The watershed-hypothesis of schizophrenia asserts that over 200 different mutations dysregulate distinct pathways that converge on an unspecified common mechanism(s) that controls disease ontogeny. Consistent with this hypothesis, our RNA-sequencing of neuron committed cells (NCCs) differentiated from established iPSCs of 4 schizophrenia patients and 4 control subjects uncovered a dysregulated transcriptome of 1349 mRNAs common to all patients. Data reveal global dysregulation of developmental genome, deconstruction of coordinated mRNA, and mRNA networks, and the formation of aberrant, new coordinated mRNA networks indicating a concerted action of the responsible factor(s). Sequencing of miRNA transcriptomes demonstrated an overexpression of 16 miRNAs and deconstruction of coordinated miRNA–mRNA networks in schizophrenia NCCs. ChiPseq revealed that the nuclear (n) form of FGFR1, a pan-ontogenic regulator, is overexpressed in schizophrenia NCCs and overtargets dysregulated mRNA and miRNA genes. The nFGFR1 targeted 54% of all human gene promoters and 84.4% of schizophrenia dysregulated genes. The upregulated genes reside within major developmental pathways that control neurogenesis and neuron formation, whereas downregulated genes are involved in oligodendrogenesis. Our results indicate (i) an early (preneuronal) genomic etiology of schizophrenia, (ii) dysregulated genes and new coordinated gene networks are common to unrelated cases of schizophrenia, (iii) gene dysregulations are accompanied by increased nFGFR1-genome interactions, and (iv) modeling of increased nFGFR1 by an overexpression of a nFGFR1 lead to up or downregulation of selected genes as observed in schizophrenia NCCs. Together our results designate nFGFR1 signaling as a potential common dysregulated mechanism in investigated patients and potential therapeutic target in schizophrenia.
In this cross-sectional study, 53 cervicovaginal lavage samples (CVL) from 41 women were analyzed for the chemokines interleukin-8 (IL-8), regulated-on-activation normal T-expressed and secreted (RANTES) factor, and macrophage inflammatory protein-1alpha (MIP-1alpha) by enzyme-linked immunosorbent assay (ELISA). IL-8 was detected in 81% of CVL, whereas RANTES was detected in 32%, and MIP-1alpha in 15% of the CVL. The mean levels of IL-8, RANTES, and MIP-1alpha in positive samples were 396 pg/ml, 102 pg/ml, and 34 pg/ml, respectively. IL-8 levels correlated positively with IL-1beta and IgG in a subset of CVL samples. RANTES levels correlated positively with complement protein levels. Additionally, the levels of RANTES, but not MIP-1alpha, reached levels reported in previous studies of the effects of beta chemokines to inhibit HIV replication. These results suggest that measuring chemokines in CVL specimens can provide important information regarding immune responses in the genital tract.
Disseminated Mycobacterium avium complex (MAC) infection is an important late-stage complication of infection with the human immunodeficiency virus. Since MAC is widely dispersed in the environment, the source of infection for patients with disseminated MAC generally cannot be determined. Therefore, specific recommendations for avoiding exposure are not supported at this time. Routine screening of stools and sputum to detect MAC colonization as a means of targeting prophylaxis for disseminated disease is also not recommended at present. Two randomized, placebo-controlled trials have demonstrated that prophylactic use of rifabutin in persons with low CD4 lymphocyte counts results in a 50% decrease in MAC bacteremia as well as a reduction in some signs, symptoms, and laboratory abnormalities associated with MAC disease. Thus a prophylactic daily dose of rifabutin (300 mg) should be considered for adults who have had a previous AIDS-defining opportunistic illness and who have a CD4 lymphocyte count of < 75/microL. Many experts would consider prophylaxis appropriate only when the CD4 lymphocyte count is < 50/microL, particularly when there has not been a previous AIDS-defining opportunistic infection. Clinicians should be aware of drug interactions and potential adverse effects associated with the use of rifabutin. Preliminary reports of randomized, placebo-controlled trials suggest that chemoprophylaxis with clarithromycin is also effective in the prevention of disseminated MAC disease, and evaluation of other agents is under way. Prophylaxis for disseminated MAC infection in children has not been evaluated but is presumed to be as effective as that in adults. Decisions regarding initiation of MAC chemoprophylaxis should be individualized.
The effects of ketoconazole alone and in combination with acyclovir and adenine arabinoside upon the replication of herpes simplex virus types 1 and 2 (HSV-1 and -2) were investigated by using a yield reduction assay. Ketoconazole demonstrated antiviral activity against HSV-1 and -2 and synergistic antiviral activity when it was combined with acyclovir. Combinations of ketoconazole with adenine arabinoside resulted in either interference or indifference. The effects of ketoconazole upon the protein synthesis of HSV-2-infected cells were also determined in an effort to define the mechanism of action for the antiviral activity of ketoconazole. There was no reduction of' HSV proteins when compared with acyclovir. These findings suggest that further investigations of the use of ketoconazole for the treatment of HSV infections are warranted.Recently, several reports have described a novel approach to antiviral chemotherapy with the antifungal' agent amphotericin B. Amphotericin B, a polyene antibiotic, exerts its antifungal effect by binding to sterol components in the fungal cell membrane, which results in increased permeability of the membrane (11). By using the water-soluble the combined effects of amphotericin B and acyclovir upon the replication of pseudorabies virus. Low doses of amphotericin B in combination with acyclovir produced a synergistic reduction in viral replication as shown with a plaque reduction assay. The exact mechanism for this synergistic effect was not elucidated (9).In view of this promising work, we investigated the possibility of antiviral activity for a different antifungal agent, ketoconazole. Ketoconazole is an imidazole compound which' exerts its antifungal activity through inhibition of lanosterol demethylation. This blocks the synthesis of ergosterol, the major sterol component of the fungal cell membrane (2). In mammalian cells, ketoconazole also inhibits lanosterol demethylation, with a subsequent decrease in the biosynthesis of cholesterol, the major sterol component of mammalian cell membranes. In addition, ketoconazole interferes with cellular fatty acid and phospholipid biosynthesis (2). In this study, we examined the effects of ketoconazole alone and in combination with acyclovir and adenine arabinoside upon herpes simplex virus types 1 and 2 (HSV-1 and -2) replication with a yield reduction assay. 107 PFU/ml were grown in monolayers of Vero cells and stored at -70°C.Cells. Vero and human lung (HL) cells (derived from an HL carcinoma) were used in all assays. Vero cells were grown in RPMI 1640 supplemented with 10% inactivated fetal bovine serum, 1% glutamine, 100 U of penicillin per'ml, and 50 jig of streptomycin per ml; and HL cells were grown in Hanks balanced salt solution, basal medium Eagle improved, supplemented with 10% inactivated fetal bovine serum, 1% glutamine, 100 U of penicillin per ml, and 50 ,ug of streptomycin per ml. Maintenance medium for both cell lines was supplemented with 1% inactivated fetal bovine serum in place of 10% inactivated fetal bovine serum.Dr...
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