Complete or partial seroreversion in immunocompetent individuals after self-limited HCV infection: consequences for transfusion

BACKGROUND: The disappearance of anti-HCV antibodies over time, after a self-limited infection, also referenced seroreversion, has been observed. The frequency of this phenomenon remains controversial, especially in immunocompetent subjects. However, it has important implications in the context of transfusion inquiries, in particular in case of a blood donor suspected to have transmitted HCV through a past blood donation. STUDY DESIGN AND METHODS: Our findings are presented of a longitudinal study, including 16 patients from a cohort of 78 immunocompetent, multitransfused individuals who were positive for anti-HCV (EIA and confirmatory assay [RIBA]) and followed over a long period of time without having received any antiviral therapy. The aim was to establish whether a past and self-resolved HCV infection could evolve toward a negative serology. RESULTS: The 16 patients were classified in three groups: 1) 12 patients who remained anti-HCV positive with no evolution in their RIBA pattern after a mean follow-up of 7.6 years; 2) one patient who presented a complete seroreversion 6 years after enrollment; and 3) three patients with a partial seroreversion over a mean follow-up of 16 years. CONCLUSION: HCV infection is not always characterized by a persistent antibody response, even in immunocompetent individuals. This should be taken into consideration when transfusion inquiries are conducted.     

Effectiveness,Quality of Life,and Cost of Caring for Children in France with Recurrent Acute Rhinopharyngitis Managed by Homeopathic or Non-Homeopathic General Practitioners

Background & Objective

In France, non-homeopathic general practitioners (GPs) often use antibacterials to treat children with recurrent acute viral rhinopharyngitis; whereas homeopathic GPs tend to use homeopathic medicines. We compared the effectiveness, the quality of life of the parents, and the direct and indirect costs associated with treatment from homeopathic and non-homeopathic GPs.

Method

We assessed the direct (consultations, medicines, further tests) and indirect (time off work) costs of the two types of treatment to society, the patient, and social security. We also assessed the effectiveness of the treatment received and the quality of life of the parents.

Results

Of the 499 children included, 231 were treated by 62 non-homeopathic GPs and 268 by 73 homeopathic GPs. The effectiveness (assessed as complications/patient, total number of adverse events, and quality of life) [mean overall Parents of children with Ear, Nose, and Throat infections Quality of Life questionnaire© scale score] was better in the homeopathic GP group than in the non-homeopathic GP group. No significant difference was found between the two groups for the total costs to social security (€98.55 for homeopathic GPs vs €96.17 for non-homeopathic GPs). Homeopathic GPs initiated preventive treatment in 82.2% of their patients and used antibacterials in 20.9% of their patients, while non-homeopathic GPs initiated preventive treatment in 43.3% of patients and prescribed antibacterials for 89.6% of patients.

Conclusion

This study produced new findings that indicate that, in France, acute rhinopharyngitis is handled differently by homeopathic GPs and non-homeopathic GPs: homeopathic GPs prescribe fewer antibacterials than non-homeopathic GPs for the treatment of recurrent acute rhinopharyngitis in children aged between 18 months and 4 years. Moreover, homeopathic treatment gave better results in terms of pragmatic medical effectiveness (fewer episodes and fewer complications) and the parents’ quality of life, with similar total medical costs to social security. However, this study is potentially biased by the lack of homogeneity of the two patient-samples in terms of the ‘passive smoking’, ‘patient age’, ‘childcare’, and ‘type of occupation’ criteria because our study protocol did not provide for prior matching of the two patient-samples with respect to these criteria. The observations found in this study need to be confirmed by randomized clinical trials.

     

A method for simulation of foveal vision during wear of corrective lenses.

PURPOSE: The aim was to simulate the visual appearance of images viewed through corrective lenses having known, arbitrary types and amounts of monochromatic aberration, so that the visual effect of changing the design parameters of the lens could be explored. METHODS: We first calculate the optical response of the eye and any corrective lens using a numerical model eye. We then use this response as a filter, which we convolve with a selected original (unaberrated) image, to obtain an initial simulated retinal image. This image is then deconvolved by a second filter, which is calculated as the optical response of the eye of the observer who views the final image displayed on a video monitor. The originality of our approach to visual simulation is to take the aberrational characteristics of the observer's eye into account in the calculation. We validated our simulation by comparing images degraded by simulated dioptric blur with real defocused images seen through corresponding optical lenses. RESULTS: When using a small (2.5 mm) pupil size and a "typical" observer wavefront aberration model, there was a close resemblance between optical and simulated blurs. Although it was not necessary to consider the measured aberrations of the subject when simulating vision with a small pupil size, this requirement could not be ignored when vision through a larger pupil was simulated. With a 5.7-mm pupil diameter, use of Shack-Hartmann measurements of the ocular aberrations of the individual observers rather than "typical" levels of aberrations for the entire population gave excellent agreement between the effects of simulated and real defocus blur in monochromatic and polychromatic light. A Bland-Altman analysis of the differences between matching simulated and real blurs for a 5.7-mm pupil in polychromatic light with the model including allowance for individual measured aberrations gave mean differences close to zero and 95% confidence limits of about +/-0.25 D over a defocus range of -2.00 to +2.00 D. CONCLUSION: The simulation technique can be expected to be a useful tool to evaluate the potential performance of an eye that wears various designs of corrective lens.     

Functional characterization of genetic polymorphisms identified in the human cytochrome P450 4F12 (CYP4F12) promoter region

The human cytochrome CYP4F12 has been shown to be active toward inflammatory mediators and exogenous compounds such as antihistaminic drugs. In the present study, we report the first investigation of polymorphisms in the human CYP4F12 gene. A screening for sequence variations in the 5'-flanking region was performed by a Polymerase Chain Reaction-Single Strand Conformational Polymorphism (PCR-SSCP) strategy, using DNA samples from 53 unrelated French individuals of Caucasian origin. Several polymorphisms were identified, comprising a large deletion located in intron 1 (CYP4F12*v1), two isolated substitutions -402G>A (CYP4F12*v3) and -188 T>C (CYP4F12*v4) and nine combined mutations, -474T>C, -279A>C, -224A>G, -173G>A, -145C>G, -140T>C, -126T>C, -56T>C, and -21T>G (CYP4F12*v2). Considering the nature and location of the polymorphisms characterizing the CYP4F12*v1 and *v2, the functional relevance of those two allelic variants was further examined by transfecting different cell lines with constructs of the related region of the CYP4F12/luciferase reporter gene. Both alleles lead to a significant decrease of CYP4F12 gene expression in HepG2 cell line and, therefore, are likely to determine interindividual differences in CYP4F12 gene expression.     

On the stability of insulin delivered through a new glucose-responsive polymeric composite membrane

A new glucose-responsive polymeric composite membrane that provided pulsatile insulin release was developed in our laboratory previously. To develop a clinically useful insulin delivery system, this study was designed to investigate factors influencing insulin stability during delivery by this membrane. The effects of stirring, release duration, insulin concentration and surfactant on insulin stability were studied under both incubation and delivery conditions in a buffer solution at 37 degrees C. The structural change of insulin was characterized by reverse-phase HPLC and circular dichroism. Hydrophobicity of various contact surfaces was determined by contact angle measurement. The results indicated that insulin concentration played an important role in the insulin stability, followed by stirring. Treating the membrane with a non-ionic surfactant prevented insulin denaturation during delivery through the membrane.     

Population pharmacokinetics of ibuprofen enantiomers in very premature neonates

The objective of the present study was to evaluate the pharmacokinetic parameters for both S- and R-ibuprofen enantiomers in very premature neonates (gestational age strictly inferior to 28 weeks) and possible relationships between the pharmacokinetic parameters and various covariates. Newborns were randomized to receive ibuprofen or placebo for the prophylactic treatment of patent ductus arteriosus (PDA) at an initial dose of 10 mg/kg ibuprofen within 6 hours after birth, followed by two 5-mg/kg doses at 24-hour intervals (n = 52). If a PDA was still present afterwards, a curative course of ibuprofen using the same dosage regimen was administered (n = 10). A sparse sampling strategy was used because only 2 samples were collected after the third prophylactic injection and 1 after the third curative injection. A model including the chiral transformation of R- to S-ibuprofen was fitted to the concentration-time data using a population approach (NONMEM). R- and S-ibuprofen t(1/2) were about 10 hours and 25.5 hours, respectively. After prophylactic treatment, the mean clearance of R-ibuprofen (CLR = 12.7 mL/h) was about 2.5-fold higher than for S-ibuprofen (CLS = 5.0 mL/h). In addition, clearance of R- and S-ibuprofen increased significantly with gestational age. The mean estimation of R-ibuprofen clearance was found to be higher than for S-ibuprofen, and the clearance of both enantiomers increased with gestational age. This should be considered to assess pharmacokinetic-pharmacodynamic relationships of ibuprofen in premature neonates and subsequently to understand and refine the use of ibuprofen in managing PDA either as a prophylactic or curative treatment.     

Rational understanding of nicotinic receptors drug binding

The atomic determination of the acetylcholine binding protein (AChBP), a molluscan cholinergic protein, homologous to the amino-terminal extracellular domain of nicotinic receptors (nAChRs), offers opportunities for the modeling of the acetylcholine binding site and its ligands. Recently, we constructed three-dimensional models of the N-terminal part of nAChR and docked in the putative ligand-binding pocket, different agonists (acetylcholine, nicotine and epibatidine) and antagonist (snake alpha-bungarotoxin). These hypothetical docking models offer a structural basis for rational design of drugs differentially binding to resting and active (or desensitized) conformations of the receptor site. These models thus pave the way to investigate, at the molecular level, the exciting challenge of the fast ion channel gating mechanisms by nicotinic agonists.     

Inhibition of MUC4 expression suppresses pancreatic tumor cell growth and metastasis

The MUC4 mucin is a high molecular weight membrane-bound glycoprotein. It is aberrantly expressed in pancreatic tumors and tumor cell lines with no detectable expression in the normal pancreas. A progressive increase of MUC4 expression has also been observed in pancreatic intraepithelial neoplasia, suggesting its association with disease development. Here, we investigated the consequences of silencing MUC4 expression in an aggressive and highly metastatic pancreatic tumor cell line CD18/HPAF that expresses high levels of MUC4. The expression of MUC4 was down-regulated by the stable integration of a plasmid-construct expressing antisense-MUC4 RNA. A decrease in MUC4 expression, confirmed by Western blot and immunofluorescence analyses, resulted in diminished growth and clonogenic ability of antisense-MUC4-transfected (EIAS19) cells compared with parental, empty vector (ZEO) and sense transfected (ES6) control cells. In addition, EIAS19 cells displayed a significant decrease in tumor growth and metastatic properties when transplanted orthotopically into the immunodeficient mice. In vitro biological assays for motility, adhesion, and aggregation demonstrated a 3-fold decrease in motility of EIAS19 cells compared with control cells, whereas these cells adhered more and showed an increase in cellular aggregation. Interestingly, MUC4 down-regulation also correlated with the reduced expression of its putative interacting partner, HER2/neu, in antisense-MUC4-transfected cells. In conclusion, the present work demonstrates, for the first time, a direct association of the MUC4 mucin with the metastatic pancreatic cancer phenotype and provides experimental evidence for a functional role of MUC4 in altered growth and behavioral properties of the tumor cell.