In schizophrenia,non-remitters and partial remitters to treatment with antipsychotics are qualitatively distinct classes with respect to neurocognitive deficits and neuro-immune biomarkers: results of soft independent modeling of class analogy

Around one third of schizophrenia patients are non-responders to antipsychotic therapy. The present study aimed to delineate the pathway-phenotypes of non-remitters (NRTT) and partial remitters (PRTT) to treatment with antipsychotics as defined using the Global Clinical Impression scales. We recruited 60 NRTT, 50 PRTT and 43 healthy controls and measured schizophrenia symptoms, neurocognitive tests, plasma CCL11, interleukin-(IL)-6, IL-10, Dickkopf protein 1 (DKK1), high mobility group box-1 protein (HMGB1), κ- and μ-opioid receptors (KOR and MOR, respectively), endomorphin-2 (EM-2), and β-endorphin. Soft independent modeling of class analogy (SIMCA) showed that NRTT and PRTT are significantly discriminated with a cross-validated accuracy of 94.7% and are qualitatively distinct classes using symptomatome, and neuro-immune-opioid-cognitome (NIOC) features as modeling variables. Moreover, a NIOC pathway phenotype discriminated PRTT from healthy controls with an accuracy of 100% indicating that PRTT and controls are two qualitative distinct classes. Using NIOC features as discriminatory variables in SIMCA showed that all PRTT were rejected as belonging to the normal control class and authenticated as belonging to their target class. In conclusion, a non-response to treatment can best be profiled using a SIMCA model constructed using symptomatome and NIOC features. A partial response should be delineated using SIMCA by authenticating patients as controls or PRTT instead of using scale-derived cut-off values or a number of scale items being rated mild or better. The results show that PRTT is characterized by an active NIOC pathway phenotype and that both NRTT and PRTT should be treated by targeting neuro-immune and opioid pathways.

     

The pipeline of new anticancer agents for breast cancer treatment in 2003

In recent years, strategy in cancer therapy in general, and breast cancer in particular, has been the use of maximum tolerated doses of toxic non-specific agents as well as the investigation of a range of new agents that specifically target tumor-related molecules, in a variety of biological pathways. The trial of chemotherapy (CT) versus chemotherapy+trastuzumab (Herceptin) in HER-2-overexpressing metastatic breast cancer (MBC) was one of the first to use a biological agent in combination with chemotherapy with success and, together with some trials of taxanes in anthracycline-resistance patients one of the few to demonstrate an overall survival (OS) advantage in MBC. Five main molecular pathways are of particular interest in terms of new drug development in breast cancer: the estrogen receptor (ER) pathway, the tyrosine kinase signal transduction pathway, the cell cycle regulation pathway, the apoptosis pathway and the angiogenesis pathway. This review will focus on new agents, cytotoxic, hormonal and molecular-targeted, which are in advanced clinical stages of development for the treatment of MBC.     

Observations on cattle schistosomiasis in the Sudan, a study in comparative medicine. V. The effect of praziquantel therapy on naturally acquired resistance to Schistosoma bovis

Studies in the White Nile area of the Sudan have shown that Zebu cattle acquire a high degree of resistance to Schistosoma bovis as a result of repeated natural exposures without, however, being able to eliminate their populations of adult schistosomes, although these do show greatly suppressed fecundity. To test whether these adult worms are necessary for the maintenance of resistance we cured six "naturally resistant" cattle (TC group) with a double treatment of 25 mg/kg praziquantel and compared their response to a 70,000 cercariae challenge with groups of "naturally resistant" but untreated cattle (UC group) and with previously unexposed, challenged cattle (CC group). Challenge was carried out 7 weeks after the second dose of praziquantel. The results confirmed that untreated cattle are "naturally resistant" and also showed that resistance was not abrogated by cure of the naturally-acquired infections. Thus, fecal egg counts after challenge reached mean maxima of 2,432 eggs per gram (epg) in the CC, but only 5 epg and 28 epg in the TC and UC groups, respectively. Similarly, mean worm counts were 85% and 69% lower in the TC and UC groups, respectively, and mean tissue egg densities were reduced by 72-99%, and 56-80%. Histopathologically, the TC and UC groups were also far less affected than the CC. Effective praziquantel treatment does therefore not destroy naturally acquired resistance to S. bovis, and may benefit infected livestock even in the absence of transmission control. The situation in human schistosomiasis is less clear, but there are several epidemiological and experimental indications of a similar conclusion for S. mansoni.     

Serological studies in the elderly.

Sera from 108 elderly patients in psychiatric and general hospitals were tested for antibodies to seven viruses. Measles virus antibody levels were significantly higher in patients from the psychiatric hospital, regardless of diagnosis, than in those from other hospitals. Demented patients, regardless of their hospital, had significantly higher levels of antibody to adenovirus than control patients.     

Liver regeneration is not altered in patients with nonalcoholic steatohepatitis (NASH) when compared to chronic hepatitis C infection with similar grade of inflammation

Fatty infiltration is associated with an increased incidence of complications and mortality after liver resection and transplantation. The aim of this study was to document the regenerative response in patients with hepatic steatosis and mild inflammatory activity (NASH) and to identify potential levels of impaired regeneration. Ki-67 immunostaining was similar in patients with NASH (ages 44.6 ± 15 years, labeling index, 0.4 ± 0.3%) when compared to patients with chronic hepatitis C infection (ages 50.7 ± 17 years, labeling index; 0.4 ± 0.7%). The labeling index was not increased in patients with a higher level of inflammation, a higher level of fibrosis, and a higher level of fat in either study group. In conclusion, liver regeneration is not altered in patients with nonalcoholic steatohepatitis, suggesting that the delayed postoperative liver failure seen in these patients may be related to another mechanism.     

Multi-Step Regulation of Interferon Induction by Hepatitis C Virus

Acute hepatitis C virus (HCV) infection evokes several distinct innate immune responses in host, but the virus usually propagates by circumventing these responses. Although a replication intermediate double-stranded RNA is produced in infected cells, type I interferon (IFN) induction and immediate cell death are largely blocked in infected cells. In vitro studies suggested that type I and III IFNs are mainly produced in HCV-infected hepatocytes if the MAVS pathway is functional, and dysfunction of this pathway may lead to cellular permissiveness to HCV replication and production. Cellular immunity, including natural killer cell activation and antigen-specific CD8 T-cell proliferation, occurs following innate immune activation in response to HCV, but is often ineffective for eradication of HCV. Constitutive dsRNA stimulation differs in output from type I IFN therapy, which has been an authentic therapy for patients with HCV. Host innate immune responses to HCV RNA/proteins may be associated with progressive hepatic fibrosis and carcinogenesis once persistent HCV infection is established in opposition to the IFN system. Hence, innate RNA sensing exerts pivotal functions against HCV genome replication and host pathogenesis through modulation of the IFN system. Molecules participating in the RIG-I and Toll-like receptor 3 pathways are the main targets for HCV, disabling the anti-viral functions of these IFN-inducing molecules. We discuss the mechanisms that abolish type I and type III IFN production in HCV-infected cells, which may contribute to understanding the mechanism of virus persistence and resistance to the IFN therapy.     

Paleopathology of the juvenile Pharaoh Tutankhamun—90th anniversary of discovery

Modern paleopathology is a multidisciplinary field of research which involves archaeology, medicine and biology. The most common diseases of Ancient Egypt were traumatic injuries, malaria and tuberculosis. Exemplarily, an internistic and trauma surgery case of that time is reviewed: Pharaoh Tutankhamun (ca. 1330–1324 B.C.). Summarising all findings which have been collected between 1922 and 2010, including computed tomography and molecular pathology, a diversity of disease is verifiable: (1) chronic/degenerative diseases (mild kyphoscoliosis, pes planus and hypophalangism of the right foot, bone necrosis of metatarsal bones II–III of the left foot); (2) inflammatory disease (malaria tropica, verified by PCR analysis) and (3) acute trauma (complex fracture of the right knee shortly before death). The most likely cause of death is the severe acute knee fracture and/or the malaria, while a suspected eighteenth dynasty syndrome cannot be proven.     

Mesenchymal stem cell-conditioned medium accelerates regeneration of human renal proximal tubule epithelial cells after gentamicin toxicity

Bone marrow-derived mesenchymal stem cells (MSCs) have the capacity to regenerate renal tubule epithelia and repair renal function without fusing with resident tubular cells. The goal of the present project was to investigate the role of MSCs secreted cytokines on tubule cell viability and regeneration after a toxic insult, using a conditionally immortalized human proximal tubule epithelial cell (ciPTEC) line. Gentamicin was used to induce nephrotoxicity, and cell viability and migration were studied in absence and presence of human MSC-conditioned medium (hMSC-CM) i.e. medium containing soluble factors produced and secreted by MSCs. Exposure of ciPTEC to 0–3000 μg/ml gentamicin for 24 h caused a significant dose-dependent increase in cell death. We further demonstrated that the nephrotoxic effect of 2000 μg/ml gentamicin was recovered partially by exposing cells to hMSC-CM. Moreover, exposure of ciPTEC to gentamicin (1500–3000 μg/ml) for 7 days completely attenuated the migratory capacity of the cells. In addition, following scrape-wounding, cell migration of both untreated and gentamicin-exposed cells was increased in the presence of hMSC-CM, as compared to exposures to normal medium, indicating improved cell recovery. Our data suggest that cytokines secreted by MSCs stimulate renal tubule cell regeneration after nephrotoxicity.