New insights into the pharmacokinetics and pharmacodynamics of natalizumab treatment for patients with multiple sclerosis, obtained from clinical and in vitro studies.

BACKGROUND: The monoclonal antibody natalizumab (NAT) inhibits the migration of lymphocytes throughout the blood-brain barrier by blocking very late antigen (VLA)-4 interactions, thereby reducing inflammatory central nervous system (CNS) activity in patients with multiple sclerosis (MS). We evaluated the effects of different NAT treatment regimens. METHODS: We developed and optimised a NAT assay to measure free NAT, cell-bound NAT and VLA-4 expression levels in blood and cerebrospinal fluid (CSF) of patients using standard and prolonged treatment intervals and after the cessation of therapy. RESULTS: In paired CSF and blood samples of NAT-treated MS patients, NAT concentrations in CSF were approximately 100-fold lower than those in serum. Cell-bound NAT and mean VLA-4 expression levels in CSF were comparable with those in blood. After the cessation of therapy, the kinetics of free NAT, cell-bound NAT and VLA-4 expression levels differed. Prolonged intervals greater than 4 weeks between infusions caused a gradual reduction of free and cell-bound NAT concentrations. Sera from patients with and without NAT-neutralising antibodies could be identified in a blinded assessment. The NAT-neutralising antibodies removed NAT from the cell surface in vivo and in vitro. Intercellular NAT exchange was detected in vitro. CONCLUSIONS: Incorporating assays to measure free and cell-bound NAT into clinical practice can help to determine the optimal individual NAT dosing regimen for patients with MS.

Coxiella burnetii (Q fever) as a cause of community-acquired pneumonia during the warm season in Germany.

Q fever is a notifiable disease in Germany. The majority of the reported cases are related to outbreaks. The objective of our study was to evaluate the general role of Q fever in community-acquired pneumonia (CAP). We investigated respiratory samples and sera from 255 patients with CAP, who were enrolled into a CAPNETZ cohort in summer 2005. Altogether, our data showed a significant prevalence of Q fever as CAP (3·5%). If a patient's condition leads to a diagnostic test for Chlamydophila sp., Mycoplasma sp. or Legionella sp., then a Q fever diagnostic test should also be included. In particular, ELISA as a first diagnostic step is easy to perform. PCR should be performed at an early stage of the disease if no antibodies are detectable. Because of our highly promising findings we suggest performing PCR in respiratory samples.

Direct observation of nonaffine tube deformation in strained polymer networks.

We present a one-to-one comparison of polymer segmental fluctuations as measured by small angle neutron scattering in a network under deformation with those obtained by neutron spin echo spectroscopy. This allows an independent proof of the strain dependence of the chain entanglement length. The experimentally observed nonaffine square-root dependence of the tube channel on strain is in excellent agreement with theoretical predictions and permits us to exclude an often invoked nondeformed as well as affinely deformed tube.

The urinary antibiotic 5-nitro-8-hydroxyquinoline (Nitroxoline) reduces the formation and induces the dispersal of Pseudomonas aeruginosa biofilms by chelation of iron and zinc.

Since cations have been reported as essential regulators of biofilm, we investigated the potential of the broad-spectrum antimicrobial and cation-chelator nitroxoline as an antibiofilm agent. Biofilm mass synthesis was reduced by up to 80% at sub-MIC nitroxoline concentrations in Pseudomonas aeruginosa, and structures formed were reticulate rather than compact. In preformed biofilms, viable cell counts were reduced by 4 logs at therapeutic concentrations. Complexation of iron and zinc was demonstrated to underlie nitroxoline's potent antibiofilm activity.

Evaluating frequency, diagnostic quality, and cost of Lyme borreliosis testing in Germany: a retrospective model analysis.

BACKGROUND: Data on the economic impact of Lyme borreliosis (LB) on European health care systems is scarce. This project focused on the epidemiology and costs for laboratory testing in LB patients in Germany. MATERIALS AND METHODS: We performed a sentinel analysis of epidemiological and medicoeconomic data for 2007 and 2008. Data was provided by a German statutory health insurance (DAK) company covering approx. 6.04 million members. In addition, the quality of diagnostic testing for LB in Germany was studied. RESULTS: In 2007 and 2008, the incident diagnosis LB was coded on average for 15,742 out of 6.04 million insured members (0.26%). 20,986 EIAs and 12,558 immunoblots were ordered annually for these patients. For all insured members in the outpatient sector, a total of 174,820 EIAs and 52,280 immunoblots were reimbursed annually to health care providers (cost: 2,600,850€). For Germany, the overall expected cost is estimated at 51,215,105€. However, proficiency testing data questioned test quality and standardization of diagnostic assays used. CONCLUSION: Findings from this study suggest ongoing issues related to care for LB and may help to improve future LB disease management.

Established and emerging pathogens in Ixodes ricinus ticks collected from birds on a conservation island in the Baltic Sea.

Tick-borne pathogens such as Lyme borreliosis spirochaetes, Anaplasma phagocytophilum, Rickettsia spp. and Babesia spp. cause a great variety of diseases in animals and humans. Although their importance with respect to emerging human diseases is increasing, many issues about their ecology are still unclear. In spring 2007, 191 Ixodes ricinus (Acari: Ixodidae) ticks were collected from 99 birds of 11 species on a bird conservation island in the Baltic Sea in order to test them for Borrelia spp., A. phagocytophilum, Rickettsia spp. and Babesia spp. infections. Identification of the pathogens was performed by polymerase chain reaction (PCR), restriction fragment length polymorphism and sequence analysis. The majority of birds with ticks testing positive were European robins and thrushes. Borrelia DNA was detected in 14.1%, A. phagocytophilum in 2.6%, rickettsiae in 7.3% and Babesia spp. in 4.7% of the ticks. Co-infections with different pathogens occurred in six ticks (3.1%). The fact that 11 ticks (five larvae, six nymphs) were infected with Borrelia afzelii suggests that birds may, contrary to current opinion, serve as reservoir hosts for this species. Among rickettsial infections, we identified Rickettsia monacensis and Rickettsia helvetica. As we detected five Rickettsia spp. positive larvae and two birds carried more than one infected tick, transmission of those pathogens from birds to ticks appears possible. Further characterization of Babesia infections revealed Babesia divergens and Babesia microti. The occurrence of Babesia spp. in a total of five larvae suggests that birds may be able to infect ticks, at least with Ba. microti, a species considered not to be transmitted transovarially in ticks.

Structure of the Arabidopsis RPM1 gene enabling dual specificity disease resistance.

Plants can recognize pathogens through the action of disease resistance (R) genes, which confer resistance to pathogens expressing unique corresponding avirulence (avr) genes. The molecular basis of this gene-for-gene specificity is unknown. The Arabidopsis thaliana RPM1 gene enables dual specificity to pathogens expressing either of two unrelated Pseudomonas syringae avr genes. Despite this function, RPM1 encodes a protein sharing molecular features with recently described single-specificity R genes. Surprisingly, RPM1 is lacking from naturally occurring, disease-susceptible Arabidopsis accessions.

Adsorption and pinning of multiblock copolymers on chemically heterogeneous patterned surfaces.

The results of Monte Carlo simulations carried out on a system of multiblock copolymers having two different types of monomer units adsorbed on checker board surface configurations are presented here. We investigated the adsorption behavior for a series of different chess board square dimensions and also for various block lengths of the copolymer. We find that the specific heat capacity curves for adsorption indicate double peaks showing a two stage pattern recognition of the copolymer on the surface. It is also seen that the transition that happens at lower temperature corresponds to pinning where the junction point of the different blocks gets pinned to the interface between the different surface sites. It is interesting to see that the multiblock copolymers form multiple pinning sites on the boundary between different kinds of surface sites. There exists an intermediate size of the square on the board where the recognition and pinning are most favored and for smaller and larger size of the board and block length, the adsorption proceeds like in homopolymer on homogeneous surfaces. Unlike in the case of the simplest model of diblock copolymer on stripe-patterned surfaces [K. Sumithra and E. Straube, J. Chem. Phys. 125, 154701 (2006)], here the recognition is stronger and the average adsorption energy and the perpendicular component of the radius of gyration show distinct changes corresponding to the two transitions. The conformational properties of the multiblock copolymer near the checkered surface show interesting effects with the perpendicular component showing strong deviations from the standard behavior.

The Swedish new variant of Chlamydia trachomatis (nvCT) remains undetected by many European laboratories as revealed in the recent PCR/NAT ring trial organised by INSTAND e.V., Germany.

The May 2009 round of INSTAND's ring trial "Chlamydia trachomatis detection PCR/NAT" included a sample with high amount of the Swedish new variant of C. trachomatis (nvCT). A spectrum of at least 12 different commercial diagnostic nucleic acid amplification tests (NAATs) and many different in house NAATs were applied by the 128 participating laboratories which reported 152 results. Approximately 80% of the results correctly reported the presence of C. trachomatis in the nvCT specimen. The nvCT sample was mainly missed, as expected, by participants using the Roche COBAS Amplicor CT/NG (15.5% of reported results) but also by several participants using in house NAATs. The trend towards using nvCT-detecting NAATs is obvious and in addition to the new dual-target NAATs from Roche and Abbott, and BD ProbeTec ET, also a number of new CE mark-certified commercial tests from smaller diagnostic companies as well as many different in house NAATs were used. Laboratories using commercial or in house NAATs that do not detect the nvCT are encouraged to carefully monitor their C. trachomatis incidence, participate in appropriate external quality assurance and controls schemes, and consider altering their testing system. The reliable detection of low amounts of the wildtype C. trachomatis strain in other samples of the ring trial set indicates a good diagnostic performance of all applied commercial NAATs while also detecting the nvCT strain.

Low-grade infections as a possible cause of arthrofibrosis after total knee arthroplasty.

PURPOSE: Arthrofibrosis after total knee arthroplasty represents a considerable burden for the patient and a therapeutic challenge for the practitioner. One possible cause discussed in the literature is a low-grade infection. This hypothesis should be examined within the scope of this retrospective study. PATIENTS AND METHODS: Nineteen patients with clinical symptoms of arthrofibrosis after primary total knee arthroplasty were examined between January, 1999 and January, 2012. Incorrect positioning was radiologically ruled out. All patients were examined clinically (score of Freeman as well as Blauth and Jäger), radiologically (component and leg alignment, patella height according to Insall and Salvati), microbiologically (culture-based procedures), molecular biologically (PCR) and histologically in the course of an open revision of the prosthesis. RESULTS: According to the score of Freeman et al. (1977), a highly significant improvement in pain (p = 0.007) and in the overall score (p = 0.003) was shown. The knee joint mobility did not change significantly (p = 0.795). PCR was negative in 17 patients. One patient showed a PCR-positive result of the synovial membrane for Corynebacterium spp., while Staphylococcus warneri was detected in the culture. Another patient had a positive result of synovia PCR for Enterococcus cecorum as well as Corynebacterium spp. However, this culture was sterile. In 16 patient samples, no bacterial growth was detectable. Two samples were not evaluable. The main histopathological findings were synovialitis and fibrosis. CONCLUSION: The hypothesis of low-grade-infection-induced arthrofibrosis after total knee arthroplasty could not be confirmed in this study. However, based on this small study population the conclusion needs to be confirmed by new and larger studies, ideally prospectively designed including a control group.