Liver fibrosis-induced muscle atrophy is mediated by elevated levels of circulating TNFα

Liver cirrhosis is a critical health problem associated with several complications, including skeletal muscle atrophy, which adversely affects the clinical outcome of patients independent of their liver functions. However, the precise mechanism underlying liver cirrhosis-induced muscle atrophy has not been elucidated. Here we show that serum factor induced by liver fibrosis leads to skeletal muscle atrophy. Using bile duct ligation (BDL) model of liver injury, we induced liver fibrosis in mice and observed subsequent muscle atrophy and weakness. We developed culture system of human primary myotubes that enables an evaluation of the effects of soluble factors on muscle atrophy and found that serum from BDL mice contains atrophy-inducing factors. This atrophy-inducing effect of BDL mouse serum was mitigated upon inhibition of TNFα signalling but not inhibition of myostatin/activin signalling. The BDL mice exhibited significantly up-regulated serum levels of TNFα when compared with the control mice. Furthermore, the mRNA expression levels of Tnf were markedly up-regulated in the fibrotic liver but not in the skeletal muscles of BDL mice. The gene expression analysis of isolated nuclei revealed that Tnf is exclusively expressed in the non-fibrogenic diploid cell population of the fibrotic liver. These findings reveal the mechanism through which circulating TNFα produced in the damaged liver mediates skeletal muscle atrophy. Additionally, this study demonstrated the importance of inter-organ communication that underlies the pathogenesis of liver cirrhosis.Subject terms: Mechanisms of disease, Diseases     

Class-Specific Antibody Response in Acyclovir-Treated and Adenine Arabinoside-Treated Patients with Primary Genital Herpes Simplex Virus Infection

Herpes simplex virus (HSV) class-specific antibody responses after primary genital herpes infection were evaluated with an enzyme-linked immunosorbent assay (ELISA) in 16 patients treated with acyclovir (ACV), given orally, and 17 patients treated with adenine arabinoside (Ara-A), given topically. ACV significantly suppressed the levels of IgM, IgA, and IgG. In the ACV-treated patients, IgM and IgG were not detected in 4 of the 16 and in 1 of the 16 patients, respectively. We must take into account this suppressive effect of ACV on antibody responses, especially on the IgM response, when serodiagnosis of HSV infection is made.     

Clinical application of recombinant human erythropoietin for treatments in patients with head and neck cancer

Summary The therapeutic effects of intravenous recombinant human erythropoietin (r-hEPO) administration on anemia induced by radiation therapy (3 cases), chemotherapy (18 cases) and combined therapies (5 cases) in patients with head and neck malignancies were examined. The effectiveness was evaluated by the changes in the hemoglobin concentration examined before and after the r-hEPO administration. The r-hEPO administration combined with anticancer therapies improved anemia induced by all three treatments. The therapeutic effectiveness of r-hEPO injection was also noted on anemia induced by all of four different chemotherapeutic regimens that have been ordinarily used for head and neck malignancies. Furthermore, the efficacy of the different dose schedules, 3000 IU (12 cases) or 6000 IU (14 cases), three times a week, was compared. Both of the r-hEPO dose schedules were effective for anemia, but the efficacy of 6000 IU was superior to that of 3000 IU. No significant changes were observed in the number of white blood cells and platelets and the results of biochemical examinations after the r-hEPO injection. There were no objective side-effects related to the r-hEPO administration. These results suggest that anemia induced by chemotherapy and/or radiotherapy could be prevented by r-hEPO administration. The addition of r-hEPO to anticancer therapies would make it possible to pursue the planned therapeutic schedules, prevent the decrease of immunity after allogeneic blood transfusion and bring about an improvement in the prognosis of patients with malignancies.     

Locus prl5 improves lodging resistance of rice by delaying senescence and increasing carbohydrate reaccumulation.

We investigated the reason for carbohydrate retention in the stem of rice (Oryza sativa L.) at full-ripe stage in a near-isogenic line (NIL63) carrying prl5, which confers lodging resistance without yield loss. NIL63 showed higher lodging resistance than Nipponbare (control) without reduced yield. At heading, the carbohydrate content in the NIL63 stem (culm and leaf sheathes) was the same as in Nipponbare. At 2 weeks after heading, the carbohydrate content in NIL63 was significantly higher than in Nipponbare. At 4 weeks after heading, the carbohydrate content in NIL63 had decreased to near the level in Nipponbare. At 6 weeks after heading, NIL63 showed higher carbohydrate reaccumulation. Chlorophyll degradation in the leaf blades of NIL63 was slower, and the chlorophyll content at 6 weeks after heading was higher than in Nipponbare. These results suggest that the delay in leaf senescence by prl5 results in carbohydrate reaccumulation in the stem after grain filling, increasing lodging resistance.     

A 460-kb DNA Sequence of the Escherichia coli K-12 Genome Corresponding to the 40.1-50.0 min Region on the Linkage Map

The 465,813 base pair sequence corresponding to the 40.1–50.0min region on the genetic map of Escherichia coli K-12 (W3110)was determined. Analysis of the sequence revealed that thisregion contained at least 466 potential open reading frames,of which 187 (40%) were previously reported, 105 (23%) werehomologous to other known genes, 103 (22%) were identical orsimilar to hypothetical genes registered in databases, and theremaining 71 (15%) did not show a significant similarity toany other gene. At the 45.2–46.0 min region, we founda very large cluster of about 30 genes, whose functions areinvolved in the biosynthesis of polysaccharides as the componentsof outer membranes. In addition, we identified anew asn-tRNAgene, designated asnW, between the asnT and asnU genes and anew lysogenic phage attachment site as the cis-element.     

Herpes Simplex Virus-Specific IgM,IgA and IgG Subclass Antibody Responses in Primary and Nonprimary Genital Herpes Patients

To clarify the humoral immunity in herpes simplex virus (HSV) infection, HSV-specific IgM, IgA and IgG subclass antibody responses were studied in patients with genital herpes: 17 primary, 13 recurrent and 6 nonprimary first episode. A total of 181 serum samples serially collected from the patients, 5 per patient until 213 days after the onset of disease (on average), were analyzed by an enzyme-linked immunosorbent assay. IgGl, IgG3 and IgA were detected in all patients with primary and nonprimary infections, whereas IgG4 was detected in 74% of only those with nonprimary infections and IgG2 was detected in none. IgM was detected in 100% of the patients with primary infections, but also in 68% of those with nonprimary infections. IgA showed a peak similar to that of IgM in patients with primary infections. No significant difference was observed in the detection rate or pattern of antibody responses between the recurrent and nonprimary first episode infections, nor between the HSV-1 and HSV-2 infections. These findings may be useful to improve the diagnostic potential of HSV serology.