Effect of a CCR5 inhibitor on viral loads in macaques dual-infected with R5 and X4 primate immunodeficiency viruses

Human immunodeficiency virus type 1 (HIV-1) fusion with its target cells is initiated by sequential interactions between its envelope glycoprotein, CD4, and a co-receptor, usually CCR5 or CXCR4. Small molecules that bind to CCR5 and prevent its use by R5 HIV-1 strains are now being developed clinically as antiviral drugs. To test whether a block to CCR5 promotes the replication of viruses that enter cells via CXCR4 and are associated with accelerated disease progression, we administered a small molecule CCR5 inhibitor, CMPD 167, to three macaques dual-infected with both R5 (SIVmac251) and X4 (SHIV-89.6P) viruses. CMPD 167 caused a rapid and substantial (on average, 50-fold) suppression of R5 virus replication in each animal. In two of the animals, but not in the third, a rapid, transient, 8- to 15-fold increase in the amount of plasma X4 virus occurred. In neither animal was the increase in X4 viral load sustained throughout therapy, however. These observations may have relevance for the development of CCR5 inhibitors for treatment of HIV-1 infection of humans.     

Baraitser–Winter cerebrofrontofacial syndrome: Report of two adult siblings

Baraitser–Winter cerebrofrontofacial syndrome (BWCS) is a rare, autosomal dominant condition that is characterized by intellectual disability, distinctive craniofacial features, structural brain abnormalities, seizures, microcephaly, hearing loss, and ocular colobomas. The first three cases were described in 1988 by Baraitser and Winter and included two siblings and an unrelated third patient. Subsequently, causative missense variants in the ACTB and ACTG1 genes were identified, with de novo occurrence in patients with the condition. Herein, we describe two adult siblings who were born to unaffected parents and who were diagnosed with BWCS in their fourth and sixth decade of life following exome sequencing performed for intellectual disability. We review the literature reports of adult patients with BWCS to document the clinical features and phenotypic variability that can occur later in life. This is the first molecularly confirmed report of germline mosaicism in BWCS and one of only a few reports to describe two BWCS patients belonging to the same family.     

Demystified. Human endogenous retroviruses.

Human endogenous retroviruses (HERVs) are a family of viruses within our genome with similarities to present day exogenous retroviruses. HERVs have been inherited by successive generations and it is possible that some have conferred biological benefits. However, several HERVs have been implicated in certain cancers and autoimmune diseases. This article demystifies these retroviruses by providing an insight into HERVs, their means of classification, and a synopsis of HERVs implicated in cancer and autoimmunity. Furthermore, the biological roles of HERVs are explored.     

Inhibition of allergic airways inflammation and airway hyperresponsiveness in mice by dexamethasone: role of eosinophils,IL-5, eotaxin,and IL-13

BACKGROUND: Glucocorticoids inhibit allergen-induced airway eosinophilia and airway hyperresponsiveness (AHR). Whether glucocorticoids mediate their effects on AHR by inhibiting eotaxin and IL-5, 2 of the principal mediators of eosinophilia, or through IL-13, an important mediator of AHR, has not been established. OBJECTIVE: We sought to investigate the effects of glucocorticoids on airway eosinophilia and the expression of IL-5, eotaxin, and IL-13 in relation to the induction of AHR in a murine model of allergic asthma. METHODS: Dexamethasone (4 mg/kg) and mAbs against eotaxin (80 micro g/kg) and IL-5 (100 micro g/kg) singly and in combination were administered to immunized mice before antigen challenge. Airway responsiveness to methacholine was measured in anesthetized and mechanically ventilated animals. Eotaxin, IL-5, and IL-13 in bronchoalveolar lavage fluid (BALF), lung homogenates, or both were measured by means of ELISA. RESULTS: A single antigen challenge induced AHR that lasted at least 10 days. Eotaxin protein and mRNA levels increased in lung tissue but not in BALF after challenge. IL-5 protein and mRNA levels increased both in BALF and in lung tissue. Dexamethasone reduced airway eosinophilia, AHR, and protein and mRNA for eotaxin and IL-5. Anti-murine eotaxin and anti-IL-5 antibodies alone and in combination reduced the ovalbumin-induced airway eosinophilia significantly but failed to inhibit AHR. Both dexa-methasone and anti-IL-5/anti-eotaxin inhibited the increases in lung IL-13 levels after ovalbumin challenge to a similar extent. CONCLUSION: These findings suggest that the inhibition of AHR by the glucocorticoid dexamethasone does not appear to be explained by effects on eosinophilia, eotaxin, IL-5, or IL-13.     

Predicting the outcome of renal replacement therapy in severe acute renal failure

Continuous renal replacement therapy (CRRT), such as continuous venovenous hemofiltration, has theoretical advantages over intermittent hemodialysis (IHD) that are related to cardiorespiratory stability, metabolic control, and fluid balance allowing nutritional supplementation. However, retrospective and controlled studies fail to show these advantages because of comorbidity associated with triage to CRRT. To compare outcomes using IHD versus CRRT, we applied published risk stratification models (Cleveland Clinic Foundation, Lohr index, and APACHE II) to the 349 patients with acute renal failure requiring renal replacement therapy at University of Michigan over the 2 year period including 1995 and 1996. The Cleveland Clinic Foundation model best predicted overall mortality, but our CRRT patients had excess, unpredicted mortality that was particularly prominent in the lower risk categories. The Lohr clinical score predicted mortality less accurately but also was associated with higher, unpredicted mortality at lower risk scores among the CRRT patients. APACHE II scores did not predict mortality very well among IHD, CRRT, or the combined group of patients. We conclude that the need for CRRT itself predicts mortality over and above that included in published risk models. Either CRRT is associated with some unidentified morbidity (e.g., treatment associated infection) or, more likely, triage to CRRT is associated with as yet unspecified comorbidity not detected in existing risk stratification schemes. It will be important to address these issues in any future studies evaluating outcome or comparing renal replacement therapy modalities among patients with severe acute renal failure.     

Stimulation of human monocyte/macrophage-derived growth factor (MDGF) production by plasma fibronectin

Culture supernatants from human peripheral blood monocytes, isolated free of platelet contamination and cultured in the absence of serum, stimulate DNA synthesis and cell growth in Balb/c 3T3 fibroblasts and bovine aortic smooth-muscle cells. Monocytes cultured in serum-free medium for 24 hours with plasma fibronectin, added as either a surface-attached or soluble molecule, secrete significantly increased amounts of growth-promoting activity. Fibronectin also stimulates an increase in intracellular growth factor content and in protein synthesis by monocytes. Both the enhanced growth-promoting activity and protein synthesis are inhibited by cycloheximide. Thus, fibronectin-monocyte interactions may influence the production of growth-promoting activity by monocytes and contribute to fibroblast and smooth-muscle replication in wound healing, chronic inflammation and atherosclerosis.     

Restriction endonuclease analysis of varicella-zoster vaccine virus and wild-type DNAs

The DNA from several clinical isolates of varicella-zoster virus (VZV) were compared with the DNA from the vaccine strain VZV using three restriction endonucleases: BamHI, BgII, and HpaI. When electrophoresed through an agarose gel, the vaccine DNA digestion pattern was significantly different from the digestion patterns of the wild-type DNAs. Variations in the digestion pattern of the separate clinical isolates were also observed.     

Chromosome triplication found across the tribe Brassiceae

We have used an approximately 8.7-Mb BAC contig of Arabidopsis thaliana Chromosome 4 to trace homeologous chromosome regions in 21 species of the family Brassicaceae. Homeologs of this segment could be identified in all tested species. Painting of pachytene chromosomes of Calepina, Conringia, and Sisymbrium species (2n = 14, 16), traditionally placed in tribe Brassiceae, showed one homeologous copy of the Arabidopsis contig, while the remaining taxa of the tribe (2n = 14-30) revealed three, and three Brassica species (2n = 34, 36, and 38) and Erucastrum gallicum (2n = 30) had six copies corresponding to the 8.7-Mb segment. The multiple homeologous copies corresponded structurally to the Arabidopsis segment or were rearranged by inversions and translocations within the diploidized genomes. These chromosome rearrangements accompanied by chromosome fusions/fissions led to the present-day chromosome number variation within the Brassiceae. Phylogenetic relationships based on the chloroplast 5'-trnL (UAA)-trnF(GAA) region and estimated divergence times based on sequence data of the chalcone synthase gene are congruent with comparative painting data and place Calepina, Conringia, and Sisymbrium outside the clade of Brassiceae species with triplicated genomes. Most likely, species containing three or six copy pairs descended from a common hexaploid ancestor with basic genomes similar to that of Arabidopsis. The presumed hexaploidization event occurred after the Arabidopsis-Brassiceae split, between 7.9 and 14.6 Mya.     

Meta-analysis of four new genome scans for lipid parameters and analysis of positional candidates in positive linkage regions

Lipid levels in plasma strongly influence the risk for coronary heart disease. To localise and subsequently identify genes affecting lipid levels, we performed four genome-wide linkage scans followed by combined linkage/association analysis. Genome-scans were performed in 701 dizygotic twin pairs from four samples with data on plasma levels of HDL- and LDL-cholesterol and their major protein constituents, apolipoprotein AI (ApoAI) and Apolipoprotein B (ApoB). To maximise power, the genome scans were analysed simultaneously using a well-established meta-analysis method that was newly applied to linkage analysis. Overall LOD scores were estimated using the means of the sample-specific quantitative trait locus (QTL) effects inversely weighted by the standard errors obtained using an inverse regression method. Possible heterogeneity was accounted for with a random effects model. Suggestive linkage for HDL-C was observed on 8p23.1 and 12q21.2 and for ApoAI on 1q21.3. For LDL-C and ApoB, linkage regions frequently coincided (2p24.1, 2q32.1, 19p13.2 and 19q13.31). Six of the putative QTLs replicated previous findings. After fine mapping, three maximum LOD scores mapped within 1 cM of major candidate genes, namely APOB (LOD=2.1), LDLR (LOD=1.9) and APOE (LOD=1.7). APOB haplotypes explained 27% of the QTL effect observed for LDL-C on 2p24.1 and reduced the LOD-score by 0.82. Accounting for the effect of the LDLR and APOE haplotypes did not change the LOD score close to the LDLR gene but abolished the linkage signal at the APOE gene. In conclusion, application of a new meta-analysis approach maximised the power to detect QTLs for lipid levels and improved the precision of their location estimate.