Citations

Clinically observed differences in airway reactivity and asthma exacerbations in women at different life stages suggest a role for sex steroids in modulating airway function although their targets and mechanisms of action are still being explored. We have previously shown that clinically relevant concentrations of exogenous estrogen acutely decrease intracellular calcium ([Ca2+]i) in human airway smooth muscle (ASM), thereby facilitating bronchodilation. In this study, we hypothesized that estrogens modulate cyclic nucleotide regulation, resulting in decreased [Ca2+]iin human ASM. In Fura-2-loaded human ASM cells, 1 nM 17β-estradiol (E2) potentiated the inhibitory effect of the β-adrenoceptor (β-AR) agonist isoproterenol (ISO; 100 nM) on histamine-mediated Ca2+entry. Inhibition of protein kinase A (PKA) activity (KT5720; 100 nM) attenuated E2effects on [Ca2+]i. Acute treatment with E2increased cAMP levels in ASM cells comparable to that of ISO (100 pM). In acetylcholine-contracted airways from female guinea pigs or female humans, E2potentiated ISO-induced relaxation. These novel data suggest that, in human ASM, physiologically relevant concentrations of estrogens act via estrogen receptors (ERs) and the cAMP pathway to nongenomically reduce [Ca2+]i, thus promoting bronchodilation. Activation of ERs may be a novel adjunct therapeutic avenue in reactive airway diseases in combination with established cAMP-activating therapies such as β2-agonists.

Object The goal of this study was to determine the risk of using antithrombotic agents in patients with established intracerebral cavernous malformations (ICMs). Methods From a previously described cohort of 292 patients with radiographically defined ICMs, 40 required an antithrombotic after the ICM was diagnosed. Patients underwent follow-up to determine the incidence of hemorrhage. Results The mean age of these 40 patients was 62.4 years; there were 21 male and 19 female patients. Five (12.5%) of the 40 patients initially presented with hemorrhage and 4 (10%) had multiple ICMs. Of these patients, 32 were placed on an antiplatelet agent alone, 6 on an anticoagulant alone, and 2 were placed on both. In patients necessitating any antithrombotic agent, 1 patient developed a prospective hemorrhage over the 258 person-years of follow-up (prospective hemorrhage rate 0.41% per person-year). Conclusions Antithrombotics likely do not precipitate hemorrhage in patients with known ICMs. However, caution should be exercised in the use of antithrombotics in patients with ICMs at high risk for hemorrhage. The risks and benefits of antithrombotics in each situation should be carefully weighed against the natural history of ICM.

Conventional resuscitation (CR) from hemorrhagic shock (HS) results in gut and liver hypoperfusion, organ and cellular edema, and vital organ injury. Adjunct direct peritoneal resuscitation (DPR) with dialysate prevents gut vasoconstriction, hypoperfusion, and injury. We hypothesized that DPR might also improve hepatocellular edema, inflammation, and injury. Anesthetized male SD rats were assigned to groups ( n = 8/group): 1) sham (no HS); 2) HS (40% MAP/60 min) + intravenous fluid conventional resuscitation [CR; shed blood + 2 vol saline (SAL)/30 min]; 3) HS+CR+DPR (30 ml ip 2.5% glucose dialysate); or 4) HS+CR+SAL (30 ml ip saline). Histopathology showed lung and liver injury in HS+CR and HS+CR+SAL up to 24-h postresuscitation (post-RES) that was not in shams and which was prevented by adjunct DPR. Wet-to-dry weight ratios in HS+CR revealed organ edema formation that was prevented by adjunct DPR. HS+CR and HS+CR+SAL had 34% mortality by 24-h post-RES, which was absent with DPR (0%). Liver IFN-γ and IL-6 levels were elevated in CR compared with DPR or shams. TNF-α mRNA was upregulated in CR/sham and DPR/sham. IL-17 was downregulated in DPR/sham. CXCL10 mRNA was upregulated in CR/sham but downregulated in DPR/sham. Despite restored central hemodynamic performance after CR of HS, liver blood flow was compromised up to 24 h post-RES, and the addition of DPR restores and maintains liver perfusion at 24-h post-RES. DPR prevented liver injury, histological damage, and edema formation compared with CR alone. DPR provided a mitigating anti-inflammatory dampening of the systemic inflammatory response. In all, these effects likely account for improved survivorship in the DPR-treated group.

Intestinofugal neurons sense and receive information regarding mechanical distension of the bowel and transmit this information to postganglionic sympathetic neurons in the prevertebral ganglia. Previous studies have demonstrated that trinitrobenzene sulfonic acid (TNBS)-induced colitis is associated with a loss of myenteric neurons that occurs within the first 12 h following the inflammatory insult. The purpose of this study was to test the hypothesis that intestinofugal neurons are among the myenteric neurons lost during TNBS-induced colitis. The retrograde tracing dye Fast Blue was used to label intestinofugal neurons, and immunohistochemical staining for the RNA-binding proteins HuC/D was used to count all myenteric neurons. Ongoing synaptic input to neurons in the guinea pig inferior mesenteric ganglion (IMG) was recorded via conventional intracellular electrophysiology. In control preparations, intestinofugal neurons account for 0.25% of myenteric neurons. In the distal colon of TNBS-treated animals, the proportion of intestinofugal neurons was reduced to 0.05% (an 80% reduction) within the region of inflammation where 20–25% of myenteric neurons were lost. Neither intestinofugal neurons specifically nor myenteric neurons were reduced in more proximal uninflamed regions. There is a reduction in the frequency of ongoing synaptic potentials in visceromotor neurons of the IMG at 12 and 24 h and 6 and 56 days after TNBS. Collectively, the results of this study suggest that intestinofugal neurons are among the myenteric neurons lost during inflammation and may be selectively targeted. Because intestinofugal neurons are a major driver of sympathetic output to the gut, the loss of intestinofugal neurons may have a profound pathophysiological significance.