Purpose
The purpose of this study is to assess the intra‐ and interscan repeatability of free‐breathing phase‐resolved functional lung (PREFUL) MRI in stable pediatric cystic fibrosis (CF) lung ...disease in comparison to static breath‐hold hyperpolarized 129‐xenon MRI (Xe‐MRI) and pulmonary function tests.
Methods
Free‐breathing 1‐hydrogen MRI and Xe‐MRI were acquired from 15 stable pediatric CF patients and seven healthy age‐matched participants on two visits, 1 month apart. Same‐visit MRI scans were also performed on a subgroup of the CF patients. Following the PREFUL algorithm, regional ventilation (RVent) and regional flow volume loop cross‐correlation maps were determined from the free‐breathing data. Ventilation defect percentage (VDP) was determined from RVent maps (VDPRVent), regional flow volume loop cross‐correlation maps (VDPCC), VDPRVent ∪ VDPCC, and multi‐slice Xe‐MRI. Repeatability was evaluated using Bland–Altman analysis, coefficient of repeatability (CR), and intraclass correlation.
Results
Minimal bias and no significant differences were reported for all PREFUL MRI and Xe‐MRI VDP parameters between intra‐ and intervisits (all P > 0.05). Repeatability of VDPRVent, VDPCC, VDPRVent ∪ VDPCC, and multi‐slice Xe‐MRI were lower between the two‐visit scans (CR = 14.81%, 15.36%, 16.19%, and 9.32%, respectively) in comparison to the same‐day scans (CR = 3.38%, 2.90%, 1.90%, and 3.92%, respectively). pulmonary function tests showed high interscan repeatability relative to PREFUL MRI and Xe‐MRI.
Conclusion
PREFUL MRI, similar to Xe‐MRI, showed high intravisit repeatability but moderate intervisit repeatability in CF, which may be due to inherent disease instability, even in stable patients. Thus, PREFUL MRI may be considered a suitable outcome measure for future treatment response studies.
Diabetic nephropathy (DN), a microvascular complication of diabetes, is the leading cause of end-stage renal disease worldwide. Multiple studies have shown that podocyte dysfunction is a central ...event in the progression of the disease. Beside chronic hyperglycemia, dyslipidemia can induce insulin resistance and dysfunction in podocytes. However, the exact mechanisms of free fatty acid (FFA)-induced podocyte insulin unresponsiveness are poorly understood. We used a type 2 diabetic mouse model (db/db) and mouse podocytes exposed to palmitic acid for 24 h followed by an insulin stimulation. Renal function and pathology were evaluated at 25 weeks of age to confirm the DN development. Our results demonstrate that saturated FFA activated the serine/threonine kinases IκB kinase (IKK)β/IκBα and mTORC1/S6K1, but not protein kinase C and c-jun N-terminal kinase, in podocytes and glomeruli of db/db mice. Activation of both kinases promoted serine 307 phosphorylation of IRS1, a residue known to provoke IRS1 inhibition. Using IKK, mTORC1 and ceramide production inhibitors, we were able to blunt IRS1 serine 307 phosphorylation and restore insulin stimulation of Akt. In conclusion, our results indicate that FFA and diabetes contribute to insulin resistance through the activation of IKKβ and S6K1 leading to podocyte dysfunction and DN.
Abstract
A tunable ultrashort soliton pulse source reaching up to 4.8 µm is demonstrated based on a 2.8 µm femtosecond fiber laser coupled to a zirconium fluoride fiber amplifier followed by a small ...core indium fluoride fiber. This demonstration is extending by 300 nm the long wavelength limit previously reported with soliton self-frequency shift (SSFS) sources based on fluoride fibers. Our experimental and numerical investigation highlighted the spectral dynamics associated with the generation of highly redshifted pulses in the mid-infrared using SSFS enhanced by soliton fission. This study is intended at providing a better understanding of the potential and limitations of SSFS based tunable femtosecond fiber sources in the 3–5 µm spectral range.
Tissue-specific expression of CYP450s can regulate the intracellular concentration of drugs and explain inter-subject variability in drug action. The overall objective of our study was to determine ...in a large cohort of samples, mRNA levels and CYP450 activity expressed in the human heart.
CYP450 mRNA levels were determined by RTPCR in left ventricular samples (n = 68) of explanted hearts from patients with end-stage heart failure. Samples were obtained from ischemic and non-ischemic hearts. In some instances (n = 7), samples were available from both the left and right ventricles. A technique for the preparation of microsomes from human heart tissue was developed and CYP450-dependent activity was determined using verapamil enantiomers as probe-drug substrates.
Our results show that CYP2J2 mRNA was the most abundant isoform in all human heart left ventricular samples tested. Other CYP450 mRNAs of importance were CYP4A11, CYP2E1, CYP1A1 and CYP2C8 mRNAs while CYP2B6 and CYP2C9 mRNAs were present at low levels in only some of the hearts analyzed. CYP450 mRNAs did not differ between ischemic and non-ischemic hearts and appeared to be present at similar levels in the left and right ventricles. Incubation of verapamil with heart microsomes led to the formation of nine CYP450-dependent metabolites: a major finding was the observation that stereoselectivity was reversed compared to human liver microsomes, in which the R-enantiomer is metabolized to a greater extent.
This study determined cardiac mRNA levels of various CYP450 isozymes involved in drug metabolism and demonstrated the prevalent expression of CYP2J2 mRNA. It revealed that cardiomyocytes can efficiently metabolize drugs and that cardiac CYP450s are highly relevant with regard to clearance of drugs in the heart. Our results support the claim that drug metabolism in the vicinity of a drug effector site can modulate drug effects.
Recent strides towards precision medicine in Cystic Fibrosis (CF) have been made possible by patient-derived in-vitro assays with the potential to predict clinical response to small molecule-based ...therapies. Here, we discuss the status of primary and stem-cell derived tissues used to evaluate the preclinical efficacy of CFTR modulators highlighting both their potential and limitations. Validation of these assays requires correlation of in-vitro responses to in-vivo measures of clinical biomarkers of disease outcomes. While initial efforts have shown some success, this translation requires methodologies that are sensitive enough to capture treatment responses in a CF population that now predominantly has mild lung disease. Future development of in-vitro and in-vivo biomarkers will facilitate the generation of new therapeutics particularly for those patients with rare mutations where clinical trials are not feasible so that in the future every CF patient will have access to effective targeted therapies.
Prolonged central vascular access is a source of significant morbidity in children with intestinal failure (IF). In an effort to decrease morbidity, our multidisciplinary IF team has primarily used ...peripherally inserted central catheters (PICCs) for these patients. We compared outcomes of PICCs to Broviacs®.
A review of children with IF (2006–2018) at an academic children's hospital was conducted. Inclusion criteria: total parenteral nutrition duration >42 days or small bowel length < 25% of total for gestational age. Complications/1000 catheter days were extracted, and a Poisson model was used to compare complications between PICCs and Broviacs®.
Thirty-seven patients with IF were included, accounting for 19,452 catheter days. There were 209 PICCs (1.2–4F) and 39 Broviacs® (2.7–7F). The median duration of overall PICC access/patient was 166 days (range: 35 days–8 years). Incidences of central line associated blood stream infection and venous thrombosis were 3.95 and 0.55 per 1000 catheter days, respectively. There were no significant differences in complication rates per line per catheter day between PICCs and Broviacs® on multivariate analysis. Broviacs® showed a trend towards increased of catheter-related hospital admissions when compared to PICCs.
PICCs in children with intestinal failure have similar complication rates to Broviacs® but may reduce catheter-related hospital admissions. Use of tunneled PICCs and increasing experience with this vascular access method may allow it to realize its potential advantages.
Retrospective study, level III.
Abstract Nanoparticles composed of the coat protein of a plant virus (papaya mosaic virus; PapMV) and a single-stranded RNA (ssRNA) trigger a strong innate immune stimulation in the lungs of the ...animals a few hours following instillation. A rapid recruitment of neutrophils, monocytes/macrophages and lymphocytes follows. This treatment was able to provide protection to an influenza challenge that lasts at least 5 days. Protection could be recalled for longer periods by repeating the instillations once per week for more than 10 weeks. The treatment also conferred protection to a lethal challenge with Streptococcus pneumoniae – the major cause of bacterial pneumonia. Finally, we also showed that the nanoparticles could be used to treat mice infected with influenza and significantly decrease morbidity. These data strengthen the potential for using PapMV nanoparticles as non-specific inducers of the innate immune response in lungs during viral pandemics or to combat bioterrorist attack. From the Clinical Editor In this study, virus-like nanoparticles were utilized to induce innate immune responses in a mouse model. They were also demonstrated to provide enhanced immune responses during actual pneumonia and ongoing viral infection. Strategies like this may become very helpful in human applications, including bioterrorism countermeasures.
Commercial seasonal flu vaccines induce production of antibodies directed mostly towards hemaglutinin (HA). Because HA changes rapidly in the circulating virus, the protection remains partial. ...Several conserved viral proteins, e.g., nucleocapsid (NP) and matrix proteins (M1), are present in the vaccine, but are not immunogenic. To improve the protection provided by these vaccines, we used nanoparticles made of the coat protein of a plant virus (papaya mosaic virus; PapMV) as an adjuvant. Immunization of mice and ferrets with the adjuvanted formulation increased the magnitude and breadth of the humoral response to NP and to highly conserved regions of HA. They also triggered a cellular mediated immune response to NP and M1, and long-lasting protection in animals challenged with a heterosubtypic influenza strain (WSN/33). Thus, seasonal flu vaccine adjuvanted with PapMV nanoparticles can induce universal protection to influenza, which is a major advancement when facing a pandemic.
Longitudinal data suggest that individuals who increased their visceral adiposity and who decreased their cardiorespiratory fitness over time experienced the most detrimental changes in their ...cardiometabolic risk profile.
Context:
Both excess visceral adipose tissue (VAT) and low cardiorespiratory fitness (CRF) levels are associated with a deteriorated cardiometabolic risk profile.
Objective:
The aim of the study was to examine the respective contributions of changes in VAT accumulation vs. changes in CRF to 6-yr longitudinal changes in cardiometabolic risk markers.
Design, Settings, and Participants:
We conducted a prospective, population-based study with an average follow-up of 5.9 ± 0.8 yr. We followed 132 middle-aged participants from the Quebec Family Study (mean age, 35.3 ± 13.9 yr). VAT was measured by computed tomography, whereas the level of CRF was assessed by a submaximal physical working capacity test at baseline and at follow-up. A complete cardiometabolic risk profile, including systolic and diastolic blood pressure, fasting glucose and insulin levels, C-reactive protein (n = 72), as well as a standard lipoprotein-lipid profile, was obtained at baseline and at follow-up.
Main Outcome Measures:
We measured changes in CRF, VAT, and cardiometabolic risk profile over 6 yr.
Results:
After adjusting for age and sex, 6-yr changes in VAT were negatively correlated with changes in CRF (r = −0.38; P < 0.001). In a multivariate model that included age, sex, changes in VAT, changes in CRF, as well as baseline levels of the above cardiometabolic risk factors, 6-yr changes in VAT were the most important predictor of the change in the metabolic syndrome score (R2 = 13.2%; P < 0.001). Adding 6-yr changes in CRF levels significantly improved the predictability of the model (R2 = 19.7%; P = 0.002).
Conclusions:
Changes in both VAT and CRF levels observed over 6 yr are associated with changes in parameters of the lipoprotein-lipid profile, glucose-insulin homeostasis, and inflammatory markers. Thus, maintaining a low level of VAT and a high level of CRF are important targets for maintenance of cardiometabolic health.
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