Citations

Rationale: Acute kidney injury (AKI) has a high prevalence and mortality in critically ill patients. It is also a powerful risk factor for heart failure incidence driven by hemodynamic changes and neurohormonal activation. However, no drugs have been approved by the Food and Drug Administration. Endogenous pGC-A (particulate guanylyl cyclase A receptor) activators were reported to preserve renal function and improve mortality in AKI patients, although hypotension accompanied by pGC-A activators have limited their therapeutic potential. Objective: We investigated the therapeutic potential of a nonhypotensive pGC-A activator/designer natriuretic peptide, CRRL269, in a short-term, large animal model of ischemia-induced AKI and also investigated the potential of uCNP (urinary C-type natriuretic peptide) as a biomarker for AKI. Methods and Results: We first showed that CRRL269 stimulated cGMP generation, suppressed plasma angiotensin II, and reduced cardiac filling pressures without lowering blood pressure in the AKI canine model. We also demonstrated that CRRL269 preserved glomerular filtration rate, increased renal blood flow, and promoted diuresis and natriuresis. Further, CRRL269 reduced kidney injury and apoptosis as evidenced by ex vivo histology and tissue apoptosis analysis. We also showed, compared with native pGC-A activators, that CRRL269 is a more potent inhibitor of apoptosis in renal cells and induced less decreases in intracellular Ca 2+ concentration in vascular smooth muscle cells. The renal antiapoptotic effects were at least mediated by cGMP/PKG pathway. Further, CRRL269 inhibited proapoptotic genes expression using a polymerase chain reaction gene array. Additionally, we demonstrated that AKI increased uCNP levels. Conclusions: Our study supports developing CRRL269 as a novel renocardiac protective agent for AKI treatment.

As treatment of HIV has improved, people living with HIV (PLWH) have experienced a decreased risk of AIDS and AIDS-defining cancers (non-Hodgkin’s lymphoma, Kaposi sarcoma, and cervical cancer), but the risk of Kaposi sarcoma in PLWH is still elevated about 500-fold compared with the general population in the United States. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for AIDS-Related Kaposi Sarcoma provide diagnosis, treatment, and surveillance recommendations for PLWH who develop limited cutaneous Kaposi sarcoma and for those with advanced cutaneous, oral, visceral, or nodal disease.

Atrial fibrillation (AF) is the most common cardiac arrhythmia and is a major cause of thromboembolic stroke in the United States. The risk of stroke is a 5-fold increase in patients with AF. The Sorbin and SH3 domain-containing protein 2 (Sorbs2) is a scaffolding protein known to interact with actin and several other cytoskeletal proteins in the intercalated discs and Z band of cardiomyocytes. However, the role of Sorbs2 gene in cardiovascular diseases is largely unknown. Using the loss-of-function of Sorbs2 ( Sorbs2 e8/e8 ) mice, we found that Sorbs2 e8/e8 mice had an abnormal lifespan and die at 4 to 7 months of age. Echocardiogram examine revealed that there was a significant decrease in right ventricle (RV) and left ventricular (LV) ejection fraction (EF), increase in RV end-diastolic volume (EDV) and end-systolic volume (ESV), and progressive chamber enlargement in left atria (LA) and RV, particularly in LA with severe fibrosis and intramural thrombus formation, in Sorbs2 e8/e8 mice after 3 months of age. Surface electrocardiograph also showed a significant conduction delay and spontaneous arrhythmias including those of bifid P wave configuration, right bundle branch block (RBBB), spontaneous AF and non-sustained ventricular tachycardia (VT) in Sorbs2 e8/e8 mice. Intracellular recordings in the freshly isolated LA demonstrated that Sorbs2 e8/e8 myocardium had a delayed action potential activation in response to electrical impulse excitation, reduced amplitude and upstroke velocity (dV/dt) at phase 0, slowed repolarization at phase 1 and phase 2, prolonged atrial effective refractory period (aERP), action potential durations at 50% (APD 50 ) and 90% (APD 90 ) repolarization, and decreased resting potentials. Moreover, the mRNA and protein expressions of voltage-gated Na + channels, L-type Ca 2+ channels, transient outward K + channels and inward rectifier K + channels were significantly downregulated in the LA of Sorbs2 e8/e8 mice, compared wo those of wild type mice. Our results indicate that Sorbs2 gene plays an important role in atrial myocardium architecture and electrophysiology. Sorbs2 dysfunction leads to atrial cardiomyopathy, spontaneous AF and cardiac embolism in mice. Hence, Sorbs2 is a new genetic association with cardioembolic stroke.

BackgroundEnd‐stage lower extremity lymphedema (LEL) poses a particularly formidable challenge to surgeons as multiple pathological processes are at work. Because single modality treatment is often unsuccessful, we devised a comprehensive multimodal surgical treatment. The aim of this study is to share the technical considerations and examine the clinical outcomes of this combined approach.MethodsBetween 2013 and 2017, patients with International Society of Lymphology stage III, who underwent the combination treatment of Charles,’ Homan’s procedure with toe management and vascularized lymph node transfer (CHAHOVA), were included in this retrospective study. Outcomes evaluated were limb size, number of infectious episodes, compression garment usage, and rate of complications.ResultsA total of 68 patients were included. With a mean follow‐up of 29 months, the overall circumference reduction rate for the upper thigh and the rest of the extremity was 67.4% (48.2‐88.2%) and 98.1% (88‐100%), respectively. During the follow‐ups, 2 (2.9%) patients experienced episodes of cellulitis and the average number of yearly infections decreased from 4.2 to 1.2 episodes per person. All patients were able to discontinue compression therapy without recurrence of lymphedema. Nine (13.2%) patients reported minor complications.ConclusionThe combine CHAHOVA in a single‐stage procedure is an effective and safe approach in the end‐stage LEL.

BackgroundTreatment of advanced lymphedema requires not only restoration of physiological lymph drainage, but also excision of fibrotic tissue and excess skin. The aim of this study is to show how the combination of double vascularized lymph node transfers (VLNTs) and a modified radical reduction with preservation of perforators (RRPP) can accomplish both of these treatment goals.MethodsBetween 2010 and 2016, 16 patients (15 female and one male) with extremity lymphedema underwent a combined double gastroepiploic VLNTs and modified RRPP. Demographics, outcomes including circumference reduction rates, preoperative and postoperative lymphoscintigraphy, complications, and responses to the Lymphedema Quality of Life (LYMQOL) questionnaire were analyzed.ResultsAll flaps survived. The mean follow‐up period was 14.2 months (range, 12‐19). The mean circumference reduction rate was 74.5% ± 6.9% for the upper limb and 68.0% ± 4.2% for the lower limb. There were no major complications. Minor complications, including numbness and hyperesthesia, were treated conservatively. LYMQOL showed a 2.7‐fold quality‐of‐life improvement (P < 0.01). Postoperative lymphoscintigraphy showed improved lymphatic drainage in all cases.ConclusionCombined double VLNTs and modified RRPP safely and effectively improves lymphatic drainage, reduces fibrotic tissue and excess skin, decreases episodes of infections, and improves patients’ quality of life in the advanced stages of lymphedema.

BackgroundThere is no accurate method distinguishing different types of pulmonary nodules.PurposeTo investigate whether multiparametric 3T MRI biomarkers can distinguish malignant from benign pulmonary nodules, differentiate different types of neoplasms, and compare MRI‐derived measurements with values from commonly used noninvasive imaging modalities.Study TypeProspective.SubjectsSixty‐eight adults with pulmonary nodules undergoing resection.SequencesRespiratory triggered diffusion‐weighted imaging (DWI), periodically rotated overlapping parallel lines with enhanced reconstruction (PROPELLER) fat saturated T2‐weighted imaging, T1‐weighted 3D volumetric interpolated breath‐hold examination (VIBE) using CAIPIRINHA (controlled aliasing in parallel imaging results in a higher acceleration).Assessment/StatisticsApparent diffusion coefficient (ADC), T1, T2, T1 and T2 normalized to muscle (T1/M and T2/M), and dynamic contrast enhancement (DCE) values were compared with histology to determine whether they could distinguish malignant from benign nodules and discern primary from secondary malignancies using logistic regression. Predictability of primary neoplasm types was assessed using two‐sample t‐tests. MRI values were compared with positron emission tomography / computed tomography (PET/CT) to examine if they correlated with standardized uptake value (SUV) or CT Hounsfield unit (HU). Intra‐ and interreader agreements were assessed using intraclass correlations.ResultsForty‐nine of 74 nodules were malignant. There was a significant association between ADC and malignancy (odds ratio 4.47, P < 0.05). ADC ≥1.3 μm2/ms predicted malignancy. ADC, T1, and T2 together predicted malignancy (P = 0.003). No MRI parameter distinguished primary from metastatic neoplasms. T2 predicted PET positivity (P = 0.016). T2 and T1/M correlated with SUV (P < 0.05). Of 18 PET‐negative malignant nodules, 12 (67%) had an ADC ≥1.3 μm2/ms. With the exception of T2, all noncontrast MRI parameters distinguished adenocarcinomas from carcinoid tumors (P < 0.05). T1, T2, T1/M, and T2/M correlated with HU and therefore can predict nodule density. Combined with ADC, washout enhancement, arrival time (AT), peak enhancement intensity (PEI), Ktrans, Kep, Ve collectively were predictive of malignancy (P = 0.012). Combined washin, washout, time to peak (TTP), AT, and PEI values predicted malignancy (P = 0.043). There was good observer agreement for most noncontrast MRI biomarkers.Data ConclusionMRI can contribute to pulmonary nodule analysis. Multiparametric MRI might be better than individual MRI biomarkers in pulmonary nodule risk stratification.Level of Evidence: 1Technical Efficacy: Stage 2J. Magn. Reson. Imaging 2018.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are an ideal therapy for type 2 diabetes and, as of recently, for obesity. In contrast to visceral fat, subcutaneous fat appears to be protective against metabolic diseases. Here, we aimed to explore whether liraglutide, a GLP-1RA, could redistribute body fat via regulating lipid metabolism in different fat depots. After being fed a high-fat diet for 8 weeks, 50 male Wistar and Goto-Kakizaki rats were randomly divided into a normal control group, a diabetic control group, low- and high-dose liraglutide-treated groups and a diet-control group. Different doses of liraglutide (400 μg/kg/day or 1200 μg/kg/day) or an equal volume of normal saline were administered to the rats subcutaneously once a day for 12 weeks. Body composition and body fat deposition were measured by dual-energy X-ray absorptiometry and MRI. Isotope tracers were infused to explore lipid metabolism in different fat depots. Quantitative real-time PCR and Western blot analyses were conducted to evaluate the expression of adipose-related genes. The results showed that liraglutide decreased visceral fat and relatively increased subcutaneous fat. Lipogenesis was reduced in visceral white adipose tissue (WAT) but was elevated in subcutaneous WAT. Lipolysis was also attenuated, and fatty acid oxidation was enhanced. The mRNA expression levels of adipose-related genes in different tissues displayed similar trends after liraglutide treatment. In addition, the expression of browning-related genes was upregulated in subcutaneous WAT. Taken together, the results suggested that liraglutide potentially redistributes body fat and promotes browning remodeling in subcutaneous WAT to improve metabolic disorders.

BackgroundThe medial thigh is a well‐hidden area. The two most common flaps from this area are the transverse upper gracilis (TUG) and profunda artery perforator (PAP) flaps. Herein, we explored the applications of combined TUGPAP flap to reconstruct large and complex defects in different regions.MethodsBetween November 2015 and May 2017, 28 patients who underwent reconstruction and extensive soft tissue coverage with the TUGPAP flap for the breasts, head and neck, and pelvi‐perineal regions were included. The defects size ranged from 22 to 29 × 6–8 cm. All flaps were based on the two pedicles: the medial circumflex femoral artery for TUG flap and the profunda artery perforator for PAP flap. They were each anastomosed to a set of recipient vessels. A “Y”‐shaped interposition vein graft (YVG) was used if only one recipient artery was available.ResultsThe harvested skin paddle had dimensions ranged from 20 to 30 × 6–9 cm and all flaps survived completely. Postoperative complications included one case each of donor and recipient site seroma, and one case of wound dehiscence. They were all successfully managed conservatively. During an average follow‐up period of 12.7 months, one patient reported permanent paresthesia in the donor site and another developed hypertrophic scar. All patients were able to resume daily activity without major concerns.ConclusionThe combined TUGPAP flap is a safe, effective, and a good alternative to the common workhorse flaps as it offers the potential for a large skin paddle and decent soft tissue volume with low donor site morbidity in a well‐concealed area.

IntroductionComposite and large head and neck defects requiring extensive skin‐mucosa coverage are often reconstructed by combining flaps. Herein, we present a simple and reliable two‐stage fibula osteocutaneous (FOC) flap technique to improve the survival of a large skin paddle for oromandibular reconstructions.MethodsFrom October 2011 to September 2016, 47 patients with through‐and‐through oromandibular defects were reconstructed using FOC flaps with large skin paddles. To ensure optimum survival of skin paddles, temporary orocutaneous fistula were left in place and closed during the second stage operation via de‐epithelialization of the skin paddle and suturing of mucosa. Demographic data, operative details, and postoperative complications were recorded.ResultsThe skin paddle dimensions ranged from 20 to 31.5 cm in length and 12 to 17 cm in width with an average area of 430.4 cm2 (range 300–504). The average time between the two stages and hospital stay were 10 days and 14 days, respectively. Complications at the donor site included wound dehiscence (n = 3, 6.4%), partial skin graft loss (n = 3, 6.4%) and hematoma (n = 2, 4.3%). Recipient site complications included two (4.3%) early postoperative venous congestions that resolved after elevation and three (6.4%) partial skin flap necrosis (less than 5% surface area). All complications resolved with bedside conservative management. There was only one take‐back for evacuation of recipient site hematoma (2.1%) but no flap loss.ConclusionTwo‐staged large skin paddle FOC flaps can simplify reconstruction of extensive oromandibular defects by improving the reliability of the sizable skin paddle and negating the need for a second flap.