Discrete microstructural cues for the attenuation of fibrosis following myocardial infarction

Chronic fibrosis caused by acute myocardial infarction (MI) leads to increased morbidity and mortality due to cardiac dysfunction. We have developed a therapeutic materials strategy that aims to mitigate myocardial fibrosis by utilizing injectable polymeric microstructures to mechanically alter the microenvironment. Polymeric microstructures were fabricated using photolithographic techniques and studied in a three-dimensional culture model of the fibrotic environment and by direct injection into the infarct zone of adult rats. Here, we show dose-dependent down-regulation of expression of genes associated with the mechanical fibrotic response in the presence of microstructures. Injection of this microstructured material into the infarct zone decreased levels of collagen and TGF-β, increased elastin deposition and vascularization in the infarcted region, and improved functional outcomes after six weeks. Our results demonstrate the efficacy of these discrete anti-fibrotic microstructures and suggest a potential therapeutic materials approach for combatting pathologic fibrosis.     

De novo large cell neuroendocrine carcinoma of the prostate gland with pelvic lymph node metastasis: a case report with review of literature

Neuroendocrine (NE) differentiation in prostate carcinomas can be seen in two settings: as a focal finding in conventional acinar adenocarcinoma, identifiable by immunohistochemical staining, or as a primary NE tumor of the prostate gland, such as carcinoid, small cell carcinoma, or large cell NE carcinoma. Of particular interest is the large cell NE carcinoma, which had been previously reported in isolated cases or in limited case series. In this report, we describe a case of a large cell NE carcinoma diagnosed in a 48-year-old man who presented with difficulty in voiding and urine retention. A cystoscopy revealed an enlarged, elongated prostate with an intra-urethral obstructing mass in the prostatic urethra. Subsequently, a transurethral resection of prostate (TURP) was performed at an outside hospital under the clinical diagnosis of benign prostatic hyperplasia (BPH). Microscopic examination of the TURP specimen revealed several foci of low-grade transitional-zone-type adenocarcinoma corresponding to Gleason score 5 (3 + 2), and a focus of high-grade large cell NE carcinoma. Concurrent x-ray computed tomography scans of the chest, abdomen, and pelvis demonstrated an enlarged left pelvic lymph node, which was biopsied and the patient was diagnosed with metastatic large cell NE carcinoma. He subsequently underwent 8 cycles of neoadjuvant chemotherapy with Lupron, a laparoscopic robotic-assisted radical retropubic prostatectomy, and pelvic lymphadenectomy. He died of widely metastatic prostatic carcinoma with leptomeningeal metastases 13 months after radical prostatectomy. Here, we present a rare case of large cell NE carcinoma with a review of the published literature.     

Heterogeneous clinicopathological features of intraductal carcinoma of the prostate: a comparison between “precursor-like” and “regular type” lesions

Intraductal carcinoma of the prostate (IDC-P) has been described as a lesion associated with intraductal spread of invasive carcinoma and consequently aggressive disease. However, there are a few reported cases of pure IDC-P without an associated invasive component, strongly suggesting that this subset of IDC-P may represent a precursor lesion. We compared the clinicopathological features between the morphologically “regular type” IDC-P and “precursor-like” IDC-P. IDC-P was defined as follows; 1) solid/dense cribriform lesions or 2) loose cribriform/micropapillary lesions with prominent nuclear pleomorphism and/or non-focal comedonecrosis. We defined precursor-like IDC-P as follows; 1) IDC-P without adjoining invasive adenocarcinoma but carcinoma present distant from the IDC-P or 2) IDC-P having adjoining invasive microcarcinoma (less than 0.05 ml) and showing a morphologic transition from high-grade prostatic intraepithelial neoplasia (HGPIN) to the IDC-P. IDC-P lacking the features of precursor-like IDC-P was categorized as regular type IDC-P. Of 901 radical prostatectomies performed at our hospital, 141 and 14 showed regular type IDC-P and precursor-like IDC-P in whole-mounted specimens, respectively. Regular type IDC-P cases had significantly higher Gleason score, more frequent extraprostatic extension and seminal vesicle invasion, more advanced pathological T stage, and lower 5-year biochemical recurrence-free rate than precursor-like IDC-P cases. Multivariate analysis revealed nodal metastasis and the presence of regular type IDC-P as independent predictors for biochemical recurrence. Our data suggest that IDC-P may be heterogeneous with variable clinicopathological features. We also suggest that not all IDC-P cases represent intraductal spread of pre-existing invasive cancer, and a subset of IDC-P may be a precursor lesion.     

The RUSH2A Study: Dark-Adapted Visual Fields in Patients With Retinal Degeneration Associated With Biallelic Variants in the USH2A Gene

PurposeTo measure visual fields using two-color dark-adapted chromatic perimetry in a subset of participants in the Rate of Progression of USH2A-related Retinal Degeneration (RUSH2A), a study of USH2A-mediated syndromic (USH2) and autosomal recessive nonsyndromic retinitis pigmentosa, determine percentage retaining rod function, and explore relationships between dark-adapted visual fields (DAVF) and rod function from ERG and full-field stimulus thresholds (FST).MethodsFull-field rod mean sensitivity, number of rod loci, maximum sensitivity, DAVF full-field hill of vision (DAVF V_TOT), and 30° hill of vision (DAVF V₃₀) were measured in one eye for DAVF ancillary study participants (n = 49). Loci where cyan relative to red sensitivity was more than 5 dB on dark-adapted chromatic perimetry were considered rod mediated. Correlation coefficients between the DAVF measures and standard clinical measures were estimated, as were kappa statistics (κ) for agreement between DAVF and other measures of rod function.ResultsOf 49 participants tested with DAVF, 38 (78%) had evidence of rod function, whereas 15 (31%) had measurable rod ERGs. DAVF maximum sensitivity was highly correlated with FST white thresholds (r = −0.80; P < .001). Although not statistically significant, the number of rod loci and DAVF V_TOT were lower in eyes with longer disease duration by 0.82 (95% confidence interval, −1.76, 0.12) loci/year and 0.59 (95% confidence interval, −1.82, 0.64) dB-steradians/year, respectively.ConclusionsRod-mediated function on FST and DAVF is present in many patients with symptomatic USH2A-related retinal degeneration, including some without measurable rod ERGs. RUSH2A longitudinal data will determine how these measures change with disease progression and whether they are useful for longitudinal studies in inherited retinal degenerations.     

Perturbed hematopoiesis in individuals with germline DNMT3A overgrowth Tatton-Brown-Rahman syndrome

Tatton-Brown-Rahman syndrome (TBRS) is an overgrowth disorder caused by germline heterozygous mutations in the DNA methyltransferase DNMT3A. DNMT3A is a critical regulator of hematopoietic stem cell (HSC) differentiation and somatic DNMT3A mutations are frequent in hematologic malignancies and clonal hematopoiesis. Yet, the impact of constitutive DNMT3A mutation on hematopoiesis in TBRS is undefined. In order to establish how constitutive mutation of DNMT3A impacts blood development in TBRS we gathered clinical data and analyzed blood parameters in 18 individuals with TBRS. We also determined the distribution of major peripheral blood cell lineages by flow cytometric analyses. Our analyses revealed non-anemic macrocytosis, a relative decrease in lymphocytes and increase in neutrophils in TBRS individuals compared to unaffected controls. We were able to recapitulate these hematologic phenotypes in multiple murine models of TBRS and identified rare hematological and non-hematological malignancies associated with constitutive Dnmt3a mutation. We further show that loss of DNMT3A in TBRS is associated with an altered DNA methylation landscape in hematopoietic cells affecting regions critical to stem cell function and tumorigenesis. Overall, our data identify key hematopoietic effects driven by DNMT3A mutation with clinical implications for individuals with TBRS and DNMT3A-associated clonal hematopoiesis or malignancies.     

Left ventricular assist device implants in patients on extracorporeal membrane oxygenation: do we need cardiopulmonary bypass?

Open in a separate window OBJECTIVESImplanting a durable left ventricular assist device (LVAD) in a patient on extracorporeal life support (ECLS) is challenging. The goal of this study was to compare the results of patients from a European registry who had a durable LVAD implanted with or without transition from ECLS to cardiopulmonary bypass (CPB).METHODSA total of 531 patients on ECLS support who had an LVAD implant between January 2010 and August 2018 were analysed; after 1:1 propensity score matching, we identified and compared 175 patients in each group.RESULTSThe duration of preoperative ECLS was 7 [standard deviation (SD) 6] vs 7 (SD 6) days in patients with or without CPB (P = 0.984). The surgical time was longer in the CPB group [285 (SD 72) vs 209 [SD 75] min; P ≤ 0.001). The postoperative chest tube output was comparable [1513 (SD 1311) vs 1390 (SD 1121) ml; P = 0.3]. However, re-exploration for bleeding was necessary in 41% vs 29% of patients with or without CPB (P = 0.01) and a significantly higher number of packed red blood cells and fresh frozen plasma [8 (SD 8) vs 6 (SD 4) units; P = 0.001 and 6 (SD 7) vs 5 (SD 5) units; P = 0.03] were administered to patients operated on with CPB. A postoperative mechanical right ventricular support device was necessary in 50% vs 41% of patients (P = 0.08). The stroke rate was not significantly different (P 0.99). No difference in survival was observed.CONCLUSIONSOmitting CPB for an LVAD implant in patients on ECLS is safe and results in shorter operating time, less re-exploration for bleeding and fewer blood products. However, no survival benefit is observed.     

高血压的时间治疗学

1血压变异性的时间生物学 血压(BP)受很多因素影响,外因如:环境温度(湿度)、躯体活动、情感状况(焦虑,愤怒)、摄入酒精或咖啡因、膳食成分及睡眠(觉醒)作息规律等;内因如:种族、性别、自主神经张力、血管活性激素及血液学和肾脏变化因素,很难清楚地区分外因与内因相互作用对BP昼夜变化的影响[1].     

Melatonin inhibits nuclear factor kappa B activation and oxidative stress and protects against thioacetamide induced liver damage in rats

BACKGROUND/AIMS: Free radical-mediated oxidative stress has been implicated in the pathogenesis of acute liver injury. The aim of our study was to investigate whether melatonin, a potent free radical scavenger could prevent fulminant hepatic failure in rats. METHODS: Liver damage was induced by two consecutive injections of thioacetamide (TAA, 300 mg/kg/i.p.) at 24 h intervals. Treatment with melatonin (3 mg/kg/daily, i.p) was initiated 24 h prior to TAA. RESULTS: Twenty-four h after the second TAA injection, serum liver enzymes and blood ammonia were lower in rats treated with TAA+melatonin compared to TAA (P<0.001). Liver histology was significantly improved and the mortality in the melatonin-treated rats was decreased (P<0.001). The increased nuclear binding of nuclear factor kappa B in the livers of the TAA-treated rats, was inhibited by melatonin. The hepatic levels of thiobarbituric acid reactive substances, protein carbonyls and inducible nitric oxide synthase were lower in the TAA+melatonin-treated group (P<0.01), indicating decreased oxidative stress and inflammation. CONCLUSIONS: In a rat model of TAA-induced fulminant hepatic failure, melatonin improves survival and reduces liver damage and oxidative stress. The results suggest a causative role of oxidative stress in TAA-induced hepatic damage and suggest that melatonin may be utilized to reduce liver injury associated with oxidative stress.