Achieving sustained virologic response after interferon-free hepatitis C virus treatment correlates with hepatic interferon gene expression changes independent of cirrhosis.

Chronic hepatitis C virus (HCV) infection can now be treated with oral directly acting antiviral agents, either with or without ribavirin (RBV). Virologic relapse after treatment can occur, and in some studies was more common in cirrhotic subjects. We previously observed changes in hepatic immunity during interferon (IFN)-free therapy that correlated with favourable outcome in subjects with early liver disease. Here, we compared changes in endogenous IFN pathways during IFN-free, RBV-free therapy between cirrhotic and noncirrhotic subjects. mRNA and microRNA (miRNA) expression analyses were performed on paired pre- and post-treatment liver biopsies from genotype-1 HCV subjects treated with sofosbuvir/ledipasvir (SOF/LDV) for 12 weeks (n = 4, 3 cirrhotics) or SOF/LDV combined with GS-9669 or GS-9451 for 6 weeks (n = 6, 0 cirrhotics). Nine of ten subjects achieved a sustained virologic response (SVR), while one noncirrhotic subject relapsed. Hepatic IFN-stimulated gene expression decreased with treatment in the liver of all subjects, with no observable impact of cirrhosis. Hepatic gene expression of type III IFNs (IFNL1, IFNL3, IFNL4-ΔG) similarly decreased with treatment, while IFNA2 expression, undetectable in all subjects pretreatment, was detected post-treatment in three subjects who achieved a SVR. Only the subject who relapsed had detectable IFNL4-ΔG expression in post-treatment liver. Other IFNs had no change in gene expression (IFNG, IFNB1, IFNA5) or could not be detected. Although expression of multiple hepatic miRNAs changed with treatment, many miRNAs previously implicated in HCV replication and IFN signalling had unchanged expression. In conclusion, favourable treatment outcome during IFN-free HCV therapy is associated with changes in the host IFN response regardless of cirrhosis.

Autoerotic death due to electrocution.

Autoerotic death is a very rare case in forensic medicine. It is usually caused by asphyxia, but other reasons are also possible. Herein we present a case of autoerotic death due to electrocution caused by a self-made electrical device. The device was constructed to increase sexual feelings through stimulation of the scrotal area.

Contribution of Cat8 and Sip4 to the transcriptional activation of yeast gluconeogenic genes by carbon source-responsive elements.

The carbon source-responsive element (CSRE) functions as an activating promoter motif of gluconeogenic genes in Saccharomyces cerevisiae. The positively acting regulatory genes CAT8 and SIP4 encode CSRE-binding proteins which contribute unequally to the regulated expression of a CSRE-dependent reporter gene (85% and 15%, respectively, under conditions of glucose derepression). Deregulated variants of Cat8 and Sip4 are able to bind to the CSRE and allow glucose-insensitive gene activation, even in the absence of the other protein, arguing against the physiological significance of heterodimer formation. Gel retardation assays provide evidence for a different binding affinity of Cat8 and Sip4 to at least some CSRE sequence variants. Both efficient biosynthesis of and transcriptional activation by Sip4 require a functional CAT8 gene, while Cat8 was not dependent on SIP4. Thus, our data suggest that the apparent minor importance of Sip4 may be the result of autoregulatory cross-talk among the isofunctional activators Cat8 and Sip4. The derepression deficiency of a CSRE-dependent reporter gene in a strain lacking the Cat1 (Snf1) protein kinase can be suppressed by Sip4 fused to a strong heterologous activation domain. This finding agrees with the idea that phosphorylation by Cat1 may convert Sip4 into a functional activator.

BRCA1-associated growth arrest is RB-dependent.

BRCA1 is a susceptibility gene for breast and ovarian cancer with growth-inhibitory activity for which the mechanism of action remains unclear. When introduced into cells, BRCA1 inhibits growth of some but not all cell lines. In an attempt to uncover the mechanism of growth suppression by BRCA1, we examined a panel of cell lines for their ability to reduce colony outgrowth in response to BRCA1 overexpression. Of all variables tested, only those cells with wild-type pRb were sensitive to BRCA1-induced growth suppression. In cells with an intact rb gene, inactivation of pRb by HPV E7 abrogates the growth arrest imposed by BRCA1. In accordance with these observations, we found that BRCA1 could not suppress BrdUrd uptake in primary fibroblasts from rb-/- mice and exhibited an intermediate ability to inhibit DNA synthesis in rb+/- as compared with rb+/+ cells. We further found that the BRCA1 protein complexes with the hypophosphorylated form of pRb. This binding is localized to amino acids 304-394 of BRCA1 protein and requires the ABC domain of pRb. In-frame deletion of BRCA1 fragment involved in interaction with pRb completely abolished the growth-suppressive property of BRCA1. Although it has been reported that BRCA1 interacts with p53, we find the p53 status did not affect the ability of BRCA1 to suppress colony formation. Our data suggest that the growth suppressor function of BRCA1 depends, at least in part, on Rb.

Use of serum PIVKA-II (DCP) determination for differentiation between benign and malignant liver diseases.

BACKGROUND: The concentration of Des-gamma-carboxy-prothrombin (DCP) or PIVKA-II has been described to be increased in patients with hepatocellular cancer, along with its elevation in vitamin K deficient states by warfarin or dicoumarol treatment. The aim of the study was to investigate its clinical value in HCC in comparison with alpha-fetoprotein. PATIENTS AND METHODS: Measurements were performed in duplicate in serum of 87 patients with benign (acute/chronic hepatitis B/C/autoimmune, liver cirrhosis B/C/alcoholic) and 154 patients with highly probable (CT, MRT imaging) or histologically proven HCC. Two commercial or research ELISA tests (1: Eitest MonoP-II, Eisai, Tokyo, Japan; 2: Asserachrom PIVKA-II, Stago, France) using murine monoclonal anti-PIVKA-II antibodies were used comparatively and compared with a laboratory-developed conventional AFP-RIA. RESULTS: By ROC analysis, a highly significant discrimination (p < 0.0001) was found at cutoffs of 0.09 AU/ml (Eisai) or 0.8 ng/ml (Stago) at a specificity of about 90% (Eisai: s = 78.6%, ppv = 0.92, npv = 0.70; Stago: s = 77.9%, ppv = 0.93, npv = 0.70) compared with the AFP-test at a cutoff of 45 ng/ml (sp = 91%, s = 58.4%, ppv = 0.92, npv = 0.55). A higher significant correlation was seen between both DCP tests in malignant (rS = 0.89, p < 0.0001) than benign groups (rS = 0.41, p < 0.001) and a lower correlation between the AFP and Eisai (rS = 0.27/0.36, p < 0.01) and Stago test for the malignant group (0.16; p < 0.05). CONCLUSION: DCP determination in serum/plasma adds significantly in the discrimination between benign and malignant liver diseases.

[Thrombolytic therapy in pulmonary embolism. Indications and therapeutic strategies]. / Thrombolysetherapie bei Lungenembolie. Indikationsstellung und Behandlungsverfahren.

The absence of significant symptoms and signs makes the diagnosis of pulmonary embolism difficult. Sensitivity and specificity of laboratory tests, chest X-ray, ECG, echocardiography and venous studies is low. Ventilation-perfusion scanning is also often not diagnostic. The combination of several diagnostic techniques, however, and pulmonary angiography confirm the diagnosis. Heparin remains the standard therapy for patients with stable haemodynamics. Thrombolytic therapy is recommended in haemodynamically compromised patients, since it yields accelerated clot lysis and pulmonary reperfusion. In standard dose regimes streptokinase, urokinase and t-PA are equally efficient. t-PA, however, acts more rapidly than the other agents. So far there is no study to prove that thrombolytic therapy significantly reduces mortality in pulmonary embolism.

[Acute pulmonary embolism]. / Akute Lungenembolie.

In the absence of significant symptoms and signs the diagnosis of pulmonary embolism remains difficult. Sensitivity and specificity of laboratory tests, chest x-ray, ECG, echocardiography and venous studies on their own is low. Ventilation-perfusion scanning establishes or excludes the diagnosis only in those patients with "high-probability" or "normal" scanning results. The diagnosis of pulmonary embolism should be made by combining clinical assessment, several diagnostic techniques, and, finally, pulmonary angiography in doubtful cases. Heparin remains the standard therapy for patients with stable hemodynamics. Thrombolytic therapy is recommended in hemodynamically compromised patients. In short-term dose regimens the thrombolytic agents urokinase and rt-PA seem to be equally effective. So far, however, no study has proven that thrombolytic therapy significantly reduces mortality in pulmonary embolism.

[Artificial intravascular oxygenation (IVOX). Application to the treatment of postoperative respiratory failure]. / Artifizielle intravaskuläre Oxygenierung (IVOX). Zur Therapie des postoperativen Lungenversagens.

Very recently, the concept of artificial intracorporeal oxygenation of blood for patients suffering from respiratory failure has been introduced into clinical practice through development of a totally implantable intravascular oxygenator (IVOX). We report on the use of such a device in a patient who developed severe respiratory insufficiency secondary to prolonged hypovolaemic shock and pneumonia following successful repair of a ruptured abdominal aortic aneurysm in September, 1990. Postoperatively, severe hypoxaemia occurred (AaDO2 548-602 torr) despite extensive mechanical ventilatory support. There was no obvious chance to overcome this situation by conventional therapeutic measures and the decision was made to institute IVOX therapy. Hypoxaemia was resolved immediately and both FiO2 and tidal volume could be reduced within hours. The patient's respiratory condition continued to improve over the next days leading to termination of IVOX therapy after 71 hours. However, the necessity of long-term ventilatory support secondary to recurrent pneumonia and sepsis, multiple abdominal reoperations for ischemic colitis and retroperitoneal abscess prolonged his recovery. He was discharged from the hospital after four months and is alive and well now 14 months after his operation. He is the first long-term survivor after IVOX therapy in Europe. IVOX may be successfully used in selected patients while the indications and it's potential role in the therapy of severe respiratory failure still need to be defined.

[Experimental studies of administration of perfluoroalkane to the anterior chamber and vitreous body of rabbits]. / Badania doswiadczalne nad zastosowaniem perfluoroalkanu do komory przedniej i ciala szklistego królika.

Presented are the results of experimental investigations evaluating the influence of perfluoroalcane on the ocular tissue in rabbits. The examined animals were divided into 2 groups. The rabbits from the first one received the compound into the anterior chamber of the right eye, the rabbits from the 2-nd group to the vitreous of the right eye. The left eye was the control one. Evaluated was the degree of absorption of the compound from the anterior chamber and vitreous, its influence on the anterior segment, transparency of the lens and intraocular pressure. An ERG was performed before the application of the compound and after 7, 14 and 49 days; subsequently the eyes were excised and a histopathological examination was performed in a light microscope.

Effects of clonidine and nifedipine on left ventricular hypertrophy and muscle mass in hypertensive patients.

In a parallel group randomized trial we compared the echocardiographically documented effects of clonidine (cl) versus nifedipine (nf) on left ventricular hypertrophy (LVH) and muscle mass (LVM) in hypertensive subjects. Twenty-one patients with concentric LVH (thickness of interventricular septum, IVS, and left posterior wall, LPW, above 11 mm) were given a 2D and M-mode echocardiogram before (pre) and 12 and 24 weeks, respectively, after therapy was initiated (mean oral cl dosage 150 micrograms; nf, 30 mg/day). At the end of the follow-up period in the cl group blood pressure declined by an average of 16/11 mm Hg compared with 30/20 mm Hg in the nf group (intergroup differences, NS). The thickness of the IVS decreased from a mean of 15.0 +/- 1.9 mm and 15.1 +/- 1.5 pre-therapy to 12.6 +/- 2.3 for cl (p = 0.0001) and 13.1 +/- 1.5 mm for nf (p = 0.001) after 24 weeks, respectively. This was similar to the regression of the LV posterior wall with 14.7 +/- 1.5 and 14.5 +/- 1.6 mm pre-therapy to 12.0 +/- 1.1 in the cl group (p = 0.0001) and 12.7 +/- 1.7 for nf (p = 0.006). As the internal LV-diameter were relatively constant over the treatment period, the calculated values for LVM dropped from a mean of 406.5 +/- 125.9 and 401.4 +/- 106.6 to 274.8 +/- 78.7 and 297.5 +/- 85.0 g, respectively, corresponding to -31.6 +/- 11.0% for cl (p = 0.0001) and -25.2 +/- 12.6% for nf (p = 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)