Citations

Objective: We sought to investigate the biological effects of pre-reperfusion treatments of the liver after warm and cold ischemic injuries in a porcine donation after circulatory death model. Summary of Background Data: Donation after circulatory death represents a severe form of liver ischemia and reperfusion injury that has a profound impact on graft function after liver transplantation. Methods: Twenty donor pig livers underwent 60 minutes of in situ warm ischemia after circulatory arrest and 120 minutes of cold static preservation prior to simulated transplantation using an ex vivo perfusion machine. Four reperfusion treatments were compared: Control-Normothermic (N), Control- Subnormothermic (S), regulated hepatic reperfusion (RHR)-N, and RHR-S (n = 5 each). The biochemical, metabolic, and transcriptomic profiles, as well as mitochondrial function were analyzed. Results: Compared to the other groups, RHR-S treated group showed significantly lower post-reperfusion aspartate aminotransferase levels in the reperfusion effluent and histologic findings of hepatocyte viability and lesser degree of congestion and necrosis. RHR-S resulted in a significantly higher mitochondrial respiratory control index and calcium retention capacity. Transcriptomic profile analysis showed that treatment with RHR-S activated cell survival and viability, cellular homeostasis as well as other biological functions involved in tissue repair such as cytoskeleton or cytoplasm organization, cell migration, transcription, and microtubule dynamics. Furthermore, RHR-S inhibited organismal death, morbidity and mortality, necrosis, and apoptosis. Conclusion: Subnormothermic RHR mitigates IRI and preserves hepatic mitochondrial function after warm and cold hepatic ischemia. This organ resuscitative therapy may also trigger the activation of protective genes against IRI. Sub- normothermic RHR has potential applicability to clinical liver transplantation.

Abstract Rationale To improve disease outcomes in idiopathic pulmonary fibrosis (IPF), it is essential to understand its early pathophysiology so that it can be targeted therapeutically. Objectives Perform three-dimensional assessment of the IPF lung microstructure using stereology and multiresolution computed tomography (CT) imaging. Methods Explanted lungs from patients with IPF (n = 8) and donor control subjects (n = 8) were inflated with air and frozen. CT scans were used to assess large airways. Unbiased, systematic uniform random samples (n = 8/lung) were scanned with microCT for stereological assessment of small airways (count number, and measure airway wall and lumen area) and parenchymal fibrosis (volume fraction of tissue, alveolar surface area, and septal wall thickness). Measurements and Main Results The total number of airways on clinical CT was greater in IPF lungs than control lungs (P < 0.01), owing to an increase in the wall (P < 0.05) and lumen area (P < 0.05) resulting in more visible airways with a lumen larger than 2 mm. In IPF tissue samples without microscopic fibrosis, assessed by the volume fraction of tissue using microCT, there was a reduction in the number of the terminal (P < 0.01) and transitional (P < 0.001) bronchioles, and an increase in terminal bronchiole wall area (P < 0.001) compared with control lungs. In IPF tissue samples with microscopic parenchymal fibrosis, terminal bronchioles had increased airway wall thickness (P < 0.05) and dilated airway lumens (P < 0.001) leading to honeycomb cyst formations. Conclusions This study has important implications for the current thinking on how the lung tissue is remodeled in IPF and highlights small airways as a potential target to modify IPF outcomes.

AbstractBackgroundComprehensive treatment recommendations for Merkel cell carcinoma are complex. We aimed to systematically review the published data on recurrence and mortality rates associated with various treatment approaches for Merkel cell carcinoma.MethodsSearch of MEDLINE, Embase, Web of Science, and Scopus from inception to August 2015. Studies were included that reported comparative survival and recurrence data for two or more treatment modalities. Two reviewers independently reviewed and abstracted recurrence and mortality rates. Event rates for individual treatment arms in each study were pooled and meta‐analyzed across studies using a random‐effects model.ResultsFifty‐two retrospective studies met inclusion criteria, revealing a total of 1,804 patients with primary Merkel cell carcinoma with data available for analyses. The recurrence rate was higher for surgery alone (55.0%) versus a combination of surgery and radiotherapy (39.0%) (odds ratio, 2.089; 95% CI, 1.374–3.177; P < 0.001). Combination therapy including surgery, radiotherapy, and chemotherapy had a higher mortality rate (44.6%) than did combined surgery and radiotherapy (23.2%) (odds ratio, 2.688; 95% CI, 1.196–6.037; P = 0.02).ConclusionsThe treatment of Merkel cell carcinoma with surgery plus adjuvant radiotherapy may produce lower recurrence rates.

A history of preeclampsia (PE) places women at higher risk for future cardiovascular disease and cognitive decline. We have previously shown that postmenopausal women with a history of PE demonstrated a reduced cerebral blood flow response to hypercapnia compared with postmenopausal women with a history of a normotensive pregnancy (NP). These findings suggest cerebrovascular effects of PE 30+ years postpartum. In addition, we have reported that women with a history of PE did not have an exaggerated pressor response to a sympathoexcitatory stimulus. However, it is possible that women with a history of PE may have an altered cerebral blood flow response to a sympathoexcitatory stimulus. In this study, middle cerebral artery blood velocity (MCAv) and beat‐to‐beat mean arterial blood pressure (MAP) were measured during isometric handgrip to fatigue (IHG) at 30% of maximal voluntary contraction followed by post‐exercise ischemia (PEI) for 90 seconds and a two minute recovery period (REC). Participants were postmenopausal women with a history of PE (n = 21; age at study = 58±5 y; years since last pregnancy = 35±3 y) and NP (n = 27; age at study = 58±5 y; years since last pregnancy = 35±3 y). Baseline MAP and MAP responses to IHG and PEI were similar between groups (p>0.05). PE women demonstrated lower MCAv at baseline (NP: 72±3 cm/s vs. PE: 57±4 cm/s), IHG (NP: 78±4 cm/s vs. PE: 63±4 cm/s), PEI (NP: 74±4 cm/s vs. PE: 60±4 cm/s), and REC (NP: 70±3 cm/s vs. PE: 58±4 cm/s) compared with NP women (p<0.05 for all). MCAv, when calculated as a percent change from baseline, was elevated during IHG in both PE and NP women as expected (p<0.05); however, PE women had an augmented MCAv response during the last third of IHG compared with NP women (NP: 9±2 % vs. PE: 13±2 %; p<0.05). PE women also had a higher MCAv response during REC compared with NP women (NP:−2±2% vs. PE: 3±2%; p<0.05). Importantly, these elevated MCAv responses occurred despite the fact that MAP was not different between groups. In summary, PE women demonstrated a lower basal cerebral blood velocity but an elevated cerebrovascular response to a sympathoexcitatory stimulus compared with NP women. This suggests that in postmenopausal women, there is an effect of pregnancy history on the sensitivity of the cerebral blood flow response to a sympathoexcitatory stimulus. Support or Funding Information NIH: AG 044170. This investigation was supported by the National Institutes of Health, under Ruth L. Kirschstein National Research Service Award T32 HL 007936 from the National Heart Lung and Blood Institute to the University of Wisconsin‐Madison Cardiovascular Research Center. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

Hypertensive pregnancy (HP) is considered a risk factor for cardiovascular disease. Blood pressure (BP) response to physical stressor is an independent marker of cardiovascular risk. However, there is limited data regarding the pressor response to acute physical stress in women with a history of HP. Hence, the aim of the study was to compare BP responses in women with a history of HP to age and parity matched controls. Beat to beat BP was recorded in postmenopausal women (age = 59 ± 1 yrs, BMI = 31 ± 2 kg/m2) with and without a history of HP at baseline and during isometric handgrip (HG) exercise (30% of MVC) to fatigue. Isometric handgrip exercise was followed by 90 seconds of supra‐systolic cuff occlusion on the exercising arm. In both groups combined (N=31), systolic blood pressure (SBP) increased significantly from baseline to HG to cuff inflation (143 ± 3 to 161 ± 3 to 167 ± 4 mmHg). Similarly, mean arterial pressure (MAP) increased significantly from baseline to HG to cuff inflation (106 ± 2 to 119 ± 2 to 122 ± 2 mmHg). Diastolic pressure (DBP) increased significantly only from baseline to HG (80 ± 1 to 88 ± 1 mmHg) and baseline to cuff inflation (89 ± 2 mmHg). However, there were no significant differences in SBP, DBP and MAP between women with and without a history of HP (p>0.05). Even though both groups had an increase in BP variables in response to HG and cuff occlusion, there was no difference in the BP response to acute physical stressors in women with a history of HP as compared to control participants. Funding: National Institute of Aging 1P50AG044170‐01 and CTSA UL1 TR000135 and HL 118154 (JNB)

<a name=“OLE_LINK2”></a><a name=“OLE_LINK1”>Hypertensive pregnancy (HP) disorders have been linked to a four‐fold increased risk for development of future cardiovascular diseases. We examined whether history of HP in postmenopausal women (N=20, 59±5 yr) influenced the risk factors for cardiovascular disease as assessed by aortic pulse wave characteristics, compared to age and parity matched controls (N=18, 60±4 yr). Non‐invasive aortic pressure waveforms were synthesized from high‐fidelity pressure waveforms obtained from SphygmoCor applanation tonometry using the radial artery. Aortic systolic and diastolic blood pressure (ASBP, ADBP), aortic augmentation index (AI x ), augmented pressure (AP), aortic pulse pressure (APP), and left ventricular wasted energy (E w ) were calculated from the generated aortic pressure waveform. There were no differences in ASBP (125±4 vs. 129±4 mmHg), ADBP (79±2 vs. 81±2 mmHg), AP (17±2 vs. 17±2 mmHg), AI x (35±2 vs. 29±1%), AI x @75BPM (31±2 vs. 29±1%), E w (3313±338 vs. 3364±432 dynes/cm 2 /s), between women with a history of HP vs. matched controls, respectively (P>0.05 for all). Body mass index was significantly higher in women with a history of HP (30.6±1 vs. 26.7±1 kg/m 2 , P<0.05), however it did not statistically influence any of the indices (P>0.05 for all). Our results suggest that postmenopausal women with a history of HP do not demonstrate elevated aortic blood pressure or altered aortic pulse wave characteristics in comparison to matched controls. </a> Supported by: National Institute of Aging 1P50AG044170‐01 and CTSA UL1 TR000135 and HL 118154

Cerebrovascular reactivity to hypercapnia is higher in women receiving menopausal hormone therapy (MHT) compared with controls, and this may persist after cessation of MHT. We hypothesized that the effect of MHT may be influenced by mean arterial pressure (MAP). Therefore, we examined both middle cerebral artery velocity (MCAv) and MAP responses to stepped hypercapnia in 60 postmenopausal women who were previously randomized to receive oral conjugated equine estrogen (oCEE, n=15), transdermal 17β estradiol (tE2, n=22), or placebo (PLA, n=23) for 4 years. After a 3 year washout period, reactivity was calculated from the slope of the relationship between MCAv or MAP and end‐tidal CO 2 . MCAv reactivity was higher in the oCEE group compared with the PLA group (1.6±0.2 vs. 1.1±0.1 cm/s/mmHg; oCEE vs. PLA, respectively, p<0.05), but similar between the tE2 and PLA group (1.3±0.2 vs. 1.1±0.1 cm/s/mmHg; tE2 vs. PLA, respectively, p>0.05). There were no significant differences in MAP reactivity (1.0±0.2, 0.6±0.1, 0.7±0.2 mmHg/mmHg of CO 2 , oCEE vs. tE2 vs. PLA, respectively, p>0.05) among the groups. However, in the combined MHT group, MAP reactivity was positively correlated with MCAv reactivity (r=0.58, p<0.001), such that women with higher MAP responses demonstrate greater MCAv responses to hypercapnia. In conclusion, there were no differences in MAP reactivity 3 years after cessation of MHT. In addition, our results suggest that greater cerebrovascular reactivity in postmenopausal women who received MHT may be driven by augmented blood pressure responses to hypercapnia. Funding: K99 HL 118164, AG 044170 and HL 83947.