Heparin coated poly(alkylcyanoacrylate) nanoparticles coupled to hemoglobin: a new oxygen carrier

A new generation of drug delivery systems based on heparin-poly(isobutylcyanoacrylate) copolymers has been developed to carry hemoglobin. These copolymers spontaneously form, in water, nanoparticles with a ciliated surface of heparin. These nanoparticles maintain the heparin antithrombotic properties and inhibit complement activation. One ml of nanoparticle suspension can be loaded with up to 2.1mg of hemoglobin, which preserves its ligand binding capacity. This work constitutes the first demonstration of hemoglobin loaded on nanoparticle surface, rather than being encapsulated. With a size of 100 nm, these drug delivery systems make suitable tools in the treatment of thrombosis oxygen deprived pathologies.     

In vivo efficacy of linezolid in combination with gentamicin for the treatment of experimental endocarditis due to methicillin-resistant Staphylococcus aureus

Indifference or even antagonism has mainly been reported with combinations including linezolid. The presence of in vitro antagonism is not always correlated with in vivo failure. The purpose of this study was to evaluate the in vivo activity of linezolid combined with gentamicin using a methicillin-resistant Staphylococcus aureus (MRSA) endocarditis experimental model. A human-like pharmacokinetic simulation was used for linezolid and gentamicin to improve the extrapolation of the results to human therapy. Contrary to the antagonism previously described in vitro, linezolid combined with gentamicin exhibited bactericidal activity on the two strains with a decrease of at least 4 log(10)cfu/g of vegetation compared with controls. These data suggest that linezolid plus gentamicin could be an appropriate combination for the treatment of severe MRSA infections.     

Altered response to benzodiazepine anxiolytics in mice lacking GABA B(1) receptors

Recently, we demonstrated that mice lacking the GABA(B(1)) subunit were more anxious than wild-type animals in several behavioural paradigms, most notably in the light-dark test. In an attempt to assess the effects of classical benzodiazepine anxiolytics on anxiety-like behaviour observed in these mice, animals were administered either chlordiazepoxide (10 mg/kg, p.o.) or diazepam (7.5 mg/kg, p.o.) prior to testing in the light-dark box. Surprisingly, in contrast with the wild-type mice, neither benzodiazepines decreased anxiety-like behaviour in GABA(B(1))(-/-) mice. These data suggest that targeted deletion of GABA(B(1)) subunit alters GABA(A) receptor function in vivo.     

Role of ultraviolet B irradiance and vitamin D in prevention of ovarian cancer

BACKGROUND: There is a north-south gradient in age-adjusted mortality rates of ovarian cancer in the United States, with the highest rates in the Northeast and the lowest in the South through Southwest. This suggests that lower levels of solar irradiance might be associated with higher risk of ovarian cancer. Laboratory findings also suggest that low levels of vitamin D metabolites could play a role in the etiology of ovarian cancer. METHODS: The association of solar ultraviolet B (UVB) irradiance, stratospheric column ozone, and fertility rates at ages 15 to 19 years with incidence rates of ovarian cancer in 175 countries in 2002 were examined using multiple linear regression in 2006. RESULTS: Age-adjusted ovarian cancer incidence rates generally were highest in countries located at higher latitudes (R(2)=0.45, p< or =0.01). According to multivariate analysis, UVB irradiance (p< or =0.002) and fertility rates at ages 15 to 19 (p=0.01) were inversely associated with incidence rates, while stratospheric ozone (p< or =0.0008), which reduces transmission of UVB, was positively associated with incidence (R(2)=0.49, p<0.0001). CONCLUSIONS: Solar UVB irradiance was inversely associated with incidence rates of ovarian cancer in this study, adding new evidence to the theory that vitamin D might play a role in the prevention of ovarian cancer. Cohort studies are needed to confirm this possible association.     

Toxic death-case after capecitabine + oxaliplatin (XELOX) administration: probable implication of dihydropyrimidine deshydrogenase deficiency

This report here is the case of a 52-year-old male patient who suffered from extremely severe haematological toxicities (G4 neutropenia, G4 thrombocytopenia) while undergoing Xelox (Xeloda + Oxaliplatin) treatment for his multifocal hepatocarcinoma. Despite appropriate supportive treatment, his condition quickly deteriorated and led to death. It was hypothesized that dihydropyrimidine deshydrogenase (DPD) gene polymorphism could be, at least in part, responsible for this fatal outcome. To test this hypothesis, both phenotypic and genotypic studies were undertaken, and fully confirmed the DPD-deficient status of this patient. Uracil to dihydrouracil ratio in plasma was evaluated as a surrogate marker for DPD deficiency, and showed values out of the range previously recorded from a reference, non-toxic population. Interestingly, the canonical IVS14+1G>A single nucleotide polymorphism, usually associated with the most severe toxicities reported with 5-fluorouracil (5-FU), was not found in this patient, but further investigations showed instead a heterozygosity for the 1896C>T mutation located in the exon 14 of the DPYD gene. Taken together, the data strongly suggest for the first time that a toxic-death case after capecitabine-containing protocol could be, at least in part, linked with a DPD-deficiency syndrome. The case reported here warrants therefore systematic detection of patients at risk, including when oral capecitabine is scheduled.     

An efficient proteomics-based approach for the screening of autoantibodies

This study presents an improved method for the complete transfer of proteins separated by two-dimensional gel electrophoresis to a membrane, specifically designed for the screening and identification of antigens recognized by autoantibodies in patients with breast cancer (BCP) and healthy volunteers. This paper reports the evaluation of this technique using proteins from MCF7 as a source of antigens following 2-DE separation. The appropriate quantity of protein to be loaded on gels (150 microg) has been determined, the aim being a complete and reproducible recovery of all separated proteins onto the polyvinylidene fluoride membrane (2D-blot) after a semi-dry electrotransfer. Several different transfer methods were tested in parallel, resulting in the selection and optimisation of one using a discontinuous buffer system, based on the isotachophoresis theory. To facilitate the comparative analysis of the different sets of 2D-blots probed with individual sera from BCP and healthy volunteers, the 2D-blots were stained with colloidal gold following the immunodetection step. The gels and 2D-blots were scanned and analysed by imaging software. The matching permitted exact localisation of particular relevant protein spots hybridised by antibodies on the 2D-blots. These spots were subsequently located on preparative gels for identification by mass spectrometry. A set of 40 2D-blots was probed with 20 sera from patients with breast cancer and 20 sera from healthy volunteers. In the protein profiles submitted to immunodetection, 15 proteins were repeatedly immunodetected by both BCP and sera from healthy people. Those proteins were identified by mass spectrometry. Conversely, some protein isoforms were preferentially immunodetected by BCP sera and may reflect the presence of this cancer. The improved isotachophoretic method described in this study is suitable for comparing the overall profile of autoimmunity between different populations and for subsequent identification of relevant antigens.     

Patellar fracture after total knee arthroplasty

BACKGROUND: Patellar fracture can occur as a complication following total knee arthroplasty. The purpose of this study was to evaluate a large series of patellar fractures to determine the results of different forms of treatment of specific fracture types. METHODS: A retrospective review identified eighty-five fractures (in seventy-seven patients) following 12,464 consecutive total knee arthroplasties performed between 1985 and 1998. Seventy-eight fractures occurred after primary total knee arthroplasty and seven, after revision total knee arthroplasty. Five fractures were treated elsewhere, and two others were lost to follow-up. The results of treatment of the remaining seventy-eight fractures were reviewed. Fractures were classified according to three main criteria: integrity of the extensor mechanism, fixation status of the patellar implant, and quality of the remaining bone stock. The mean duration of follow-up was 3.6 years. RESULTS: The prevalence of patellar fracture after total knee arthroplasty was 0.68%; fractures were significantly more prevalent among men (1.01%) than among women (0.40%) (p = 0.0004). Thirty-eight fractured patellae had a stable implant and an intact extensor mechanism (Type I). All but one were treated nonoperatively, and there was only one late failure of nonoperative treatment, which required operative intervention. Twelve fractures were associated with disruption of the extensor mechanism (Type II). Eleven were treated operatively; six knees had complications and five had a reoperation. Twenty-eight fractures occurred in association with a loose patellar component (Type III). Twenty were treated operatively; nine knees had complications, and four had a reoperation. CONCLUSIONS: Patellar fractures after total knee arthroplasty are infrequent. Treatment can be guided by three main criteria: integrity of the extensor mechanism, fixation status of the patellar implant, and quality of the remaining bone. Fractures associated with a stable implant and an intact extensor mechanism were usually treated successfully with nonoperative means, with minimal complications. When operative treatment was required, it was associated with a high rate of complications and reoperations.     

Lessons learned from the Hospital Without Walls project

The Hospital Without Walls is an ongoing ambitious project in home telecare that incorporates research into physiological monitoring, low-power radio communication, database storage of physiological data and methods of viewing clinically relevant information from large quantities of stored data. The system records vital signs from patients in their homes using a body-mounted, two-way radio system and a base station located in the home, which transmits data records to a central recording facility every day or in response to predefined emergency events. The prototype system has successfully undergone preliminary clinical trials, with a particular clinical emphasis on monitoring activity using three-axis accelerometers. Our experience with the trial suggests that there are significant differences in the technical design required for a long-term, home monitoring system and one where monitoring takes place in an environment staffed by health professionals.