Negative pressure ventilation via diaphragmatic pacing: a potential gateway for treating systemic dysfunctions.

Programmed diaphragmatic pacing using implanted neuromodulators represents an emerging method for providing pulmonary support using negative pressure ventilation. The implantable, rechargeable, programmable and miniaturized nature of diaphragmatic pacers may obviate many of the management issues associated with noninvasive positive pressure ventilation devices. Closed loop systems may facilitate the implementation of diaphragmatic pacing for the treatment of many indications. They may allow for wider adoption of ventilatory support in central sleep apnea and improve quality of life in diseases of chronic hypoventilation, such as amyotrophic lateral sclerosis. In addition, it might alleviate subclinical hypoventilation--a condition that may affect a significant proportion of the aging population. Diaphragmatic pacing could also reduce sympathetic bias, which may contribute to a wide range of diseases associated with autonomic dysfunction.

Martius flap: an adjunct for repair of complex, low rectovaginal fistula.

BACKGROUND: Complex, rectovaginal fistula (RVF) are uncommon but difficult therapeutic problems. Local repair and flap advancement techniques have a high incidence of recurrence with poor functional outcomes. Transperineal repair with anal sphincter reconstruction, when indicated, and placement of a Martius flap (bulbocavernosus pedicled transplant) result in improved rates of repair and better functional outcomes. METHODS: A consecutive series of patients were retrospectively reviewed from a prospective database between 2002 and 2006. Data were gathered from 2 colon- and rectal-specialty practices. Patient demographics and operative and functional outcomes were documented. RESULTS: Sixteen patients with a mean age of 39.5 years (17-62) were treated. Etiology of the fistula was obstetric (9), cryptoglandular (5), and Crohn's disease (2). They had undergone a mean of 1.5 (0-4) prior repairs, and 6 had a preexisting diverting stoma before repair. Preoperatively, anal sphincter disruption was identified in 11 patients, and fecal incontinence was identified in 5 patients all with anal sphincter disruption. Dyspareunia was identified in 1 of 13 sexually active patients preoperatively. At a mean follow-up of 75 weeks (24-190), 1 recurrent fistula was identified (6.2%). Stomas were reversed in all patients. Two patients complained of fecal incontinence postoperatively. Five patients had dyspareunia postoperatively (5/16, 31%). One patient had a labial wound complication requiring local wound care. CONCLUSION: Selected complex RVF can be reliably repaired with good functional outcomes using the Martius flap with anal sphincter reconstruction. Persistent or recurrent fecal incontinence and dyspareunia are common sequela of the underlying perineal injury and repair. No acute or delayed morbidity related to the Martius flap was identified.

Is atherosclerosis a neurogenic phenomenon?

Identified risk factors for atherosclerosis include diet, age, gender, family history, stress, lifestyle, smoking, diabetes, dyslipidemias, hypertension, and HIV. The mechanistic rationale to explain these associations remains poorly understood. We believe that these seemingly unrelated entities may promote atherosclerosis through a common pathway by inducing adventitial autonomic dysfunction, specifically as an adventitial stress dysfunction of neurogenic origin. Atherosclerosis may represent a local vascular manifestation of the global autonomic dysfunction induced by age, smoking, hypertension, HIV, and diabetes. Atherosclerosis may also participate in a feed-forward cycle as aging, diabetes, dyslipidemia, and hypertension may also represent independent downstream consequences of global sympathetic bias. Chronic physiologic stress and behavioral stress can shift the autonomic balance towards a state of sympathetic predominance. The highly communicable nature of behavioral stress may partially implicate the familial association of atherosclerosis as an epigenetic phenomenon, independent of putative genetic mechanisms. Host stress, global autonomic dysfunction, and sympathetic bias may also arise from chronic maladaptive consumption of stressed foods, as organisms detect and assimilate the stress phenotypes of their dietary constituents through a process called xenohormesis. The benefits of exercise may operate through reduction of chronic physiologic stress associated with global sympathetic bias. The neurogenic adventitial stress response may explain the local tissue remodeling seen in atherosclerosis, including adventitial adipose dysfunction, inflammation, adventitial angiogenesis, thrombosis, and endothelial dysfunction. We believe that the locations of atherosclerotic lesions correspond to regions of neurogenic adventitial autonomic dysfunction, in similar fashion to the segmental patterns of involvement found in inflammatory bowel disease. The diffuse atherosclerosis exhibited in transplanted hearts may reflect a diffuse sympathetic bias of the donor heart, since tissues and organs exhibit an intrinsic sympathetic bias in the absence of an extrinsic source of autonomic hegemony. Once we regard atherosclerosis as a neurogenic phenomenon manifested in adventitial autonomic dysfunction, novel diagnostic and therapeutic paradigms become evident.

Peripheral arterial disease: a manifestation of evolutionary dislocation and feed-forward dysfunction.

Peripheral arterial disease in the legs represents a subset of atherosclerosis that manifests a particularly sinister profile. A predominance of sympathetic activity in the periphery favors the development of neurogenic atherosclerosis. Atherosclerosis may then produce flow derangements and decreased physical activity that serves to escalate sympathetic bias in a vicious cycle. Restoration of normal flow in peripheral arterial disease may not only produce local benefit due to improved perfusion, but also represent a gateway to correcting many systemic conditions that may at first glance appear unrelated but share a common etiology of autonomic dysfunction, such as gout, acute coronary syndromes, stroke, sleep apnea, arrhythmias, depression, erectile dysfunction, inflammation, hypercoagulability, sleep disorders, bowel dysfunction, renal failure, and aging.

Osteoarthritis: an example of phenoptosis through autonomic dysfunction?

Phenoptosis, the programmed death of organisms akin to cellular apoptosis, constitutes a type of Darwinian selection that enhances inclusive fitness. It provides a means by which senescent and pre-senescent members can self-terminate if they have incurred sufficient cumulative stress such that their continued survival detracts from inclusive fitness. Sepsis, vascular disease, menopause, cancer, and aging all represent examples of phenoptosis at work. We previously proposed that feed-forward autonomic dysfunction fundamentally drives phenoptosis in all its guises. Accordingly, we now postulate that osteoarthritis defines a type of biomechanical phenoptosis, mediated by feed-forward autonomic dysfunction, and manifested through joint destruction associated with fitness disadvantages. Biomechanical capability plays a significant role in evolutionary fitness, and sustained joint insults such as immobility or undue biomechanical stress may serve as proxies for inferior fitness. By both hindering an individual's ability to compete for energy and increasing that individual's vulnerability to predation, feed-forward joint destruction may facilitate adaptive phenoptosis among impaired or senile members. Empirical data suggests that contrary to common belief, heavy joint use does not necessarily cause osteoarthritis, whereas immobility and neuropathy can predispose to the condition. From a Darwinian perspective, another process mediated by sympathetic activity, the alarm cry of attacked prey, simultaneously promotes the escape of kin while attracting predators and scavengers. By effectively enabling the martyrdom of biomechanically-challenged individuals, osteoarthritis may serve to optimize system energy efficiency in a similar fashion. This framework may generalize to other situations where regenerative capacity dissipates in conjunction with maturation, typically leading to fibrosis. By allowing environmental pressure to sort the phenotypes, imperfect repair mechanisms may accelerate adaptation and optimize long-term inclusive fitness for all individuals. As the basis of competition shifts from biomechanical to cognitive skills, and as novel triggers for physical stress emerge, osteoarthritis may now represent a modern maladaptation.

A paradigm for viewing biologic systems as scale-free networks based on energy efficiency: implications for present therapies and the future of evolution.

A network constitutes an abstract description of the relationships among entities, respectively termed links and nodes. If a power law describes the probability distribution of the number of links per node, the network is said to be scale-free. Scale-free networks feature link clustering around certain hubs based on preferential attachments that emerge due either to merit or legacy. Biologic systems ranging from sub-atomic to ecosystems represent scale-free networks in which energy efficiency forms the basis of preferential attachments. This paradigm engenders a novel scale-free network theory of evolution based on energy efficiency. As environmental flux induces fitness dislocations and compels a new meritocracy, new merit-based hubs emerge, previously merit-based hubs become legacy hubs, and network recalibration occurs to achieve system optimization. To date, Darwinian evolution, characterized by innovation sampling, variation, and selection through filtered termination, has enabled biologic progress through optimization of energy efficiency. However, as humans remodel their environment, increasing the level of unanticipated fitness dislocations and inducing evolutionary stress, the tendency of networks to exhibit inertia and retain legacy hubs engender maladaptations. Many modern diseases may fundamentally derive from these evolutionary displacements. Death itself may constitute a programmed adaptation, terminating individuals who represent legacy hubs and recalibrating the network. As memes replace genes as the basis of innovation, death itself has become a legacy hub. Post-Darwinian evolution may favor indefinite persistence to optimize energy efficiency. We describe strategies to reprogram or decommission legacy hubs that participate in human disease and death.

Efficient inefficiency: biochemical "junk" may represent molecular bridesmaids awaiting emergent function as a buffer against environmental fluctuation.

The biochemical function of many parts of the genome, transcriptome, proteome, and interactome remain largely unknown. We propose that portions of these fundamental building blocks of life have no current biochemical function per se. Rather, sections of these "omes" may contribute to an inventory of biochemical parts and circuits that participate in the development of emergent functions. Low fidelity deoxyribonucleic acid replication, transcription, translation, and post-translational modification all represent potential mechanisms to produce an inventory of parts. Stochastic processes that influence the conformations of ribonucleic acid molecules and proteins may also contribute to potential biochemical inventory. Some components of the biochemical inventory may enable future adaptations, some may produce disease, and some may remain useless. The function of many of these components await discovery, not by science, but by evolution. While carrying such purposeless biochemical units may appear to dilute fitness by exacting a thermodynamic cost, we argue that net fitness becomes enhanced when considering the value for potential future innovations. One can envision components that intermingle, interact, and act out mock pathways, but in most cases remain molecular bridesmaids. Given sufficiently low thermodynamic cost, such stochastic cycling may persist until a markedly advantageous or cataclysmically disadvantageous trait emerges. Maladaptive screening and utilization of inventory content can lead to disease phenotypes, a process buffered and regulated in part by the heat shock protein and stress response network. Whereas failure of the ubiquitin pathway to recycle misfolded proteins has become increasingly recognized as a source of disease, protein misfolding may itself represent one step in a process that maximizes functional innovation through increasing proteomic diversity. Fractal correlates of these processes occur at the organizational level of cells and organisms. That the abnormal accumulation of units induces local collapse may serve to limit the extension of damage to the greater system at large. The immune and cognitive systems that selectively sample and prune environmental content may serve as additional portals for innovation.

Integrating systems biology and medical imaging: understanding disease distribution in the lung model.

OBJECTIVE: Many chronic diseases exhibit characteristic pulmonary distribution patterns, but the underlying biologic explanations remain elusive. On the basis of emerging evidence from systems biology, we propose that gradients of T helper immune function exist as an epiphenomenon of the hypoxic pulmonary vasoconstriction response. Regional variation of immune function may contribute to preferential distribution patterning of lung diseases. CONCLUSION: The lungs represent but one example in which the distribution of immune function throughout the body may explain disease location. This hypothetic framework can apply to diseases outside the realm of pulmonary biology and illustrates the potential benefit of integrating advances in systems biology and medical imaging.

Are we eating more than we think? Illegitimate signaling and xenohormesis as participants in the pathogenesis of obesity.

Resource utilization may represent a central force driving evolution. A tight link between sensing energy availability and managing energy acquisition and utilization constitutes a common feature among all organisms. While such a link was likely adaptive during prehistoric evolution, modern lifestyles may decouple perceived cues from actual energy availability so as to promote obesity in humans. A particular illegitimate signal is chronic stress, which may shift body phenotype to suit a more conservative state of energy management. In prehistoric times, such a response likely aided survival during periods of low resource availability. However, new sources of chronic stress have emerged that bear little relationship to contextual energy, which is generally abundant in the modern world. In addition, modern techniques of husbandry and agriculture can produce stress in the food chain, such that food itself can act as an illegitimate signal of chronic stress. Obese livestock and unusual fat profiles in farmed fish, meat, and eggs may reflect stress phenotypes. Consumers of stressed foods may sense those signals--a phenomenon known as xenohormesis--and assume the stressed phenotype. This maladaptive process may promote obesity by erroneously biasing hosts towards caloric accumulation in the context of energy abundance. Regional tissue accumulation of fat may indicate local tissue stress. Atherosclerosis may result from stress signals that induce sympathetic bias and regional fat accumulation in vessel adventitia. Medications such as neuroleptics and foods such as diet drinks may generate illegitimate signals by mimicking molecules used for energy management. Implications for the prevention and treatment of dysfunctions related to these derangements are discussed. New strategies for manufacturing biologics by manipulating stress conditions or controlling fatty acid attachments to proteins are envisioned.

Obesity and ADHD may represent different manifestations of a common environmental oversampling syndrome: a model for revealing mechanistic overlap among cognitive, metabolic, and inflammatory disorders.

Obesity and attention-deficit hyperactivity disorder (ADHD) are both increasing in prevalence. Childhood exposure to television has shown linkage to both ADHD and obesity with the former ascribed to dysfunctional cognitive hyperstimulation and the latter to altered patterns of diet and exercise. Empirical evidence has contradicted prior presumptions that the hyperactivity of ADHD would decrease the risk of obesity. Instead, obesity and ADHD demonstrate significant comorbidity. We propose that obesity and ADHD represent different manifestations of the same underlying dysfunction, a phenomenon we term environmental oversampling syndrome. Oversupply of information in the form of nutritional content and sensory content may independently predispose to both obesity and ADHD. Moreover, the pathogenic mechanisms of these conditions may overlap such that nutritional excess contributes to ADHD and cognitive hyperstimulation contributes to obesity. The overlapping effects of medications provide further evidence towards the existence of shared etiologic pathways. Metabolism and cognition may represent parallel systems of intelligence, and oversampling of content may constitute the source of parallel dysfunctions. The emerging association between psychiatric and metabolic disorders suggests a fundamental biologic link between these two systems. In addition, the immune system may represent yet another form of intelligence. The designation of syndrome X subsumes seemingly unrelated metabolic and inflammatory entities. Environmental oversampling syndrome may represent an even more inclusive concept that encompasses various metabolic, inflammatory, and behavioral conditions. Apparently disparate conditions such as insulin resistance, diabetes, hypertension, syndrome X, obesity, ADHD, depression, psychosis, sleep apnea, inflammation, autism, and schizophrenia may operate through common pathways, and treatments used exclusively for one of these conditions may prove beneficial for the others.

A general theory of evolution based on energy efficiency: its implications for diseases.

We propose a general theory of evolution based on energy efficiency. Life represents an emergent property of energy. The earth receives energy from cosmic sources such as the sun. Biologic life can be characterized by the conversion of available energy into complex systems. Direct energy converters such as photosynthetic microorganisms and plants transform light energy into high-energy phosphate bonds that fuel biochemical work. Indirect converters such as herbivores and carnivores predominantly feed off the food chain supplied by these direct converters. Improving energy efficiency confers competitive advantage in the contest among organisms for energy. We introduce a term, return on energy (ROE), as a measure of energy efficiency. We define ROE as a ratio of the amount of energy acquired by a system to the amount of energy consumed to generate that gain. Life-death cycling represents a tactic to sample the environment for innovations that allow increases in ROE to develop over generations rather than an individual lifespan. However, the variation-selection strategem of Darwinian evolution may define a particular tactic rather than an overarching biological paradigm. A theory of evolution based on competition for energy and driven by improvements in ROE both encompasses prior notions of evolution and portends post-Darwinian mechanisms. Such processes may involve the exchange of non-genetic traits that improve ROE, as exemplified by cognitive adaptations or memes. Under these circumstances, indefinite persistence may become favored over life-death cycling, as increases in ROE may then occur more efficiently within a single lifespan rather than over multiple generations. The key to this transition may involve novel methods to address the promotion of health and cognitive plasticity. We describe the implications of this theory for human diseases.

Contrast nephropathy may be partly mediated by autonomic dysfunction: renal failure considered as a modern maladaptation of the prehistoric trauma response.

The mechanism behind iodinated radiocontrast nephropathy remains elusive. Direct oxidative damage is the prevailing hypothesis, but the apparent protective effect of iodine against oxidation contradicts this view. We propose that autonomic dysfunction participates in the pathogenesis of radiocontrast nephropathy and may account for other contrast-associated reactions previously attributed to allergy. Iodine, through its effects on thyroid function and chemoreceptor response to metabolic acidosis, may induce hyperadrenergia and consequently diminish renovascular flow and urine output. The renal response to adrenergia likely served an adaptive function during prehistoric evolution when trauma was a dominant source of hypovolemia and adrenergia, but the response may behave maladaptively today as evolutionarily nai ve triggers for adrenergia have emerged. Autonomic dysfunction can further impair renal function by deranging renovascular autoregulation and inducing oxidative reperfusion injury as a secondary phenomenon. Many other causes of acute renal failure such as drug toxicity, surgery, hospitalization, and diabetes may operate through hyperadrenergia, impaired renovascular autoregulation, and oxidative reperfusion injury. Dialysis, a volume reduction therapy for renal failure, can counterintuitively worsen renal dysfunction by exacerbating adrenergia, which may explain its association with accelerated atherosclerosis, inflammation, and cancer. Other examples of vicious cycles that perpetuate renal dysfunction may include renal artery stenosis, carotid stenosis, and atherosclerosis as well as the cardio-renal, hepato-renal, and pulmonary-renal syndromes. The benefits of hydration and bicarbonate in protecting renal function may operate in part through baroreceptor- and chemoreceptor-mediated reduction of sympathovagal ratio, respectively. New treatment paradigms for renal failure including pharmacologic and electro-mechanical therapies are envisioned based on autonomic remodeling, reduced sympathovagal ratio, and neuromodulation of pathways typically associated with trauma such as renin, angiotensin, vasopressin, and aldosterone.

Adventitial dysfunction: an evolutionary model for understanding atherosclerosis.

Endothelial and smooth muscle dysfunctions are widely implicated in the pathogenesis of atherosclerosis. Modern mechanical and pharmacologic treatments aim to remodel abnormalities of the vessel intima and media. We hypothesize that adventitial dysfunction comprises the dominant source of atherosclerosis by originating many endothelial and smooth muscle abnormalities. The autonomic nervous system innervates the adventitia, and autonomic dysfunction induces many end-organ dysfunctions including inflammation and thrombosis. The link between diabetes and atherosclerosis may operate through adventitial autonomic neuropathy. Smoking may promote atherosclerosis by inducing adventitial autonomic dysfunction related to nicotine-mediated compensatory upregulation of sympathetic bias independent of endothelial injury induced by purported tobacco toxins. While hypertension is thought to cause atherosclerosis, the two conditions may instead represent independent consequences of autonomic dysfunction. The link between aging and atherosclerosis may operate through adventitial dysfunction induced by autonomic dysregulations. Exercise may ameliorate atherosclerosis by restoring adventitial autonomic function, thereby normalizing adventitial regulation of medial and intimal biology. Feed-forward adventitial vascular baroreceptor and chemoreceptor dysregulation may further exacerbate atherosclerosis as intimal plaque interferes with these sensors. Since penetrating external physical injury likely represented a dominant selective force during evolution, the adventitia may be preferentially equipped with sensors and response systems for vessel trauma. The convergent response of adrenergia, inflammation, and coagulation, which is adaptive for physical trauma, may be maladaptive today when different stressors trigger the cascade. Endoluminal therapies including atherectomy, angioplasty, and stent deployment involve balloon expansion that traumatizes all layers of the vessel wall. These interventions may paradoxically reinitiate the cascade of atherogenesis that begins with adventitial dysfunction and leads to restenosis. Methods to reduce adventitial trauma, a maladaptive trigger of adventitial dysfunction, may reduce the risk of restenosis. We envision novel mechanical and biopharmaceutical solutions that target the adventitia to prevent or treat atherosclerosis including novel drug delivery strategies, exo-stents that wrap vessels, and neuromodulation of vessels.

The incorporation of iodine in thyroid hormone may stem from its role as a prehistoric signal of ecologic opportunity: an evolutionary perspective and implications for modern diseases.

To optimize fitness under conditions of varying Darwinian opportunity, organisms demonstrate tremendous plasticity in their life-history strategies based on their perception of available resources. Higher-energy environments generally promote more aggressive life-history strategies, such as faster growth, larger adult size, greater genetic variation, shorter lifespan, larger brood sizes, and offspring ratio skewed towards the larger-sized gender. While numerous mechanisms regulate life-history plasticity including genetic imprinting, methylation, and growth factors, evidence suggests that thyroid hormone plays a central role. Given the pivotal adaptive role of thyroid hormone, the teleology of its dependence on dietary iodine for production remains unexplained. We hypothesize that iodine may have emerged as a substrate for production of thyroid hormone in prehistoric ecosystems because the former represented a reliable proxy for ecologic potential that enabled the latter to modulate growth, reproduction, metabolic rate, and lifespan. Such a scenario may have existed in early marine ecosystems where ocean-surface vegetation, which concentrates iodine for its antimicrobial and antioxidant properties, formed the basis of the food chain. Teleologic parallels can be drawn to the food-chain accumulation of antimicrobials that also exhibit antioxidant properties and promote adult size, brood size, and offspring quality by modulating central hormonal axes. As each higher species in the food chain tunes its life-history strategy based on iodine intake, the coupling of this functional role of iodine with its value as a resource signal to the next member of the food-chain may promote runaway evolution. Whereas predators in prehistoric ecosystems successfully tuned their life-history strategy using iodine as a major input, the strategy may prove maladaptive in modern humans for whom the pattern of iodine intake is decoupled from resource availability. Iodine acquired through sodium iodide supplementation may independently contribute to some biologic dysfunctions currently attributed to sodium.

The link between T helper balance and lymphoproliferative disease.

Lymphoproliferative disorders comprise a heterogeneous group of neoplasms whose behaviors range from indolent to very aggressive. The increased incidence seen in the context of immunodeficiency provides evidence that the host immune system plays a vital role in their pathogenesis. We believe that T-helper (Th)-2 dominant states favor development of lymphoproliferative disorders, including lymphoma, and conversely T-helper (Th)-1 immunity protects against lymphoproliferative disease. The age distribution of lymphomas favors childhood and post-reproductive senescence, suggesting that exposure to these periods of Th-2 bias constitutes a key risk factor for developing the disease. The tendency of lymphomas to arise in Th-2 biased locations such as mucosal interfaces, immunoprivileged sites, and regions of B-cell differentiation may likewise reflect a corresponding spatial predilection. Various clinical conditions or treatments that shift Th1/Th2 balance, including HIV infection, transplant-related immune suppression, and autoimmune disorders, can also influence the status of lymphoproliferative diseases.

Integrating the theories of Darwin and Bernoulli: maladaptive baroreceptor network dysfunction may explain the pathogenesis of aortic aneurysms.

Current treatment options for aortic aneurysms are suboptimal and their pathogenic mechanisms remain unclear. We propose the existence of a coordinated multi-node baroreceptor network that measures pressures at all vascular bifurcations and enables system-wide hemodynamic coordination and vasomotor regulation, in accordance with the principle of Bernoulli. While the presence of baroreceptors at bifurcations remains unknown, behavior at the level of systems predicts their existence, possibly as glomus cell derivatives. We propose that pressure misregistration among sensor nodes at different vascular bifurcations can precipitate feed-forward dysfunctions that promote thrombosis, inflammation, and vasomotor dysregulation resulting in aneurysm formation. One example of this phenomenon is aortic aneurysm, which is currently attributed to focal anatomic defects. As plaque builds in the infrarenal aorta, the increased blood velocity through this segment can widen the difference between pressures sensed at the iliac and the renal artery bifurcations. Due to the Bernoulli effect, this change creates an incorrect impression of reduced dynamic pressure at the kidneys. The erroneous perception of hypovolemia can induce a pernicious cycle of maladaptive adrenergia and associated coagulation and thrombosis, particularly in the infrarenal aortic segment as the body attempts to normalize renal perfusion. Atherosclerosis can further exacerbate baroreceptor dysfunction by interfering with sensor biology in feed-forward fashion. Hypertension may be a consequence as well as a source of atherosclerosis and aneurysm. The described system may have evolved when trauma-related hypovolemia was a far more prevalent driver of natural selection but may be rendered maladaptive in the setting of modern stressors. Failure to address these factors may explain the suboptimal long-term outcomes with current surgical and endovascular treatments for aneurysms. Implications for other potential sensor networks including chemoreceptors and lymphoid tissues at bifurcating biologic branch-points such as vessels, airways, nerves, lymphatics, and ducts are discussed. Our framework may also provide a new basis for understanding thoracic aneurysm, renovascular dysfunctions, coronary artery disease, carotid artery disease, pulmonary embolism, portal hypertension, venous thrombosis, biliary disease, pancreatic disease, and neurologic disease. Novel treatment paradigms based on drugs or interconnected networks of devices that modulate sensors are envisioned. Improving the interface between sensors and their substrate information by techniques such as minimally traumatic atherectomy or thrombectomy may also restore appropriate sensor function. Lessons learned from bifurcation sensors and their potential maladaptations may generalize to other types of branching systems including botany, civil engineering, and Pitot tube aeronautics.

Can chronic use of anti-inflammatory agents paradoxically promote chronic inflammation through compensatory host response?

A higher relative risk of thrombotic cardiovascular complications has recently emerged in studies evaluating the use of non-steroidal anti-inflammatory drugs (NSAIDs) such as rofecoxib, celecoxib, and naproxen. Direct pro-thrombotic effects of selective cyclooxygenase-2 inhibition were originally speculated to be the potential mechanism behind these results, but this proposal fails to explain the pro-thrombotic effects of non-selective NSAIDs. We hypothesize that the paradoxical pro-inflammatory, pro-thrombotic effects associated with chronic use of anti-inflammatory agents are attributable to compensatory host response rather than direct effects of the drugs. Chronic pharmacologic inhibition of inflammation may induce physiologic dependence, and cessation of therapy has been shown to produce rebound effects in aspirin, statins, and other immunomodulatory agents. By down-regulating inflammatory pathways in a pulsatile fashion, chronic use of NSAIDs may promote compensatory up-regulation of these same pathways and shift the host baseline equilibrium towards an inflammatory state. The host may be susceptible to inflammation between intermittent doses and after withdrawal of therapy. Inflammation is a promoter of adrenergia and thrombosis, and the constellation of these effects may predispose to excess risk of acute cardiovascular events.