Histamine is a mediator of allergic inflammation released mainly from mast cells. Although histamine strongly increases vascular permeability, its precise mechanism under in vivo situation remains unknown. We here attempted to reveal how histamine induces vascular hyperpermeability focusing on the key regulators of vascular permeability, blood flow and endothelial barrier. Degranulation of mast cells by antigen-stimulation or histamine treatment induced vascular hyperpermeability and tissue swelling in mouse ears. These were abolished by histamine H1 receptor antagonism. Intravital imaging showed that histamine dilated vasculature, increased blood flow, while it induced hyperpermeability in venula. Whole-mount staining showed that histamine disrupted endothelial barrier formation of venula indicated by changes in vascular endothelial cadherin (VE-cadherin) localization at endothelial cell junction. Inhibition of nitric oxide synthesis (NOS) by L-NAME or vasoconstriction by phenylephrine strongly inhibited the histamine-induced blood flow increase and hyperpermeability without changing the VE-cadherin localization. In vitro, measurements of trans-endothelial electrical resistance of human dermal microvascular endothelial cells (HDMECs) showed that histamine disrupted endothelial barrier. Inhibition of protein kinase C (PKC) or Rho-associated protein kinase (ROCK), NOS attenuated the histamine-induced barrier disruption. These observations suggested that histamine increases vascular permeability mainly by nitric oxide (NO)-dependent vascular dilation and subsequent blood flow increase and maybe partially by PKC/ROCK/NO-dependent endothelial barrier disruption.
Astronauts experience osteoporosis‐like loss of bone mass because of microgravity conditions during space flight. To prevent bone loss, they need a riskless and antiresorptive drug. Melatonin is reported to suppress osteoclast function. However, no studies have examined the effects of melatonin on bone metabolism under microgravity conditions. We used goldfish scales as a bone model of coexisting osteoclasts and osteoblasts and demonstrated that mRNA expression level of acetylserotonin O‐methyltransferase, an enzyme essential for melatonin synthesis, decreased significantly under microgravity. During space flight, microgravity stimulated osteoclastic activity and significantly increased gene expression for osteoclast differentiation and activation. Melatonin treatment significantly stimulated Calcitonin (an osteoclast‐inhibiting hormone) mRNA expression and decreased the mRNA expression of receptor activator of nuclear factor κB ligand (a promoter of osteoclastogenesis), which coincided with suppressed gene expression levels for osteoclast functions. This is the first study to report the inhibitory effect of melatonin on osteoclastic activation by microgravity. We also observed a novel action pathway of melatonin on osteoclasts via an increase in CALCITONIN secretion. Melatonin could be the source of a potential novel drug to prevent bone loss during space flight.
BACKGROUND AND PURPOSEPGE2 is a major prostanoid that regulates inflammation by stimulating EP1-4 receptors. However, how PGE2 induces an initial inflammatory response to vascular hyper-permeability remains unknown. Here we investigated the role of the PGE2-EP receptor signal in modulating vascular permeability both in vivo and in vitro. EXPERIMENTAL APPROACHWe used a modified Miles assay and intravital microscopy to examine vascular permeability in vivo. Endothelial barrier property was assessed by measuring transendothelial electrical resistance (TER) in vitro. KEY RESULTSLocal administration of PGE2, an EP2 or EP4 receptor agonist into FVB/NJcl mouse ear skin caused vascular leakage, indicated by dye extravasation. Intravital microscopy and laser Doppler blood-flow imaging revealed that these treatments dilated peripheral vessels and increased local blood flow. Pretreatment with the vasoconstrictor phenylephrine inhibited the PGE2-induced blood flow increase and vascular leakage. In contrast to the EP2 and EP4 receptor agonists, administration of an EP3 receptor agonist suppressed vascular leakage without altering vascular diameter or blood flow. In isolated HUVECs, the EP3 receptor agonist elevated TER and blocked thrombin-induced dextran passage. Inhibiting PKA restored the hypo-permeability induced by the EP3 receptor agonist. CONCLUSIONS AND IMPLICATIONSActivation of the PGE2-EP2 or -EP4 receptor signal induces vasodilatation in mural cells, resulting in increased local blood flow and hyper-permeability. In contrast, activation of the PGE2-EP3 receptor signal induces a cAMP-dependent enhancement of the endothelial barrier, leading to hypo-permeability. We provide the first evidence that endothelial cells and mural cells cooperate to modulate vascular permeability.
Study Design: This is a prospective study. Objective: The purpose of this study was to analyze the factors influencing subsidence following anterior cervical discectomy and fusion (ACDF) using a stand-alone cage. Summary of Background Data: The relationship between cage subsidence and cage height and material has been reported in previous studies. Methods: Clinical and radiologic data from 78 patients, 105 levels, undergoing single-level and 2-level ACDF without plates from 2007 to 2015 were collected prospectively. Patients were followed for at least 12 months after surgery. Radiographs were obtained preoperatively, at 1 week, and at 1, 3, 6, and 12 months postoperatively to determine the presence of fusion and cage subsidence. Results: There was a correlation in cage height and subsidence (Spearman P<0.05). Cage subsidence was significantly shorter in the polyetheretherketone cages than in titanium cages (P<0.05). However, when cage height was <5 mm, the difference between the 2 groups was not significant. Large subsidence (>3 mm) was observed in 17 patients, 20 levels, many of whom exhibited sinking in the first month after surgery. Conclusions: The greater the cage height, the greater the risk of cage subsidence in ACDF. Polyetheretherketone cages are superior to titanium cages for the maintenance of intervertebral height in cases where cage height is >5.5 mm. Level of Evidence: Level 3.
Patients with preoperative sagittal imbalance have a statistically significant increased risk of ASD. The risk of ASD incidence was 5.1 times greater in subjects with preoperative PT of more than 22.5°.
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