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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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 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.

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.

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.

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.

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.

The dynamic range of biologic functions and variation of many environmental cues may be declining in the modern age: implications for diseases and therapeutics.

We hypothesize that declining dynamic range and variation of environmental cues may contribute to health dysfunctions, and that judicious expansion of biologic dynamic ranges may be beneficial. Three disparate examples involving the endocrine, autonomic, and musculoskeletal systems are discussed. Daytime sheltering, optical shading, and nighttime use of artificial light may reduce circadian luminal variation.

"Starve a fever and feed a cold": feeding and anorexia may be adaptive behavioral modulators of autonomic and T helper balance.

Anorexia is a common symptom accompanying infections, but the teleology of the phenomenon remains unexplained. We hypothesize that anorexia may represent a prehistoric behavioral adaptation to fight infection by maintaining T helper (Th)2 bias, which is particularly vital in fighting bacterial pathogens. Specifically, we propose that anorexia may avert the reduction of Th2/Th1 ratio by preventing feeding-induced neurohormonal and vagal output from the gut.

The smoking gun: many conditions associated with tobacco exposure may be attributable to paradoxical compensatory autonomic responses to nicotine.

Tobacco exposure is implicated in many illnesses such as cardiovascular disease and cancer, but the mechanisms underlying these associations are poorly understood. The mechanisms by which tobacco induces pro-sympathetic and pro-inflammatory changes also remain elusive. Some studies have attributed these changes to the direct effects of nicotine, but such findings run counter to the pro-vagal, anti-inflammatory nature of the nicotinic pathway.

Paradoxical strategy for treating chronic diseases where the therapeutic effect is derived from compensatory response rather than drug effect.

Reversing chronic conditions remains an elusive goal of medicine. The modern medical paradigm based on blocking overactive pathways or augmenting deficient pathways offers symptomatic benefit, but tolerance to therapy can develop and treatment cessation can produce rebound symptoms due to compensatory mechanisms. We propose a paradoxical strategy for treating chronic conditions based on harnessing compensatory mechanisms for therapeutic benefit.

Can thromboembolism be the result, rather than the inciting cause, of acute vascular events such as stroke, pulmonary embolism, mesenteric ischemia, and venous thrombosis?: a maladaptation of the prehistoric trauma response.

Thromboembolism is considered the inciting cause of many vascular disorders including acute coronary syndrome (ACS), ischemic stroke, pulmonary embolism (PE), deep vein thrombosis (DVT), and mesenteric ischemia. Adrenergia and inflammation are known to accompany these conditions, particularly among arterial thromboembolic disorders, but the teleologic basis of these associations remains poorly understood. We argue that thromboembolism may sometimes be the result, rather than the cause, of acute vascular events, and may be precipitated by underlying adrenergia.