Retrospective-prospective study of safety and efficacy of sofosbuvir-based direct-acting antivirals in HIV/HCV-coinfected participants with decompensated liver disease pre– or post–liver transplant

Direct-acting antiviral (DAA) therapy has transformed the management of human immunodeficiency virus (HIV) and hepatitis C (HCV) coinfected patients with advanced liver disease. STOP-Coinfection was a multicenter prospective and retrospective, open-label study using sofosbuvir-based DAA therapy to treat HIV/HCV-coinfected participants pre– or post–liver transplant (LT). Sixty-eight participants with end-stage liver disease (Child-Turcotte-Pugh score ≥7 and Model for End-Stage Liver Disease score 6–29) were enrolled, 26 had hepatocellular carcinoma. Forty-two participants were treated pre–LT and 26 post–LT. All participants completed therapy without need for dose reduction or transfusion; eight required two or more courses of therapy. Ninety-three percent achieved a sustained virologic response and DAA therapy was well tolerated. Despite HCV cure, 12 end-stage liver disease participants required subsequent LT, 7 for decompensated liver disease. Thirteen participants died, 10 with decompensated liver disease pre–LT and three post–LT. Overall, transplant free survival was 42.8% at 4 years and post–LT survival was 87.9% at 5 years. We conclude that sofosbuvir-based DAA therapy is safe and highly effective in HCV-HIV patients with decompensated liver disease and post–LT, with post–LT survival rates comparable to other indications. This removes one of the last barriers to liver transplantation in this challenging cohort of recipients.     

The behavioral genetics ofCaenorhabditis elegans

Caenorhabditis elegans, a small free-living soil nematode, is an ideal organism for the genetic dissection of simple behaviors. Over 150 genes required for normal behavior have been identified. We review here the neural and genetic pathways underlying four of the best-studied C. elegans behaviors: locomotion, response to gentle touch, egg-laying, and chemotaxis. Mutations affecting these behaviors have identified genes which specify neuronal cell lineage, neuronal cell fate, and the formation of cell matrix cues involved in axonal guidance. Molecular analysis of genes required for normal behavior offers the prospect of characterizing functionally important nervous system proteins, regardless of their abundance or biochemical role.     

半胱氨酸蛋白酶抑制剂C在肾脏功能早期损伤评估中的应用

目的:探讨半胱氨酸蛋白酶抑制剂C(Cystatin C)在肾脏功能早期损伤评估中的应用。方法:检测1338例患者Cystatin C、血尿素(Urea)、血肌酐(Scr)和尿微量蛋白(UMP)。结果:Scr在UMP正常和异常组的比较中,P值>0.05;而Cystatin C的P值<0.01。结论:Cystatin C在肾功能早期损伤评估中灵敏度和特异性比Scr高,可作为肾功能早期损伤的标志物。     

Pilot study of an HLA-A2 peptide vaccine using flt3 ligand as a systemic vaccine adjuvant

A pilot vaccine study was conducted to test the safety and immunological efficacy of four monthly immunizations of an MHC class I peptide vaccine, the E75 HLA-A2 epitope from HER-2/neu, using flt3 ligand as a systemic vaccine adjuvant. Twenty HLA-A2-expressing subjects with advanced stage prostate cancer were randomly assigned to one of four immunization or treatment schedules: (a) Flt3 ligand (20 g/kg per day) administered subcutaneously daily for 14 days on a 28-day cycle, monthly for four months; (b) flt3 ligand course as above with the E75 peptide vaccine administered on day 7 of each flt3 ligand cycle; (c) flt3 ligand course as above with the E75 peptide vaccine administered on day 14 of each flt3 ligand cycle; or (d) E75 peptide admixed with granulocyte–macrophage colony-stimulating factor and administered intradermally once every 28 days, as has previously been reported. The primary endpoints of the study were the determination of safety and immunological efficacy in generating E75-specific T cells as determined by peptide-specific interferon-gamma ELIspot. Adverse events included one grade 3 skin reaction and the development of grade 2 autoimmune hypothyroidism in two subjects with preexisting subclinical autoimmune hypothyroidism. Dendritic cells were markedly increased in the peripheral blood of subjects receiving flt3 ligand with each repetitive cycle, but augmentation of antigen-presenting cells within the dermis was not observed. Apart from a single subject, no significant peptide-specific T-cell responses were detected by ELIspot, whereas delayed-type hypersensitivity responses were detectable in control subjects and in subjects receiving peptide vaccine early in the course of flt3 ligand administration. The absence of robust peripheral immune responses in the current study may be attributable to the small numbers of subjects or differences in the subject population. In addition, the inability of flt3 ligand to augment the number of peripheral skin antigen-presenting cells may have contributed to the absence of robust peptide-specific immunity detectable in the peripheral blood of immunized subjects treated with flt3 ligand.     

Polarisation impendance of pacemaker electrodes:in vitro studies simulating practical operation

The electrical properties of pacemaker electrodes were studiedin vitro under conditions prevailing in practical pacemaker operation. Emphasis was laid on a clear distinction between the changing modes of the pacemaker action. During sensing, the electrode can be represented by an a.c. series polarisation resistance and capacitance, generally accepted for biological electrodes obeying linearity rules. During stimulation, the electrode operates in the non-linear region. A nearly constant-voltage, short, rectangular pulse applied directly to the electrode-heart system, causes the electrode voltage and current to respond as a transient exponential, characterised approximately by a single time constant. This response allows modelling of the d.c. equivalent circuit of the electrode, in the form of a polarisation capacitance with a small resistance in series, shunted by a parallel resistance. Formulae were derived for calculation of these elements. The response of the electrode-heart system to a single stimulus was tested as a function of the amplitude and duration of the applied pulse. Also, the effect of repetitive stimulations was checked at a normal pacing rate. A nearly constant-voltage pacing source, as compared with a constant-current one, appears to be advantageous for preservation of the longevity of the electrode.     

激活素A对免疫细胞活性的影响

观察了激活素Ａ对小鼠Ｔ／Ｂ淋巴细胞增殖和ＮＫ细胞毒活性的影响。结果表明，激活素Ａ在１０ｎｇ／ｍｌ条件下，对体外培养的Ｔ／Ｂ淋巴细胞增殖和ＮＫ细胞毒活性有明显的促进作用，与对照组比较具有明显的统计学差异（Ｐ〈０．０５），信号传递系统的研究表明，激活素Ａ有协同ＰＫＣ信号传递系统刺激物ＴＰＡ的促细胞增殖效应，并能促进Ｃａ＾２＋载体Ａ２３１８７的作用，上述资料提示，激活素Ａ可能是通过增加细胞钙离子浓度，激     

Fulminant meningococcal septic shock in a boy with combined inherited properdin and protein C deficiency.

A 7-year-old patient with fulminant septic shock due to Neisseria meningitidis of the uncommon serogroup Y developed extensive gangrene of the limbs. Multiple amputations were necessary and a pulmonary embolism occurred within 2 days post-operatively. Complement and haemostatic system studies, done after recovery, showed a complete absence of properdin antigen and a low protein C antigen and activity level in plasma. Defective haemolytic activity in gel by the alternative pathway of complement activation could be restored with purified properdin, indicating a properdin deficiency type 1. Protein C antigen level as well as activity were in agreement with a protein C deficiency type I. The polymerase chain reaction (PCR) product of exon five of the protein C gene showed a substitution of 72Gly by Arg. Both deficiencies were traced among relatives of the patient. Serum of the father of the patient's mother was also properdin-deficient. Microsatellite haplotyping of the X-chromosome of the patient and his relatives showed that a distinct haplotype cosegregated with the properdin deficiency (Lodscore 2.25; four informative meioses). The protein C type I deficiency was present in the patient's mother and her mother and cosegregated with the mutation found. So far as is known, this is the first patient described with combined inherited properdin deficiency and protein C deficiency.     

The increasing importance of tumor and tissue banks in the light of genomic and proteomic research

Recent technological advances in genome and proteome research offer new perspectives for diagnosis and therapy. The DNA chip technology as well as high-resolution two-dimensional gel electrophoresis in combination with mass spectrometry is able to provide comprehensive information on gene and protein expression patterns, which allow insights into the dynamic and functional aspects of diseases. The application of these techniques depends on the availability of unfixed fresh or cryopreserved tissue with short ischaemia time. For this reason tissue banks are of increasing importance. The pathologist with his expertise and responsibility for histopathological diagnosis, plays a central role in the collection of the human tissues, in accordance with medical, legal and ethical standards, not only for diagnostic purposes, but also for research. The scientific value of a tissue bank is markedly increased if tissue samples are accompanied by detailed patient data as well as blood samples. Informed consent given by the patient is an essential requirement for the use of human tissue banks in biomedical research. The informed consent should not be restricted to scientific investigations but also include the potential commercial use of the data generated.