Novel water-soluble block copolymers of dimethylaminoethyl methacrylate and dihydroxypropyl methacrylate

In this publication we describe the synthesis and properties of a novel type of block copolymer. The anionically synthesised block copolymer consists of a neutral, watersoluble block (2,3-dihydroxypropyl methacrylate, HMA) and a pH-dependently charged one (2-dimethylaminoethyl methacrylate, AMA). The adsorption on silica and its effect on the colloidal stability were evaluated. The adsorbed amount is mainly determined by the electrostatics, which leads to a maximum adsorbed amount at low AMA content. The block copolymers tend to destabilise colloidal silica, due to a charge neutralisation upon adsorption, which is not compensated by the formation of a steric layer.     

Recurrence of blackwater fever: triggering of relapses by different antimalarials

Five cases of blackwater fever (BWF) are described, all of whom had a history of recent quinine therapy. In two cases a second haemolytic crisis was induced by halofantrine, in one case also a third. Increasing frequency of this syndrome with its dramatic clinical presentation is to be expected as imported P. falciparum infection, parasite resistance to chloroquine and the use of quinine and other related antimalarials become more frequent.     

Back extensor muscle oxygenation and fatigability in healthy subjects and low back pain patients during dynamic back extension exertion

The purpose of this study was to assess if chronic low back pain patients have impaired paraspinal muscle O₂ turnover and endurance capacity as compared to healthy control subjects during dynamic exercise. Middle-aged healthy male subjects (n = 12, control) and male patients with chronic low back pain (n = 17, CLBP) participated in the study. L4–L5 level paraspinal muscle fatigue was objectively assessed during earlier validated 90 s dynamic back endurance test (spectral EMG, MPF_slope). Also EMG amplitude (EMG_amplitude) and initial MPF (MPF_initial) were assessed from the initial 5 s of the endurance contraction. Simultaneously near infrared spectroscopy (NIRS) was used for quantitative measurement of local L4–L5 paraspinal muscle O₂ consumption. Subcutaneous tissue thickness (ATT) was measured from the EMG and NIRS recording sites. The results indicated that control and CLBP groups were compatible as regarding anthropometric variables, paraspinal muscle activation levels (EMG_amplitude), initial MPF (MPF_initial) and ATT. When the ATT was used as a covariate in the ANOVA analysis, CLBP group did not show significantly greater paraspinal muscle fatigability (right MPF_slope – 12.2 ± 10.7%/min, left right MPF_slope – 12.6 ± 13.3%/min) or O₂ consumption (right NIRS_slope – 52.8 ± 79.6 μM/l/s) as compared to healthy controls (right MPF_slope – 11.9 ± 7.6%/min, left MPF_slope – 12.7 ± 8.6%/min, right NIRS_slope – 53.7 ± 95.2 μM/l/s). As a conclusion, these CLBP male patients did not show any impaired rate of paraspinal muscle oxygen consumption or excessive paraspinal muscle fatigability during dynamic exercise as compared with healthy controls. Subcutaneous tissue thickness has a strong influence on the NIRS and EMG amplitude measurements and, if unchecked, it could result in the false interpretation of the results.     

Selective sequestration of X4 isolates by human genital epithelial cells: Implication for virus tropism selection process during sexual transmission of HIV

X4 and R5 HIV strains are present in the semen of men infected with HIV but R5 isolates are transmitted preferentially. The role of human epithelial cells in this selection is addressed. Three human cervical cell lines-CaSki, SiHa, and HEC1A-and normal human vaginal cells from HIV-negative donors were characterized for HIV receptor expression and incubated with X4 and R5 laboratory-adapted strains or primary isolates. The infection was assessed by detection of intracellular HIV DNA. The three cell lines were shown to express on their surface the CXCR4 and GalCer molecules, but not the CD4 and CCR5 ones. The three cell lines and normal human vaginal cells were found to be selectively permissive to X4 HIV entry; the preincubation of the cell lines with rhSDF-1 inhibited this infection. The detection of the intracellular proviral DNA in the cell lines and in normal human vaginal cells demonstrated a selective integration of X4 strains. Additional experiments showed that no extracellular RNA was detected in the supernatants of HEC1A cells infected by X4 isolates either after 18 days of culture or after incubation with PHA-stimulated PBMCs and that no transmission occurred after co-culture between infected HEC1A cells and PHA-stimulated PBMCs. These results suggest specific sequestration of X4 strains by genital epithelial cells, which could explain, at least in part, the HIV tropism selection process during sexual intercourse.     

Early Impairment of CD8+ T Cells Immune Response Against Epstein–Barr Virus (EBV) Antigens Associated with High Level of Circulating Mononuclear EBV DNA Load in HIV Infection

Immunodeficiency related to HIV may increase the incidence of EBV-associated lymphomas, by altering EBV-specific immune control and consequently favoring EBV reactivation. The aim of the present study was to assess the relationship between the decrease of EBV-specific cellular immunity and the increase of EBV reactivation in a prospective cohort of 72 unselected HIV-infected individuals. EBV-specific immunity was evaluated by a highly sensitive IFN-gamma ELISPOT assay using 22 peptides mimicking latent and lytic antigens, and circulating mononuclear (PBMC) EBV DNA load was quantified by real-time quantitative PCR. The mean circulating cell-associated EBV DNA load was higher in HIV-infected patients (639 copies/10(6) PBMC) than in healthy controls (21, n = 14) ( P = 0.005) and was higher in patients with CD4(+) T-cell count below 350/microL than that in patients harboring higher CD4(+) T-cell count (1112 vs. 389, P = 0.003). The mean intensity of EBV-specific cellular responses was lower in HIV-infected patients than in controls ( P = 0.001), even in patients with CD4(+) T-cell count above 350/-microL ( P = 0.007). The number of EBV peptides recognized was lower in HIV-infected patients than in controls (frequency: 0.44 vs. 0.67; P = 0.02), indicating reduced polyclonality in HIV-infected patients. The polyclonality was 1.5-fold lower in HIV-infected patients with CD4(+) T-cell count below 350/-microL ( P =0.007). For EBV load >1000 copies/10(6) PBMC, the levels of cell-associated EBV DNA and those of EBV-specific cellular immunity, either in intensity or in polyclonality, or both, were inversely correlated. These findings demonstrate early impairment of the EBV-specific cellular immune control with progressive increase of EBV reactivation in the course of HIV infection. These observations likely provide a basis for appreciating the risk to develop non-Hodgkin's lymphomas in HIV-infected individuals.     

Comparison of once-daily atazanavir with efavirenz, each in combination with fixed-dose zidovudine and lamivudine, as initial therapy for patients infected with HIV

BACKGROUND: Atazanavir, an azapeptide protease inhibitor (PI), has pharmacokinetics that allow once-daily dosing, and it is not associated with significant PI-associated dyslipidemia. METHODS: A randomized, double-blind, double-dummy, active-controlled, 2-arm study comparing the antiviral efficacy and safety of atazanavir 400 mg administered once daily with efavirenz 600 mg administered once daily in combination with open-label fixed-dose zidovudine plus lamivudine twice daily. The 810 treatment-naive patients were stratified by HIV RNA level. The primary efficacy end point was the proportion of treated patients with HIV RNA levels <400 copies/mL through week 48. RESULTS: At week 48, HIV RNA levels were <400 copies/mL in 70% of patients receiving atazanavir and 64% of patients receiving efavirenz (intent-to-treat, difference; 95% confidence interval: 5.2%; -1.2%, 11.7%). Median CD4 cell counts increased at comparable magnitudes and rates in the 2 treatment arms (mean change at week 48: 176 cells/mm with atazanavir, 160 cells/mm with efavirenz). Atazanavir-treated patients relative to comparator-treated patients did not demonstrate significant increases in total cholesterol, fasting low-density lipoprotein cholesterol, or fasting triglycerides over 48 weeks of therapy. Atazanavir-linked bilirubin elevations infrequently resulted in treatment discontinuation (<1%). Atazanavir treatment did not increase fasting glucose or insulin levels. CONCLUSIONS: For initial HIV treatment, a highly active antiretroviral therapy regimen of atazanavir/zidovudine/lamivudine is as efficacious and well tolerated as the combination of efavirenz/zidovudine/lamivudine.     

A new inborn error of glycosylation due to a Cog8 deficiency reveals a critical role for the Cog1-Cog8 interaction in COG complex formation

The hetero-octameric conserved oligomeric Golgi (COG) complex is essential for the structure/function of the Golgi apparatus through regulation of membrane trafficking. Here, we describe a patient with a mild form of a congenital disorder of glycosylation type II (CDG-II), which is caused by a homozygous nonsense mutation in the hCOG8 gene. This leads to a premature stop codon resulting in a truncated Cog8 subunit lacking the 76 C-terminal amino acids. Mass spectrometric analysis of the N- and O-glycan structures identified a mild sialylation deficiency. We showed that the molecular basis of this defect in N- and O-glycosylation is caused by the disruption of the Cog1-Cog8 interaction due to truncation. As a result, Cog1 deficiency accompanies the Cog8 deficiency, preventing assembly of the intact, stable complex and resulting in the appearance of smaller subcomplexes. Moreover, levels of beta1,4-galactosytransferase were significantly reduced. The defects in O-glycosylation could be fully restored by transfecting the patient's fibroblasts with full-length Cog8. The Cog8 defect described here represents a novel type of CDG-II, which we propose to name as CDG-IIh or CDG caused by Cog8 deficiency (CDG-II/Cog8).     

Genomic and phylogenetic analyses of murine adenovirus 2

Murine adenoviruses (MAdV) are supposedly the oldest members of the genus Mastadenovirus. Currently, there are three distinct MAdV types known with rather different tropism and pathology. Here we report and annotate the DNA sequence of the full genome of MAdV-2. It was found to consist of 35,203 bp thus being considerably larger than the genomes of the other two MAdV types. The increased size of the MAdV-2 genome is generally due to larger genes and ORFs, although some differences in the number of ORFs were observed for the early regions E1, E3 and E4. The homologue of the 19K gene of E1B from MAdV-2 codes for 330 amino acids (aa) and is almost twice as large as from other mastadenoviruses. Accordingly, only the N-terminal half (155aa) has homology to the 19K protein. A homologue of the gene of the 12.5K protein was identified in the E3 region of MAdV-2, but not in MAdV-1 or MAdV-3. The other gene of yet unknown function in the E3 region of MAdV-2 seems to be unique. The E4 region of MAdV-2 contains three ORFs. One has similarity to the 34K gene of other AdVs. Two unique ORFs in the E4 region of MAdV-2 have no homology to any of the five and six ORFs in the E4 region of MAdV-1 or MAdV-3, respectively. Phylogenetic analyses showed that the three murine AdVs have a close common ancestor. They likely formed the first branching of the lineage of mastadenoviruses, and seem to be the most ancient representatives of this genus.