Pregnancy-associated plasma protein-A (PAPP-A) and cardiovascular disease.

There is strong evidence that PAPP-A, a local regulator of insulin-like growth factor signaling through proteolytic cleavage of inhibitory binding proteins, is involved in multiple physiological processes associated with cardiovascular disease. This review will describe the various roles of PAPP-A with a focus on atherosclerosis, neointimal hyperplasia, and acute coronary syndrome in animal models and in humans.

The Insulin-like Growth Factor System and Aging.

There is strong evidence that insulin-like growth factor (IGF) signaling is involved in fundamental aspects of the aging process. However, the extracellular part of the IGF system is complex with various receptors, ligand effectors, high affinity IGF binding proteins, proteinases and endogenous inhibitors that all, along with their biological context, must be considered. The IGF system components are evolutionarily conserved, underscoring the importance of understanding this system in physiology and pathophysiology.

Passive bicycle training stimulates epiphyseal bone formation and restores bone integrity independent of locomotor recovery in a rat spinal cord injury model.

It is unknown whether activity-based physical therapy (ABPT) modalities that mobilize the paralyzed limbs improve bone integrity at the highly fracture-prone epiphyseal regions of the distal femur and proximal tibia following severe spinal cord injury (SCI). In this study, 4-mo-old skeletally mature littermate-matched male Sprague-Dawley rats received either SHAM surgery or severe contusion SCI. At 1 wk postsurgery, SCI rats were stratified to undergo no-ABPT, two 20-min bouts/day of quadrupedal bodyweight-supported treadmill training (qBWSTT), or hindlimb passive isokinetic bicycle (cycle) training, 5 days/wk for another 3 wk.

Development of sterile platform for quantification of extracellular analytes via single walled carbon nanotubes.

Progress has been made studying cell-cell signaling communication processes. However, due to limitations of current sensors on time and spatial resolution, the role of many extracellular analytes is still unknown. A single walled carbon nanotube (SWNT) platform was previously developed based on the avidin-biotin immobilization of SWNT to a glass substrate.

Transcriptomics reveals transient and dynamic muscle fibrosis and atrophy differences following spinal cord injury in rats.

Background: The rate and magnitude of skeletal muscle wasting after severe spinal cord injury (SCI) exceeds most other disuse conditions. Assessing the time course of molecular changes can provide insight into the progression of muscle wasting post-SCI. The goals of this study were (1) to identify potential targets that may prevent the pathologic features of SCI in soleus muscles and (2) to establish therapeutic windows for treating these pathologic changes.

PAPP-A as a Potential Target in Thyroid Eye Disease.

Context: Proptosis in thyroid eye disease (TED) can result in facial disfigurement and visual dysfunction. Treatment with insulin-like growth factor I receptor (IGF-IR) inhibitors has been shown to be effective in reducing proptosis but with side effects.

Objective: To test the hypothesis that inhibition of IGF-IR indirectly and more selectively with PAPP-A inhibitors attenuates IGF-IR signaling in TED.

The Pregnancy-Associated Plasma Protein-A (PAPP-A) Story.

Pregnancy-associated plasma protein-A (PAPP-A) was first identified in the early 1970s as a placental protein of unknown function, present at high concentrations in the circulation of pregnant women. In the mid-to-late 1990s, PAPP-A was discovered to be a metzincin metalloproteinase, expressed by many nonplacental cells, that regulates local insulin-like growth factor (IGF) activity through cleavage of high-affinity IGF binding proteins (IGFBPs), in particular IGFBP-4. With PAPP-A as a cell surface-associated enzyme, the reduced affinity of the cleavage fragments results in increased IGF available to bind and activate IGF receptors in the pericellular environment.

Passive Cycle Training Promotes Bone Recovery after Spinal Cord Injury without Altering Resting-State Bone Perfusion.

Introduction: Spinal cord injury (SCI) produces diminished bone perfusion and bone loss in the paralyzed limbs. Activity-based physical therapy (ABPT) modalities that mobilize and/or reload the paralyzed limbs (e.g.

The Stanniocalcin-PAPP-A-IGFBP-IGF Axis.

The pappalysin metalloproteinases, PAPP-A and PAPP-A2, have emerged as highly specific proteolytic enzymes involved in the regulation of insulin-like growth factor (IGF) signaling. The only known pappalysin substrates are a subset of the IGF binding proteins (IGFBPs), which bind IGF-I or IGF-II with high affinity to antagonize receptor binding. Thus, by cleaving IGFBPs, the pappalysins have the potential to increase IGF bioactivity and hence promote IGF signaling.

Senescence induces proteolytically-active PAPP-A secretion and association with extracellular vesicles in human pre-adipocytes.

Senescence is a cellular response to various stressors characterized by irreversible cell cycle arrest, resistance to apoptosis and expression of a senescence-associated secretory phenotype (SASP). Interestingly, studies where senescent cells were deleted in mice produced beneficial effects similar to those where the zinc metalloproteinase, PAPP-A, was deleted in mice. In this study, we investigated the effect of senescence on PAPP-A secretion and activity in primary cultures of adult human pre-adipocytes.

Circulating insulin-like growth factor system adaptations in hibernating brown bears indicate increased tissue IGF availability.

Brown bears conserve muscle and bone mass during 6 mo of inactive hibernation. The molecular mechanisms underlying hibernation physiology may have translational relevance for human therapeutics. We hypothesize that protective mechanisms involve increased tissue availability of insulin-like growth factors (IGFs).

Pregnancy-associated plasma protein-A (PAPP-A) is a key component of an interactive cellular mechanism promoting pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with few effective treatment options. We found a highly significant correlation between pregnancy-associated plasma protein (PAPP)-A expression in IPF lung tissue and disease severity as measured by various pulmonary and physical function tests. PAPP-A is a metalloproteinase that enhances local insulin-like growth factor (IGF) activity.

Brain-specific PAPP-A knock-out mice?

PAPP-A knock-out (KO) mice are a valuable model for investigating the effects of down-regulating localized insulin-like growth factor (IGF) action, which has been shown to extend lifespan and healthspan when the PAPP-A gene is globally deleted. Based on previous mouse models of brain-specific reduction in IGF signaling associated with longevity, we sought to generate brain-specific PAPP-A KO mice and determine effects on metabolism and lifespan. Mice with the PAPP-A gene floxed (fPAPP-A) were crossed with Nestin promoter-driven Cre recombinase transgenic mice.

Bone loss after severe spinal cord injury coincides with reduced bone formation and precedes bone blood flow deficits.

Diminished bone perfusion develops in response to disuse and has been proposed as a mechanism underlying bone loss. Bone blood flow (BF) has not been investigated within the unique context of severe contusion spinal cord injury (SCI), a condition that produces neurogenic bone loss that is precipitated by disuse and other physiological consequences of central nervous system injury. Herein, 4-mo-old male Sprague-Dawley rats received T laminectomy (SHAM) or laminectomy with severe contusion SCI ( = 20/group).

Variability in comorbidites and health services use across homeless typologies: multicenter data linkage between healthcare and homeless systems.

Background: Homelessness is associated with substantial morbidity. Data linkages between homeless and health systems are important to understand unique needs across homeless populations, identify homeless individuals not registered in homeless databases, quantify the impact of housing services on health-system use, and motivate health systems and payers to contribute to housing solutions.

Methods: We performed a cross-sectional survey including six health systems and two Homeless Management Information Systems (HMIS) in Cook County, Illinois.

Effects of suppressing bioavailability of insulin-like growth factor on age-associated intervertebral disc degeneration.

Suppression of the insulin-like growth factor-1 (IGF-1) signaling pathway reduces age-related disorders and increases lifespan across species, making the IGF-1 pathway a key regulator of aging. Previous in vitro intervertebral disc cell studies have reported the pro-anabolic effect of exogenously adding IGF-1 on matrix production. However, the overall effects of suppressing IGF-1 signaling on age-related intervertebral disc degeneration (IDD) is not known.

Genetic and Pharmacological Inhibition of PAPP-A Protects Against Visceral Obesity in Mice.

Pathogenicity of visceral adipose tissue (VAT) has been linked to the metabolic stress of enlarging mature adipocytes and a limited ability to recruit new adipocytes. One of the major distinguishing features of VAT preadipocytes is the high expression of the zinc metalloprotease, pregnancy-associated plasma protein-A (PAPP-A), when compared to subcutaneous adipose tissue (SAT). In this study we used 2 different approaches to investigate the effect of PAPP-A inhibition on different fat depots in mice on a high-fat diet (HFD) for 15 weeks.

Electronic Measurement of a Clinical Quality Measure for Inpatient Hypoglycemic Events: A Multicenter Validation Study.

Background: Hypoglycemia related to antidiabetic drugs (ADDs) is important iatrogenic harm in hospitalized patients. Electronic identification of ADD-related hypoglycemia may be an efficient, reliable method to inform quality improvement.

Objective: Develop electronic queries of electronic health records for facility-wide and unit-specific inpatient hypoglycemia event rates and validate query findings with manual chart review.

Certificate of need laws: a systematic review and cost-effectiveness analysis.

Background: Certificate of Need (CON) laws, currently in place in 35 US states, require certain health care providers to obtain a certification of their economic necessity from a state board before opening or undertaking a major expansion. We conduct the first systematic review and cost-effectiveness analysis of these laws.

Methods: We review 90 articles to summarize the evidence on how certificate of need laws affect regulatory costs, health expenditures, health outcomes, and access to care.

Discovery and properties of a new indigoid structure type based on dimeric cis-indigos.

Reactions of indigo with quinones in the presence of sodium hydride leads unexpectedly to products containing two indigo subunits; one indigo is featured in a cis configuration and fused via its indole nitrogen atoms to a second indigo at the central C-C bond of the latter. Structural, optical, and redox properties of the new compounds are reported.