Pilot Study to Investigate the Benefits of the InnoSpire Go Mesh Nebulizer Compared to Jet Nebulizers in the Treatment of Stable COPD.

Background: Nebulizers are widely used for the delivery of aerosols to patients with chronic obstructive pulmonary disease (COPD). The InnoSpire Go mesh nebulizer has been designed to improve upon the ease of use and convenience of existing nebulizers for the treatment of COPD. Methods: This was a pilot, single-center, randomized, open-label crossover study conducted over 2 months to investigate the use of the InnoSpire Go mesh nebulizer compared to the patient's own compressor driven jet nebulizer in ambulatory patients with stable COPD. Patient preference was assessed at the end of the study; quality of life, symptom scores, treatment time, and satisfaction were assessed at multiple points during the study. Results: Data for 17 patients were eligible for analysis, patients had a mean age of 64.6 years, and 64.7% were graded 3 on the modified Medical Research Council dyspnea scale. All patients preferred the InnoSpire Go mesh nebulizer over their own compressor driven jet nebulizer (p < 0.001). Nebulization of study drugs using the InnoSpire Go mesh nebulizer was associated with statistically significant increases in health-related quality of life over baseline (Dyspnea p = 0.003, Emotion p = 0.043, Mastery p = 0.011). A mixed model analysis of Borg dyspnea scores before and after exercise showed significantly (p = 0.043) lower scores for the InnoSpire Go mesh nebulizer compared with the compressor driven nebulizers. Patient satisfaction was statistically significantly higher for each of 10 questions covering ease of use, confidence, burden of use, satisfaction, and how well the device fit into their lifestyle. Treatment time was significantly shorter with the InnoSpire Go mesh nebulizer (p = 0.003). Conclusions: Patients preferred and were more satisfied with the InnoSpire Go mesh nebulizer. Nebulization of study drugs using the InnoSpire Go mesh nebulizer resulted in improved quality of life compared with baseline, and treatments were delivered in a shorter period than the compressor driven jet nebulizers. Clinical Trial Registration number: ClinicalTrials.gov: NCT03933462.

Altered neutrophil maturation patterns that limit identification of myelodysplastic syndromes.

BACKGROUND: Altered neutrophil maturation patterns have been reported useful for identification of myelodysplastic syndromes (MDS). METHODS: Neutrophil maturation patterns based on CD11b, CD13, and CD16 were visually and numerically evaluated in 19 control, 23 MDS, 37 nondiagnostic for MDS (NDM) specimens, and 19 also processed 1 and 2 days subsequently. RESULTS: In contrast to maturation patterns illustrated previously by others as "normal," 84% of controls displayed diminished acquisition of CD16, imparting a contracted appearance. Such divergence from published "normal" patterns was usually mild-moderate, considered nonspecific, and associated with delayed processing: longer intervals between collection and processing (median 20.5 vs. 5.2 h), and following 1 and 2 days delay. Findings restricted to nonspecific contraction were found in 56% MDS and 78% NDM specimens. Evaluation for aberrant patterns was still performed with mild-moderate contraction present, but concern for over interpretation led to use of an equivocal-aberrant category. Nine cases had aberrant or equivocal-aberrant patterns (seven MDS, two NDM) with distinct visual alterations that differed from nonspecific contraction and had numerical evidence for a left shift: myeloblasts increased (67%) and least mature neutrophils (CD11b-/low, CD16-/low) increased (78%). Although evidence for a left shift was associated with MDS, it was also seen in NDM specimens with a synchronous left shift. CONCLUSIONS: Neutrophil maturation patterns that diverge from previously illustrated "normal" patterns, not specific for MDS, may be common in some settings. Laboratories seeking to implement FC evaluation for MDS must determine which findings have sufficient specificity for MDS within their own practice and patient population.

Vascular matrix metalloproteinase-9 mediates the inhibition of myogenic reactivity in small arteries isolated from rats after short-term administration of relaxin.

UNLABELLED: During pregnancy and chronic relaxin administration to nonpregnant rats (for days), vascular MMP (matrix metalloproteinase)-2 is increased and mediates renal vasodilation, hyperfiltration, and inhibition of myogenic reactivity of small renal arteries. However, the renal vasodilatory actions of relaxin also occur after only several hours of hormone administration to nonpregnant rats, and we hypothesized a pivotal role for vascular MMP-2. Accordingly, we used gelatin zymography, which reveals not only vascular MMP-2, but also MMP-9 activity in small renal arteries isolated from rats administered recombinant human relaxin (rhRLX) or vehicle for 4-6 h. Furthermore, we tested whether myogenic reactivity is inhibited, and if so, whether the inhibition is mediated by increased vascular MMP-2. Surprisingly, we detected no significant difference in either pro or active MMP-2 in small renal arteries isolated from rhRLX and vehicle control treatment groups. In contrast, vascular MMP-9 was up-regulated by 70% (P < 0.0005 vs. vehicle). These results were completely unexpected and novel. MMP-9 protein expression was confined to the vascular smooth muscle. MMP-9, but not MMP-2 activity, was also increased in mesenteric arteries after short-term rhRLX administration (P < 0.005 and >0.05 vs. vehicle, respectively). Myogenic reactivity was inhibited in small renal arteries isolated from nonpregnant rats treated with rhRLX for 4-6 h (P < 0.01 vs. vehicle) and was completely restored by incubation with MMP-9, but not MMP-2 neutralizing antibodies in vitro. CONCLUSION: In contrast to chronic rhRLX administration, MMP-9 rather than MMP-2 plays a central role in the vasodilatory effect of short-term relaxin administration.

Evidence for local relaxin ligand-receptor expression and function in arteries.

Relaxin is a 6 kDa protein hormone produced by the corpus luteum and secreted into the blood during pregnancy in rodents and humans. Growing evidence indicates that circulating relaxin causes vasodilatation and increases in arterial compliance, which may be among its most important actions during pregnancy. Here we investigated whether there is local expression and function of relaxin and relaxin receptor in arteries of nonpregnant females and males. Relaxin-1 and its major receptor, Lgr7, mRNA are expressed in thoracic aortas, small renal and mesenteric arteries from mice and rats of both sexes, as well as in small renal arteries from female tammar wallabies (an Australian marsupial). Using available antibodies for rat and mouse Lgr7 receptor and rat relaxin, we also identified protein expression in arteries. Small renal arteries isolated from relaxin-1 gene-deficient mice demonstrate enhanced myogenic reactivity and decreased passive compliance relative to wild-type (WT) and heterozygous mice. Taken together, these findings reveal an arterial-derived, relaxin ligand-receptor system that acts locally to regulate arterial function.

Matrix metalloproteinase-2 activity, protein, mRNA, and tissue inhibitors in small arteries from pregnant and relaxin-treated nonpregnant rats.

Vascular gelatinase activity is essential for pregnancy- and relaxin (Rlx)-induced renal vasodilation and hyperfiltration in rats. The objective of this study was to further elucidate the mechanisms for the increase in vascular matrix metalloproteinase (MMP)-2 activity caused by pregnancy and Rlx. We first corroborated our earlier work by showing that pro- and active forms of MMP-2 were increased in small renal arteries from pregnant compared with virgin rats and Rlx-treated compared with vehicle-treated nonpregnant rats. We next investigated other artery types and showed that MMP-2 activity was upregulated in mesenteric arteries from pregnant rats (pro-MMP-2 by 50% and active MMP-2 by 40%, both P<0.05) and from Rlx-treated nonpregnant rats (pro-MMP-2 by 50% and active MMP-2 by 90%, both P<0.005) compared with their respective controls. To corroborate these results obtained by gelatin zymography, pro-MMP-2 protein was determined by Western analysis in the same small arteries. Pro-MMP-2 protein was increased in small renal arteries from pregnant compared with virgin rats and from Rlx- compared with vehicle-treated nonpregnant rats: pro-MMP-2-to-beta-actin ratio=0.29 vs. 0.21 (P<0.01) and 0.43 vs. 0.32 (P<0.005). Findings were similar for mesenteric arteries. MMP-2 mRNA as measured by real-time PCR was increased in small renal arteries from pregnant and Rlx-treated nonpregnant rats compared with their respective controls. There were no significant differences in tissue inhibitor of metalloproteinase (TIMP-1 or TIMP-2) activity by reverse zymography in small renal arteries. Thus increases in MMP-2 mRNA and protein expression are major factors contributing to increased MMP-2 activity in small arteries from pregnant and Rlx-treated nonpregnant rats.

Evidence against the hypothesis that endothelial endothelin B receptor expression is regulated by relaxin and pregnancy.

The endothelial endothelin B (ET(B)) receptor subtype is critical for renal vasodilation induced by relaxin in nonpregnant rats and during pregnancy (the latter via endogenous circulating relaxin). Here we tested whether expression of vascular ET(B) receptor protein is regulated by relaxin. Small renal arteries were harvested from virgin and midterm pregnant rats as well as nonpregnant rats that were administered recombinant human relaxin (rhRLX) at 4 mug/h or vehicle for 5 d or 4-6 h. Small renal arteries dissected from additional virgin rats were incubated in vitro with rhRLX or vehicle for 3 h at 37 C. ET(B) expression was also evaluated in cultured human endothelial cells: aortic, coronary, umbilical vein, and dermal microvascular endothelial cells. Cells were incubated for 4, 8, or 24 h with rhRLX (5, 1, or 0.1 ng/ml) or vehicle. ET(B) protein expression in arteries and cells was evaluated by Western analysis. No regulation of ET(B) expression was observed in small renal arteries in any of the experimental protocols, nor was there an increase in the vasorelaxation response to ET-3 in small renal arteries incubated in vitro with rhRLX. rhRLX only sporadically altered ET(B) expression in human coronary artery endothelial cells and human umbilical vein endothelial cells at certain time points or doses, and no regulation was observed in human aortic endothelial cells or human dermal microvascular endothelial cells. These results suggest that regulation of ET(B) receptor protein has little or no role in relaxin stimulation of the endothelial ET(B)/nitric oxide vasodilatory pathway.