subsequent fibrinopeptide B cleavage exposes two EB polymerization sites that can also interact with platelets, fibroblasts, and endothelial cells. Fibrin generation leads to end-to-middle intermolecular Da to EA associations, resulting in linear double-stranded fibrils and equilaterally branched trimolecular fibril junctions. Side-to-side fibril convergence results in bilateral network branches and multistranded thick fiber cables. Concomitantly, factor XIII or thrombin-activated factor XIIIa introduce intermolecular covalent epsilon-(gamma glutamyl)lysine bonds into these polymers, first creating gamma dimers between properly aligned C-terminal gamma XL sites, which are positioned transversely between the two strands of each fibrin fibril. Later, crosslinks form mainly between complementary sites on alpha chains (forming alpha-polymers), and even more slowly among gamma dimers to create higher order crosslinked gamma trimers and tetramers, to complete the mature network structure.
TL;DR: Community health agencies are especially fitted for the conduct of epidemiologic studies which require access to large populations and resources for handling large numbers of subjects, and a large proportion of community health research projects are of this type.
Abstract: Those concerned with community health have a legitimate interest in all matters related to promoting the health of the community. These interests may vary depending on the purposes for which the health agency was organized, its location, the skills and resources available to it, and many other factors. In general, the major objective of community health activities is to prevent, or improve the medical care of, existing disease. In the past, research engaged in by health agencies has usually been initiated because of some real or suspected problem affecting the health of their community. Because of inability to answer certain crucial questions pertaining to the problem, an investigation is undertaken to attempt to provide the desired information. Studies might be undertaken to assist in administrative planning concerning the number of beds required for some major emergency or to meet changing patterns of disease incidence, or of ways to convert existing facilities for such purposes, e.g., conversion of tuberculosis sanatoria to chronic disease hospitals. Research may be required to discover ways of improving medical care for particular diseases by determining methods required to bring persons with given diseases under medical care early in the course of the illness, in order to minimize disability. This type of research has usually been done with specific uses in mind and can be considered under the category of applied research. In addition to research aimed directly at solving immediate local problems, it is now increasingly common for health agencies to ask how the facilities and resources available to them can best be used for purposes of research to increase general knowledge without necessarily being motivated by the immediate needs of the particular health agency. Studies may be carried out to evaluate the manner in which a particular problem has already been solved or to indicate the desirable approach to a particular health problem. Community health agencies are especially fitted for the conduct of epidemiologic studies which require access to large populations and resources for handling large numbers of subjects. For this reason, a large proportion of community health research projects are of this type. Because of the classic contributions of the epidemiologic method in determining the causes and methods of prevention of infectious and nutritional diseases, this method has been applied in an attempt to unravel the problems surrounding chronic diseases of unknown etiology. Although notable progress is being made, it remains to be demonstrated whether this approach will prove as valuable in solving the problems surrounding chronic disease.
TL;DR: The extensive studies based on the FRTA hold promise thatALE‐B and the MLS can be extended, the ALE‐B possibly by a few years, and theMLS somewhat less.
Abstract: Aging is the progressive accumulation of diverse, deleterious changes with time that increase the chance of disease and death. The basic chemical process underlying aging was first advanced by the free radical theory of aging (FRTA) in 1954: the reaction of active free radicals, normally produced in the organisms, with cellular constituents initiates the changes associated with aging. The involvement of free radicals in aging is related to their key role in the origin and evolution of life. Aging changes are commonly attributed to development, genetic defects, the environment, disease, and an inborn aging process (IAP). The latter produces aging changes at an exponentially increasing rate with age, becoming the major risk factor for disease and death for humans after the age of 28 years in the developed countries. In them the IAP limits human average life expectancy at birth (ALE-B)--a rough measure of the healthy life span--to about 85 years; few reach 100 years and only one is known to have lived to 122 years. In these countries, improvements in living conditions (ILC) have gradually raised ALE-Bs to 76-79 years, 6-9 years less than the limit imposed by aging, with no change in the maximum life span (MLS). The extensive studies based on the FRTA hold promise that ALE-B and the MLS can be extended, the ALE-B possibly by a few years, and the MLS somewhat less.
TL;DR: The terminal organization of the presubicular input to the medial entorhinal cortex indicates that the interactions between the deep and superficial entorHinal layers may be influenced by this input.
Abstract: The anatomical organization of the parahippocampal-hippocampal network indicates that it consists of different parallel circuits. Considering the topographical distribution of sensory cortical inputs, the hypothesis is that the major parallel circuits carry functionally different information. These functionally different parallel routes reach different portions of the hippocampal network along the longitudinal axis of all fields as well as along the perpendicularly oriented transverse axis of CA1 and the subiculum. In the remaining fields of the hippocampal formation, that is, the dentate gyrus and CA2/CA3, separation along the transverse axis is not present. By contrast, here the functionally different pathways converge onto the same neuronal population. The entorhinal cortex holds a pivotal position among the cortices that make up the parahippocampal region. By way of the networks of the superficial and deep layers, it mediates, respectively, the input and output streams of the hippocampal formation. Moreover, the intrinsic entorhinal network, particularly the interconnections between the deep and superficial layers, may mediate the comparison of hippocampal input and output signals. As such, the entorhinal cortex may form part of a novelty detection network. In addition, the organization of the entorhinal-hippocampal network may facilitate the holding of information. Finally, the terminal organization of the presubicular input to the medial entorhinal cortex indicates that the interactions between the deep and superficial entorhinal layers may be influenced by this input.