Association of bone marrow fibrosis with inferior survival outcomes in chronic myelomonocytic leukemia

The impact of bone marrow fibrosis grade on the prognosis of patients with chronic myelomonocytic leukemia (CMML) remains controversial. Therefore, we examined the records of 82 patients diagnosed with CMML at our institution and summarized baseline characteristics and molecular profiles by subgroups of absent or mild (grades 0/1) and moderate (grade 2) fibrosis. Cox proportional hazards models were constructed to assess the prognostic significance of fibrosis grade. Grade 2 fibrosis was identified in 63 patients (76.8%), grade 1 in 16 patients (19.5%), and grade 0 in 3 patients (3.7%). Grade 2 fibrosis was associated with reduced hemoglobin levels (median 9.75 vs 11.0 g/dL in grade 0/1; p?=?0.04) and increased percentages of ringed sideroblasts (7.5 vs 0%; p?=?0.008). In multivariable analysis, grade 2 fibrosis was an independent predictor of poor overall survival (OS; 95% CI 1.32–6.35; HR 2.90; p?=?0.008), but not event-free survival (EFS; 95% CI 0.62–2.67; HR 1.28; p?=?0.50). Absolute neutrophil count (ANC) was found to impact OS (95% CI 1.01–1.09; HR 1.05; p?=?0.009), while both ANC (95% CI 1.00–1.07; HR 1.04; p?=?0.04) and peripheral blood blast percentage (95% CI 1.02–1.32; HR 1.16; p?=?0.02) impacted EFS. These results implicate fibrosis grade is an important indicator of prognosis, with high-grade fibrosis predicting inferior survival. Given the prevalence of marrow fibrosis in CMML, fibrosis grading should be incorporated into prognostic assessment and therapeutic decision-making.     

Bottom-up analysis of emergent properties of N-acetylcysteine as an adjuvant therapy for COVID-19

N-acetylcysteine (NAC) is an abundantly available antioxidant with a wide range of antidotal properties currently best studied for its use in treating acetaminophen overdose. It has a robustly established safety profile with easily tolerated side effects and presents the Food and Drug Administration's approval for use in treating acetaminophen overdose patients. It has been proven efficacious in off-label uses, such as in respiratory diseases, heart disease, cancer, human immunodeficiency virus infection, and seasonal influenza. Clinical trials have recently shown that NAC's capacity to replenish glutathione stores may significantly improve coronavirus disease 2019 (COVID-19) outcomes, especially in high risk individuals. Interestingly, individuals with glucose 6-phosphate dehydrogenase deficiency have been shown to experience even greater benefit. The same study has concluded that NAC's ability to mitigate the impact of the cytokine storm and prevent elevation of liver enzymes, C-reactive protein, and ferritin is associated with higher success rates weaning from the ventilator and return to normal function in COVID-19 patients. Considering the background knowledge of biochemistry, current uses of NAC in clinical practice, and newly acquired evidence on its potential efficacy against COVID-19, it is worthwhile to investigate further whether this agent can be used as a treatment or adjuvant for COVID-19.     

The spectrum of renal diseases with lupus-like features: a single-center study

BackgroundA subset of patients without overt systemic lupus erythematosus (SLE) present with biopsy findings typically seen in lupus nephritis (LN). Although a minority eventually develops SLE, many do not. It remains unclear how to classify or treat these patients. Our study attempted to further understand the clinical and pathological characteristics of cases with lupus-like nephritis (LLN).MethodsAmong 2700 native kidney biopsies interpreted at University of Rochester Medical Center (URMC) from 2010 to 2019, we identified 27 patients with biopsies showing lupus-like features (LL-fx) and 96 with LN. Of those with LL-fx, 17 were idiopathic LLN and 10 were associated with a secondary etiology (e.g., infection/drugs).ResultsAt the time of biopsy, the LLN-group tended to be slightly older (44 vs. 35), male (58.8 vs. 17.7%, p = .041), and Caucasian (47.0 vs. 28.1%, p = .005). Chronic kidney disease was the most common biopsy indication in LLN (21.4 vs. 2.8%, p = .001). Both LN and LLN presented with nephrotic-range proteinuria (mean 5.73 vs. 4.40 g/d), and elevated serum creatinine (mean 1.66 vs. 1.47 mg/dL). Tubuloreticular inclusions (TRIs; p < .001) and fibrous crescents (p = .04) were more often seen in LN, while more tubulointerstitial scarring was seen in LLN (p = .011). At mean follow-up of 1684 d (range: 31–4323), none of the LLN patients developed ESRD. A subset of both LN and cases with LL-fx overlapped with other autoimmune diseases.ConclusionsLupus-like pathologic features are seen in a wide array of disease processes. The findings suggest that LLN may be a manifestation of an autoimmune process that overlaps with SLE.     

槟榔子中抗血小板聚集及抑制乙酰胆碱酯酶活性的有效成分（英文）

目的：研究槟榔子（Areca catechu）粗提取物中所含的抗血小板聚集及抑制乙酰胆碱酯酶活性的有效成分及其作用机制。方法：使用70%甲醇水溶液对槟榔子进行粗提取。使用生物发光血小板凝集仪在富血小板血浆中测定槟榔子粗提取物的抗血小板聚集作用,使用分光光度计在试管内测定槟榔子粗提取物对乙酰胆碱酯酶活性的抑制作用。检测槟榔子中的多种化合物以测定槟榔子中抗血小板聚集及抑制乙酰胆碱酯酶活性的有效成分。结果：槟榔子粗提取物能够抑制花生四烯酸、二磷酸腺苷、血小板活化因子、肾上腺素及钙离子载体引起的血小板聚集,尤其对二磷酸腺苷及钙离子载体引起的血小板聚集的抑制最为明显;槟榔子粗提取物能够显著抑制乙酰胆碱酯酶的活性。在所检测的槟榔子所含化合物中,只有儿茶素对肾上腺素引起的血小板聚集有显著的抑制作用,而这种抑制作用显著弱于槟榔子粗提取物,提示槟榔子中的其他成分参与了这种抑制作用;鞣酸、没食子酸、薯蓣皂苷元和异去甲槟榔次碱能够抑制乙酰胆碱酯酶的活性,其中鞣酸的抑制作用强于槟榔子粗提取物。结论：槟榔子中含有抗血小板聚集及抑制乙酰胆碱酯酶活性的有效成分,而发挥这些功效的确切成分有待进一步的研究证实。     

Fluorescein-labeled sinistrin as marker of glomerular filtration rate

There is an obvious and growing medical need for an accurate and easy to handle determination of glomerular filtration rate (GFR) for a broad spectrum of indications. Newly synthesized fluorescein-isothiocyanate (FITC)-sinistrin (FS) with various degrees of labeling was selected by its physicochemical properties and good tolerability out of a number of dye-labeled compounds intended for use as GFR markers for characterization of its pharmacological profile. With respect to solubility FS is more convenient in handling compared to FITC-inulin (FI). Up to 100 mg ml(-1) of FS can be dissolved in aqueous solvents at room temperature, whereas FI can only be solubilized after warming up to 55 degrees C. This reveals a considerable advantage of FS over FI in preparation of galenical formulations for intended i.v. application. A fluorometric method was established to determine FS concentration in blood serum with a comparable accuracy to the established enzymatic method for polyfructosanes. Similar concentration time curves in blood serum of FS measured fluorometrically and enzymatically suggest no relevant change of pharmacokinetic behavior by dye labeling. This notion is supported by the rapid renal and missing of biliary excretion. On the basis of these results, FS is superior in handling to the available GFR markers and makes it highly interesting as a novel diagnostic drug.     

Alcohol intake and risk of dementia

OBJECTIVES: To examine the association between intake of alcoholic beverages and risk of Alzheimer's disease (AD) and dementia associated with stroke (DAS) in a cohort of elderly persons from New York City. DESIGN: Cohort study. SETTING: The Washington Heights Inwood-Columbia Aging Project. PARTICIPANTS: Nine hundred eighty community-dwelling individuals aged 65 and older without dementia at baseline and with data on alcohol intake recruited between 1991 and 1996 and followed annually. MEASUREMENTS: Intake of alcohol was measured using a semiquantitative food frequency questionnaire at baseline. Subjects were followed annually, and incident dementia was diagnosed using Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria and classified as AD or DAS. RESULTS: After 4 years of follow-up, 260 individuals developed dementia (199 AD, 61 DAS). After adjusting for age, sex, apolipoprotein E (APOE)-epsilon 4 status, education, and other alcoholic beverages, only intake of up to three daily servings of wine was associated with a lower risk of AD (hazard ratio=0.55, 95% confidence interval=0.34-0.89). Intake of liquor, beer, and total alcohol was not associated with a lower risk of AD. Stratified analyses by the APOE-epsilon 4 allele revealed that the association between wine consumption and lower risk of AD was confined to individuals without the APOE-epsilon 4 allele. CONCLUSIONS: Consumption of up to three servings of wine daily is associated with a lower risk of AD in elderly individuals without the APOE epsilon-4 allele.     

Susceptibility to gut leakiness: a possible mechanism for endotoxaemia in non‐alcoholic steatohepatitis

Introduction: One of the proposed second hit mechanisms in the pathophysiology of non‐alcoholic steatohepatitis (NASH) is hepatic oxidative stress triggered by elevated levels of endotoxin. We investigated one possible mechanism for the endotoxaemia – disruption of intestinal barrier integrity. Methods: We enrolled 16 subjects with fatty liver (10 NASH; 6 steatosis) and 12 healthy subjects. Steatosis and NASH were diagnosed by liver biopsy using the Brunt criteria. Gastrointestinal permeability was measured using urinary excretion of 5‐h lactulose/mannitol (L/M) ratio and 24‐h sucralose. Permeability testing was repeated after aspirin challenge. Results: Groups had similar baseline urinary 0–5 h L/M ratio (small bowel permeability) and 0–24 h sucralose (whole‐gut permeability). Aspirin increased 0–5 h urinary L/M in most subjects. In contrast, aspirin significantly increased whole‐gut permeability only in NASH subjects. In fact, the major increase in the urinary sucralose occurred in the 6–24 h samples, which points towards the colon as the major site responsible for aspirin‐induced leakiness in NASH patients. Serum endotoxin levels were significantly higher in NASH subjects. Discussion: Our findings suggest that aspirin acts on the colon to unmask a susceptibility to gut leakiness in patients with NASH. This effect may be the underlying mechanism for increased serum endotoxin, which is the second hit (after altered lipid metabolism) that is required to initiate a necroinflammatory cascade in hepatocytes which are already primed with obesity‐induced abnormal lipid homoeostasis.