Controlling pulse stability in singularly perturbed reaction-diffusion systems.

The aim of this paper is to investigate the use of Pyragas control on the stability of stationary, localized coherent structures in a general class of two-component, singularly perturbed, reaction-diffusion systems. We use noninvasive Pyragas-like proportional feedback control to stabilize a singular pulse solution to a two-component, singularly perturbed reaction-diffusion system. We show that in a significant region of parameter space, the control can be adjusted to stabilize an otherwise unstable pulse.

Symmetry groupoids for pattern-selective feedback stabilization of the Chafee-Infante equation.

Reaction-diffusion equations are ubiquitous in various scientific domains and their patterns represent a fascinating area of investigation. However, many of these patterns are unstable and, therefore, challenging to observe. To overcome this limitation, we present new noninvasive feedback controls based on symmetry groupoids. As a concrete example, we employ these controls to selectively stabilize unstable equilibria of the Chafee-Infante equation under Dirichlet boundary conditions on the interval. Unlike conventional reflection-based control schemes, our approach incorporates additional symmetries that enable us to design new convolution controls for stabilization. By demonstrating the efficacy of our method, we provide a new tool for investigating and controlling systems with unstable patterns, with potential implications for a wide range of scientific disciplines.

Geometric invariance of determining and resonating centers: Odd- and any-number limitations of Pyragas control.

In the spirit of the well-known odd-number limitation, we study the failure of Pyragas control of periodic orbits and equilibria. Addressing the periodic orbits first, we derive a fundamental observation on the invariance of the geometric multiplicity of the trivial Floquet multiplier. This observation leads to a clear and unifying understanding of the odd-number limitation, both in the autonomous and the non-autonomous setting. Since the presence of the trivial Floquet multiplier governs the possibility of successful stabilization, we refer to this multiplier as the determining center. The geometric invariance of the determining center also leads to a necessary condition on the gain matrix for the control to be successful. In particular, we exclude scalar gains. The application of Pyragas control on equilibria does not only imply a geometric invariance of the determining center but surprisingly also on centers that resonate with the time delay. Consequently, we formulate odd- and any-number limitations both for real eigenvalues together with an arbitrary time delay as well as for complex conjugated eigenvalue pairs together with a resonating time delay. The very general nature of our results allows for various applications.

An integrative correlation of myopathology, phenotype and genotype in late onset Pompe disease.

AIMS: Pompe disease is caused by pathogenic mutations in the alpha 1,4-glucosidase (GAA) gene and in patients with late onset Pome disease (LOPD), genotype-phenotype correlations are unpredictable. Skeletal muscle pathology includes glycogen accumulation and altered autophagy of various degrees. A correlation of the muscle morphology with clinical features and the genetic background in GAA may contribute to the understanding of the phenotypic variability. METHODS: Muscle biopsies taken before enzyme replacement therapy were analysed from 53 patients with LOPD. On resin sections, glycogen accumulation, fibrosis, autophagic vacuoles and the degree of muscle damage (morphology-score) were analysed and the results were compared with clinical findings. Additional autophagy markers microtubule-associated protein 1A/1B-light chain 3, p62 and Bcl2-associated athanogene 3 were analysed on cryosections from 22 LOPD biopsies. RESULTS: The myopathology showed a high variability with, in most patients, a moderate glycogen accumulation and a low morphology-score. High morphology-scores were associated with increased fibrosis and autophagy highlighting the role of autophagy in severe stages of skeletal muscle damage. The morphology-score did not correlate with the patient's age at biopsy, disease duration, nor with the residual GAA enzyme activity or creatine-kinase levels. In 37 patients with LOPD, genetic analysis identified the most frequent mutation, c.-32-13T>G, in 95%, most commonly in combination with c.525delT (19%). No significant correlation was found between the different GAA genotypes and muscle morphology type. CONCLUSIONS: Muscle morphology in LOPD patients shows a high variability with, in most cases, moderate pathology. Increased pathology is associated with more fibrosis and autophagy.

Permacol™ collagen paste for cryptoglandular and Crohn's anal fistula.

BACKGROUND: Permacol™ collagen paste, an acellular crosslinked porcine dermal collagen matrix suspension, is a new treatment option for anal fistula. Data remain limited, however, and as yet only the results of one case of Crohn's fistula treated with Permacol™ paste has been reported. The aim of this study was to assess the use of Permacol™ collagen paste in patients with cryptoglandular and Crohn's perianal fistulae. METHODS: A prospective study was conducted on patients with anal fistula, treated with Permacol™ paste. Patients were followed at 1 week, 6 and 12 months, and on demand thereafter. The main focus was on fistula healing and postoperative continence. The former was defined as the absence of signs of recurrence on clinical examination, proctoscopy and rigid rectoscopy. Fecal incontinence was assessed before surgery and at each follow-up. RESULTS: Thirty patients (19 women, 11 men; mean age 46 years), 12 (40%) of whom had Crohn's disease were included. The average number of previous fistula operations was 6. All patients had ≥ 6 months of follow-up, and 24 patients (80%) had ≥ 12 months of follow-up. The healing rate in all patients was 57% (17 of 30 patients) at 6 months and 63% (15 of 24 patients) at 12 months. One patient reported a worsening of fecal incontinence at 12 months; 2 patients had adverse events (perianal pain: n = 1, fluid accumulation n = 1) requiring fistula drainage. Patient characteristics, healing, incontinence, and adverse events did not differ significantly between patients with and without Crohn's disease. CONCLUSIONS: Our data indicate that Permacol™ paste is a safe and moderately effective treatment for cryptoglandular and Crohn's fistulae.

A theoretical study of the dissociative recombination of SH+ with electrons through the 2Π states of SH.

A quantitative theoretical study of the dissociative recombination of SH+ with electrons has been carried out. Multireference, configuration interaction calculations were used to determine accurate potential energy curves for SH+ and SH. The block diagonalization method was used to disentangle strongly interacting SH valence and Rydberg states and to construct a diabatic Hamiltonian whose diagonal matrix elements provide the diabatic potential energy curves. The off-diagonal elements are related to the electronic valence-Rydberg couplings. Cross sections and rate coefficients for the dissociative recombination reaction were calculated with a stepwise version of the multichannel quantum defect theory, using the molecular data provided by the block diagonalization method. The calculated rates are compared with the most recent measurements performed on the ion Test Storage Ring (TSR) in Heidelberg, Germany.

Resonances in photoabsorption: predissociation line shapes in the 3pπD¹Π(u)⁺ ← X¹Σ(g)⁺ system in H2.

The predissociation of the 3pπD¹Π(u)⁺, v ≥ 3, N = 2, and N = 3 levels of diatomic hydrogen is calculated by ab initio multichannel quantum defect theory combined with a R-matrix type approach that accounts for interfering predissociation and autoionization. The theory yields absorption line widths and shapes that are in good agreement with those observed in the high-resolution synchrotron vacuum-ultraviolet absorption spectra obtained by Dickenson et al. [J. Chem. Phys. 133, 144317 (2010)] at the DESIRS beamline of the SOLEIL synchrotron. The theory predicts further that many of the D state resonances with v ⩾ 6 exhibit a complex fine structure which cannot be modeled by the Fano profile formula and which has not yet been observed experimentally.

[Treatability of sporadic late onset nemaline myopathy]. / Behandelbarkeit der "sporadic late onset nemaline myopathy".

Sporadic late onset nemaline myopathy (SLONM) is an extremely rare disorder which can be associated with monoclonal gammopathy of unclear significance (MGUS). Clinically SLONM appears mostly after the fourth decade of life as rapidly progressing tetraparesis, respiratory insufficiency and features, such as dropped head syndrome, facial and bulbar involvement. Diagnosis is confirmed by muscle biopsy with detection of nemaline bodies and also frequently lobulated fibres. Immunosuppressant and immunomodulating therapies have been shown to be ineffective but clinical improvement accompanied by disappearance of monoclonal gammopathy and even nemaline bodies was reported following autologous stem cell transplantation and chemotherapy with melphalan. This article presents the case of a 53-year-old man with a 4-year history of SLOMN with MGUS in which administration of intravenous immunoglobulin therapy (IVIG) was not successful in reversing gammopathy, histopathological changes or clinical symptoms.

Effect of bioaugmentation on anaerobic wastewater treatment in the dairy industry.

The creation of a biofilm as a specialized biosystem, its development, and activity were studied at 3 critical control points of biofilter operation: start-up, transition from batch to sequencing batch regimen, and set-up of stable sequencing batch process. Five variants of biosystems were investigated with an inoculum from specially adapted real activated sludge, enriched with various combinations of 3 microbial preparations. A stable and working biofilm was developed in the phase of stabilized sequencing batch process. The differences among biodegradation effectiveness of the 5 variants were insignificant during that phase and the effect of the preparations was low. The effectiveness of organic removal for the 5 bioaugmentation approaches reached 60% for protein, 70% for chemical oxygen demand, and 97% for lactose. Commercial inocula did not improve final reactor performance over an inoculum from a municipal wastewater treatment plant alone.

Induction of nitric oxide synthase protects against malaria in mice exposed to irradiated Plasmodium berghei infected mosquitoes: involvement of interferon gamma and CD8+ T cells.

Exposure of BALB/c mice to mosquitoes infected with irradiated Plasmodium berghei confers protective immunity against subsequent sporozoite challenge. Immunized mice challenged with viable sporozoites develop parasitemia when treated orally with substrate inhibitors of nitric oxide synthase (NOS). This suggests that the production of nitric oxide (NO) prevents the development of exoerythrocytic stages of malaria in liver. Liver tissue from immunized mice expressed maximal levels of mRNA for inducible NOS (iNOS) between 12 and 24 h after challenge with sporozoites. Intraperitoneal injection of neutralizing monoclonal antibody against interferon gamma (IFN-gamma) or in vivo depletion of CD8+ T cells, but not CD4+ T cells, at the time of challenge blocked expression of iNOS mRNA and ablated protection in immunized mice. These results show that both CD8+ T cells and IFN-gamma are important components in the regulation of iNOS in liver which contributes to the protective response of mice immunized with irradiated malaria sporozoites. IFN-gamma, likely provided by malaria-specific CD8+ T cells, induces liver cells, hepatocytes and/or Kupffer cells, to produce NO for the destruction of infected hepatocytes or the parasite within these cells.

Pseudotyping lentiviral vectors with the wild-type measles virus glycoproteins improves titer and selectivity.

We pseudotyped HIV-1 vectors with cytoplasmic tail-truncated envelope glycoproteins of a wild-type (WT) measles virus (MV). The particles entered the lymphatic cells exclusively through the signaling lymphocyte activation molecule (SLAM, CD150), whereas particles pseudotyped with the MV vaccine strain glycoproteins also recognized the ubiquitous membrane cofactor protein (CD46) as receptor and had less specific cell entry. MV(WT)-HIV vectors reached titers of 10(8) t.u. ml(-1), which were up to 10-fold higher than those of MV(Vac)-HIV vectors, and discriminated between SLAM-positive and SLAM-negative cells, also in mixed cell cultures. As these vectors transduce primary human cells more efficiently than vesicular stomatitis virus-G pseudotyped vectors do, they are promising candidates for gene transfer to human lymphocytes and certain epithelial cells.

Satellite-like particle of tobacco ringspot virus that resembles tobacco ringspot virus.

A satellite-like nucleoprotein serologically indistinguishable from multicomponent tobacco ringspot virus, also resembles it in size, shape, and electrophoretic mobility. Although the protein shell of the nucleoprotein is similar to, if not identical to that of tobacco ringspot virus, each ahell of the nucleoprotein conntains many small strands of nucleic acid, which replicate only in mixed infections with the virus.

Autolytic processing of dimeric plant virus satellite RNA.

Associated with some plant viruses are small satellite RNA's that depend on the plant virus to provide protective coat protein and presumably at least some of the proteins necessary for satellite RNA replication. Multimeric forms of the satellite RNA of tobacco ringspot virus are probable in vivo precursors of the monomeric satellite RNA. Evidence is presented for the in vitro autolytic processing of dimeric and trimeric forms of this satellite RNA. The reaction generates biologically active monomeric satellite RNA, apparently is reversible to form dimeric RNA from monomeric RNA, and does not require an enzyme for its catalysis.

Sporozoite-induced malaria: therapeutic effects of glycolipids in liposomes.

Liposomes containing neutral glycolipids with a terminal glucose or galactose, when injected intravenously, prevented the appearance of erythrocytic forms of malaria (Plasmodium berghei) in mice previously injected with sporozoites. Inhibitory glycolipids included glucosyl, galactosyl, or lactosyl ceramide. Inhibition was not observed with liposomes containing ceramide, phosphocholine ceramide, sulfogalactosyl ceramide (sulfatide), or ganglioside GM1. Liposomes containing glycolipids did not inhibit infection transmitted by injecting blood containing erythrocytic stages of malaria. These results may have therapeutic implications in the treatment of malaria. Analysis of the mechanism of interference with the life cycle of malaria by liposomal glycolipids may yield information about the interactions of parasites with cellular membranes.

Efficacy of murine malaria sporozoite vaccines: implications for human vaccine development.

As part of a study of potential vaccines against malaria, the protective efficacy of sporozoite subunit vaccines was determined by using the Plasmodium berghei murine malaria model. Mice were immunized with recombinant DNA-produced or synthetic peptide-carrier subunit vaccines derived from the repetitive epitopes of the Plasmodium berghei circumsporozoite gene, or with radiation-attenuated sporozoites. Immunization with subunit vaccines elicited humoral responses that were equivalent to or greater than those elicited by irradiated sporozoites, yet the protection against sporozoite challenge induced by either of the subunit vaccines was far less than that achieved by immunization with attenuated sporozoites. Passive and adoptive transfer studies demonstrated that subunit vaccines elicited predominantly antibody-mediated protection that was easily overcome whereas irradiated sporozoites induced potent cell-mediated immunity that protected against high challenge doses of sporozoites. These studies indicate that new strategies designed to induce cellular immunity will be required for efficacious sporozoite vaccines.

Immunogenicity of synthetic peptides from circumsporozoite protein of Plasmodium falciparum.

In a study of recombinant proteins that might be useful in developing a vaccine against malaria, synthetic peptides from the circumsporozoite (CS) protein of Plasmodium falciparum were found to be immunogenic for mice and rabbits. Antibody to peptides from the repeating region of the CS protein recognized native CS protein and blocked sporozoite invasion of human hepatoma cells in vitro. Antibodies to peptides from regions I and II had no biologic activity, although antibody to region I recognized processed CS protein by Western blot analysis. These data support the feasibility of developing a vaccine against the sporozoite stage of the malaria parasite by using synthetic peptides of the repeating region of the CS protein conjugated to a carrier protein.

Structure of the gene encoding the immunodominant surface antigen on the sporozoite of the human malaria parasite Plasmodium falciparum.

The gene for the circumsporozoite (CS) protein of Plasmodium falciparum has been cloned and its nucleotide sequence determined. The gene encodes a protein of 412 amino acids as deduced from the nucleotide sequence. The protein contains 41 tandem repeats of a tetrapeptide, 37 of which are Asn-Ala-Asn-Pro and four of which are Asn-Val-Asp-Pro. Monoclonal antibodies against the CS protein of Plasmodium falciparum were inhibited from binding to the protein by synthetic peptides of the repeat sequence. The CS protein of Plasmodium falciparum and the CS protein of a simian malaria parasite, Plasmodium knowlesi, have two regions of homology, one of which is present on either side of the repeat. One region contains 12 of 13 identical amino acids. Within the nucleotide sequence of this region, 25 of 27 nucleotides are conserved. The conservation of these regions in parasites widely separated in evolution suggests that they may have a function such as binding to liver cells and may represent an invariant target for immunity.

Treatment during primary HIV infection does not lower viral set point but improves CD4 lymphocytes in an observational cohort.

OBJECTIVE: To investigate if early treatment of primary HIV-1 infection (PHI) reduces viral set point and/or increases CD4 lymphocytes. METHODS: Analysis of two prospective multi-centre PHI cohorts. HIV-1 RNA and CD4 lymphocytes in patients with transient treatment were compared to those in untreated patients. Time to CD4 lymphocyte decrease below 350/ microl after treatment stop or seroconversion was calculated using Kaplan-Meier and Cox-PH-regression analyses. RESULTS: 156 cases of PHI were included, of which 100 had received transient HAART (median treatment time 9.5 months) and 56 remained untreated. Median viral load (563000 cop/ml vs 240000 cop/ml; p<0.001) and median CD4 lymphocyte (449/ microl vs. 613/ microl; p<0.01) differed significantly between treated and untreated patients. Median viral load was 38056 copies/ml in treated patients (12 months after treatment stop) and 52880 copies/ml in untreated patients (12 months after seroconversion; ns). Median CD4 lymphocyte change was +60/ microl vs. -86/ microl (p = 0.01). Median time until CD4 lymphocytes decreased to <350/ microl (including all patients with CD4 lymphocytes <500/ microl during seroconversion) was 20.7 months in treated patients after treatment stop and 8.3 months in untreated patents after seroconversion (p<0.01). Cox-PH analyses adjusting for baseline VL, CD4 lymphocytes, stage of early infection and symptoms confirmed these differences. CONCLUSIONS: Treatment during PHI did not lower viral set point. However, patients treated during seroconversion had an increase in CD4 lymphocytes, whereas untreated patients experienced a decrease in CD4 lymphocytes. Time until reaching CD4 lymphocytes <350/ microl was significantly shorter in untreated than in treated patients including patients with CD4 lymphocytes <500/ microl during seroconversion.

Dual chamber pacemaker implantation in dogs with atrioventricular block.

BACKGROUND: Pacemaker implantation is the treatment of choice for symptomatic bradyarrhythmias. In dogs, a single chamber system is commonly used. In human patients with high-grade 2nd- or 3rd-degree atrioventricular (AV) block, physiologic pacing is recommended, because it improves cardiac output, blood pressure, exercise tolerance, and quality of life. In dogs, this type of pacing is seldom used. HYPOTHESIS: The implantation of a dual chamber pacemaker in dogs with AV block is a feasible procedure for restoring AV synchrony. ANIMALS: Thirty-three privately owned dogs with high-grade 2nd- or 3rd-degree AV block were included. METHODS: Patient data of all dogs with AV block presented for pacemaker implantation between December 1997 and November 2004 were reviewed. RESULTS: Dual chamber pacemaker implantation with AV synchronous stimulation was successfully performed in 33/33 dogs (100%). In 9/33 (27%) major and in 12/33 (36%) minor complications were observed. Mean survival time for the patients discharged from hospital (n = 32) was 33.6 +/- 20.4 months (range, 3.9-83.5 months). CONCLUSION AND CLINICAL IMPORTANCE: Dual chamber pacing is a feasible procedure in dogs with 2nd- or 3rd-degree AV block and is not associated with a higher complication rate compared with single chamber pacemaker systems. A major advantage over ventricular demand pacemaker systems is the restoration of AV synchrony for a substantial period of time.

Cell entry targeting restricts biodistribution of replication-competent retroviruses to tumour tissue.

Virotherapy is currently being developed for many different types of viruses including replication-competent murine leukaemia virus (MLV) as a novel tool in cancer therapy. However, there is the risk of insertional mutagenesis associated with this virus, making careful preclinical studies necessary before its first application in man. We have previously generated conditionally replication-competent MLV variants that require activation by tumour-associated proteases to become infectious. Here we analysed in a comparative study the spreading of non-targeted and of such tumour-targeted MLV variants to tumour and extratumoural organs in immunodeficient mice. Both virus types were able to efficiently infect tumour cells after systemic administration. The non-targeted virus, however, also infected extratumoural organs like bone marrow, spleen and liver efficiently. In contrast, the targeted viruses revealed in a quantitative analysis of virus spreading an up to 500-fold more selective infection of tumour tissue than the non-targeted virus. The data raise serious doubts about a safe clinical use of non-targeted MLV. Engineering the virus to become activatable by tumour-associated proteases can significantly improve the safety of MLV.