The variability in platelet dense granule ATP release findings amongst patients assessed for diagnostic purposes suggests that the test has limited value for diagnosing platelet disorders.
AIMTo investigate gender-specific liver estrogen receptor (ER) expression in normal subjects and patients with hepatitis C virus (HCV)-related cirrhosis and hepatocellular carcinoma (HCC).METHODSLiver tissues from normal donors and patients diagnosed with HCV-related cirrhosis and HCV-related HCC were obtained from the NIH Liver Tissue and Cell Distribution System. The expression of ER subtypes, ERα and ERβ, were evaluated by Western blotting and real-time RT-PCR. The subcellular distribution of ERα and ERβ was further determined in nuclear and cytoplasmic tissue lysates along with the expression of inflammatory [activated NF-κB and IκB-kinase (IKK)] and oncogenic (cyclin D1) markers by Western blotting and immunohistochemistry. The expression of ERα and ERβ was correlated with the expression of activated NF-κB, activated IKK and cyclin D1 by Spearman’s correlation.RESULTSBoth ER subtypes were expressed in normal livers but male livers showed significantly higher expression of ERα than females (P < 0.05). We observed significantly higher mRNA expression of ERα in HCV-related HCC liver tissues as compared to normals (P < 0.05) and ERβ in livers of HCV-related cirrhosis and HCV-related HCC subjects (P < 0.05). At the protein level, there was a significantly higher expression of nuclear ERα in livers of HCV-related HCC patients and nuclear ERβ in HCV-related cirrhosis patients as compared to normals (P < 0.05). Furthermore, we observed a significantly higher expression of phosphorylated NF-κB and cyclin D1 in diseased livers (P < 0.05). There was a positive correlation between the expression of nuclear ER subtypes and nuclear cyclin D1 and a negative correlation between cytoplasmic ER subtypes and cytoplasmic phosphorylated IKK in HCV-related HCC livers. These findings suggest that dysregulated expression of ER subtypes following chronic HCV-infection may contribute to the progression of HCV-related cirrhosis to HCV-related HCC.CONCLUSIONGender differences were observed in ERα expression in normal livers. Alterations in ER subtype expression observed in diseased livers may influence gender-related disparity in HCV-related pathogenesis.
Background
The bleeding risks for nonsyndromic platelet function disorders (PFDs) that impair aggregation responses and/or cause dense granule deficiency (DGD) are uncertain.
Objectives
Our goal was to quantify bleeding risks for a cohort of consecutive cases with uncharacterized PFD.
Methods
Sequential cases with uncharacterized PFDs that had reduced maximal aggregation (MA) with multiple agonists and/or nonsyndromic DGD were invited to participate along with additional family members to reduce bias. Index cases were further evaluated by exome sequencing, with analysis of
RUNX1
‐dependent genes for cases with
RUNX1
sequence variants. Bleeding assessment tools were used to estimate bleeding scores, with bleeding risks estimated as odds ratios (ORs) relative to general population controls. Relationships between symptoms and laboratory findings were also explored.
Results
Participants with uncharacterized PFD (n = 37; 23 index cases) had impaired aggregation function (70%), nonsyndromic DGD (19%) or both (11%), unlike unaffected relatives. Probable pathogenic
RUNX1
variants were found in 2 (9%) index cases/families, whereas others had PFD of unknown cause. Participants with PFD had increased bleeding scores compared to unaffected family members and general population controls, and increased risks for mucocutaneous (OR, 4‐207) and challenge‐related bleeding (OR, 12‐43), and for receiving transfusions for bleeding (OR, 100). Reduced MA with collagen was associated with wound healing problems and bruising, and more severe DGD was associated with surgical bleeding (
P
< .04).
Conclusions
PFDs that impair MA and/or cause nonsyndromic DGD have significantly increased bleeding risks, and some symptoms are more common in those with more severe DGD or impaired collagen aggregation.
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