Early autologous and allogeneic peripheral blood stem cell transplantation for adult patients with acute B and T cell precursor neoplasms: a 12-year single center experience.

Adult acute lymphoblastic leukemia/lymphoma (ALL/LBL) is a rare and heterogeneous malignancy characterized by uncontrolled proliferation of B or T cell precursor cells. Here, we retrospectively analyzed the outcome of early autologous stem cell transplantation in standard-risk patients in first complete remission (n=24) and of allogeneic transplantation in high and highest risk, and relapsed/refractory patients (n=35). The 10-year overall survival after autologous transplantation was 45%. The 10-year overall survival after allogeneic transplantation was 58%. The cumulative incidence of relapse was 29% after allogeneic and 67% after autologous transplantation. The cumulative incidence of non-relapse mortality was 0% after autologous and 12% after allogeneic transplantation. This retrospective single center analysis in a limited number of standard-risk patients clearly demonstrates that early autologous transplantation in first complete remission leads to an acceptable long-term outcome with a short overall treatment duration of less than 6 months compared with more than 2 years with conventional chemotherapy. More sensitive and standardized methods to detect minimal residual disease (MRD) will further help to identify those patients more accurately who are most likely to benefit from such a short and intensive treatment strategy (i.e., MRD negative standard-risk patients) or those who require early targeted therapy (e.g., blinatumomab) in case of MRD positivity. Early allogeneic transplantation results in long-term survival/cure in nearly two-thirds of all high and highest risk, and relapsed/refractory patients.

Gender differences and influenza-associated mortality in hospitalized influenza A patients during the 2018/19 season.

BACKGROUND: In this study we analyzed gender differences in the clinical presentation of patients with molecular confirmed influenza A. Additionally, we tried to identify predictors of influenza-associated mortality. MATERIALS/METHODS: In this prospective observational multi-center-study we included all influenza-positive patients ≥ 18 years who were hospitalized and treated on flu-isolation-wards in three hospitals in Vienna during the 2018/19 influenza season. Diagnoses were made via Cobas® Liat® POCT. RESULTS: 490 Patients (48.8% female) tested positive for influenza A. Female patients were older (median age 76 years vs. 70 years, p < 0.001). Male patients had a higher rate of chronic liver disease in history (8.8% vs. 2.9%, p = 0.006), myositis (11.7% vs. 3.1%, p < 0.001) and ICU admissions (9.6% vs. 4.6%, p = 0.03). The in-hospital mortality rate was 4.3% and increased to 9.5% during the 90-day follow-up period. Female patients > 75 years had a significantly higher in-hospital mortality rate than ≤ 75-year-old females (9.2% vs. 1.7%, p = 0.019). This effect was not observed in male patients (5.4% vs. 1.9%, p = ns). Age > 75 years (OR 5.49, 95% CI 1.10-27.43), acute heart failure (OR 3.56, 95% CI 1.03-12.05) and ICU admission (OR 6.1, 95% CI 0.98-37.91) were predictors for in-hospital mortality for female patients, while any malignancy (OR 9.4, 95% CI 1.90-46.54) and ICU admission (OR 7.05, 95% CI 1.44-34.55) were predictors in male patients. CONCLUSIONS: Gender is associated with differences in clinical presentation and complications of influenza A virus infection. Women with acute heart failure or aged > 75 years have an increased risk of influenza associated in-hospital mortality, while ICU admission and any malignancy are predictors for male patients. Mortality rates in patients > 75 years are 5-10 times higher compared to their non-hospitalized influenza-negative Austrian counterparts.

Efficient Emission Enhancement of Single CdSe/CdS/PMMA Quantum Dots through Controlled Near-Field Coupling to Plasmonic Bullseye Resonators.

A strong increase of spontaneous radiative emission from colloidally synthesized CdSe/CdS/PMMA hybrid particles is achieved when manipulated into plasmonic bullseye resonators with the tip of an atomic force microscope (AFM). This type of antenna provides a broadband resonance, which may be precisely matched to the exciton ground state energy in the inorganic cores. Statistically analyzing the spectral photoluminescence (PL) of a large number of individual coupled and uncoupled CdSe/CdS/PMMA quantum dots, we find an order of magnitude of intensity enhancement due to the Purcell effect. Time-resolved PL shows a commensurate increase of the spontaneous emission rate with radiative lifetimes below 230 ps for the bright exciton transition. The combination of AFM and PL imaging allows for sub-200 nm localization of the particle position inside the plasmonic antenna. This capability unveils a different coupling behavior of dark excitonic states: even stronger PL enhancement occurs at positions with maximum spatial gradient of the nearfield, effectively adding a dipolar component to original quadrupole transitions. The broadband maximization of light-matter interaction provided by our nanoengineered compound systems enables an attractive class of future experiments in ultrafast quantum optics.

Escape rate of an active Brownian particle over a potential barrier.

We study the dynamics of an active Brownian particle with a nonlinear friction function located in a spatial cubic potential. For strong but finite damping, the escape rate of the particle over the spatial potential barrier shows a nonmonotonic dependence on the noise intensity. We relate this behavior to the fact that the active particle escapes from a limit cycle rather than from a fixed point and that a certain amount of noise can stabilize the sojourn of the particle on this limit cycle.

A mean-field approach to elastically coupled hair bundles.

We study the dynamics of oscillatory hair bundles which are coupled elastically in their deflection variable and are subject to noise. We present a stochastic description capturing the dynamics of the hair bundles' mean field. In particular, the presented derivation elucidates the origin of the previously described noise reduction by coupling. By comparison of simulations of the approximate dynamics and the full system, we verify our results. Furthermore, we demonstrate that the specific type of coupling considered implies coupling-induced changes in the dynamics beyond mere noise reduction.

Functional characterization and biological significance of Yersinia pestis lipopolysaccharide biosynthesis genes.

In silico analysis of available bacterial genomes revealed the phylogenetic proximity levels of enzymes responsible for biosynthesis of lipopolysaccharide (LPS) of Yersinia pestis, the cause of plague, to homologous proteins of closely related Yersinia spp. and some other bacteria (Serratia proteamaculans, Erwinia carotovora, Burkholderia dolosa, Photorhabdus luminescens and others). Isogenic Y. pestis mutants with single or double mutations in 14 genes of LPS biosynthetic pathways were constructed by site-directed mutagenesis on the base of the virulent strain 231 and its attenuated derivative. Using high-resolution electrospray ionization mass spectrometry, the full LPS structures were elucidated in each mutant, and the sequence of monosaccharide transfers in the assembly of the LPS core was inferred. Truncation of the core decreased significantly the resistance of bacteria to normal human serum and polymyxin B, the latter probably as a result of a less efficient incorporation of 4-amino-4-deoxyarabinose into lipid A. Impairing of LPS biosynthesis resulted also in reduction of LPS-dependent enzymatic activities of plasminogen activator and elevation of LD(50) and average survival time in mice and guinea pigs infected with experimental plague. Unraveling correlations between biological properties of bacteria and particular LPS structures may help a better understanding of pathogenesis of plague and implication of appropriate genes as potential molecular targets for treatment of plague.

Biological properties and structure of the lipopolysaccharide of a vaccine strain of Francisella tularensis generated by inactivation of a quorum sensing system gene qseC.

A knockout mutant with a deletion in a quorum sensing system gene qseC was generated from the vaccine strain Francisella tularensis 15 by site-directed mutagenesis. The variant with the inactivated gene qseC differed from the parental strain in growth rate on solid nutrient medium but had the same growth dynamics in liquid nutrient medium. The mutation abolished almost completely the resistance of the vaccine strain to normal rabbit serum and its ability to survive in macrophages; in addition, the strain lost the residual virulence. A significant phenotypic alteration was observed in the lipopolysaccharide of F. tularensis. Particularly, the mutant strain synthesized no noticeable amount of the lipopolysaccharide with the high-molecular-mass O-polysaccharide, presumably as a result of impairing biosynthesis of the repeating unit, namely, a loss of the ability to incorporate a formyl group, an N-acyl substituent of 4-amino-4,6-dideoxy-D-glucose.

[Structure of the oligosaccharide region (core) of the lipopolysaccharides of Shigella flexneri types 2a and 5b].

The full structure of the lipopolysaccharide core of bacteria Shigella flexneri types 2a and 5b, the causative agents of bacillary dysentery (shigellosis), was established by chemical methods, high-resolution electrospray ionization mass spectrometry, and two-dimensional NMR spectroscopy. The structure of the O-antigen repeating unit and the configuration and position of the linkage between the O-antigen and the core were determined in the lipopolysaccharide of S. flexneri type 2a.

The remarkable cochlear amplifier.

This composite article is intended to give the experts in the field of cochlear mechanics an opportunity to voice their personal opinion on the one mechanism they believe dominates cochlear amplification in mammals. A collection of these ideas are presented here for the auditory community and others interested in the cochlear amplifier. Each expert has given their own personal view on the topic and at the end of their commentary they have suggested several experiments that would be required for the decisive mechanism underlying the cochlear amplifier. These experiments are presently lacking but if successfully performed would have an enormous impact on our understanding of the cochlear amplifier.

[Incidence of anterior intertrochanteric ossifications after total hip arthroplasty--a retrospective long-term follow-up study]. / Inzidenz von anterioren intertrochantären Ossifikationen bei Hüfttotalendoprothesen--eine retrospektive Langzeituntersuchung.

AIM: This retrospective study investigates the incidence of anterior intertrochanteric ossifications (AIO), especially in comparison with heterotopic ossifications classified according to Brooker. A classification system of AIO regarding short-term results (< 1 year after surgery) was introduced in 2003: AIO occurred solely in 13 % of all cases (ossifications according to Brooker grade 0) and would have been "overlooked" without a lateral X-ray. The incidence of AIO combined with ossifications according to Brooker > 0 was 48.8 % of all cases. Our study reports long-term results, furthermore correlations between ossifications and clinical outcome, rated by the Harris hip score (HHS) and range of motion (ROM), are evaluated. MATERIAL AND METHODS: 149 cementless total hip arthroplasties (Hofer-Imhof threaded cup, straight stem), implanted into 140 patients from November 1991 to December 1994 underwent complete clinical and radiological follow-up from December 2005 to October 2006. The average age of the 81 female and 59 male patients at the time of implantation was 64 years. Without exception, a conventional, transgluteal approach (Bauer) was performed. All patients received indomethacin prophylaxis for 8 consecutive days after surgery. Current X-rays (a.-p. and lateral view) were evaluated in comparison with the former X-rays. RESULTS: AIO were found in 77 cases (51.7 %), heterotopic ossifications corresponding to Brooker in 93 cases (62.4 %), a combination of AIO and Brooker in 58 cases (38.9 %) and solitary AIO in 19 cases (12.8 %). HHS and ROM were not significantly altered by ossifications. CONCLUSION: Our long-term findings compare with the short-term results (indicating lack of new bone formation [heterotopic ossification] after more than one year after surgery, as previously described in the literature concerning ossifications according to Brooker) and verify the incidence rate of solitary AIO. Despite a minor correlation with clinical outcome, AIO could be considered as a possible indicator for predilection of heterotopic bone formation, especially if revision arthroplasty or THA of the contralateral side is needed.

Spontaneous movements and linear response of a noisy oscillator.

A deterministic system that operates in the vicinity of a Hopf bifurcation can be described by a single equation of a complex variable, called the normal form. Proximity to the bifurcation ensures that on the stable side of the bifurcation (i.e. on the side where a stable fixed point exists), the linear-response function of the system is peaked at the frequency that is characteristic of the oscillatory instability. Fluctuations, which are present in many systems, conceal the Hopf bifurcation and lead to noisy oscillations. Spontaneous hair bundle oscillations by sensory hair cells from the vertebrate ear provide an instructive example of such noisy oscillations. By starting from a simplified description of hair bundle motility based on two degrees of freedom, we discuss the interplay of nonlinearity and noise in the supercritical Hopf normal form. Specifically, we show here that the linear-response function obeys the same functional form as for the noiseless system on the stable side of the bifurcation but with effective, renormalized parameters. Moreover, we demonstrate in specific cases how to relate analytically the parameters of the normal form with added noise to effective parameters. The latter parameters can be measured experimentally in the power spectrum of spontaneous activity and linear-response function to external stimuli. In other cases, numerical solutions were used to determine the effects of noise and nonlinearities on these effective parameters. Finally, we relate our results to experimentally observed spontaneous hair bundle oscillations and responses to periodic stimuli.

Pleiotropic effects of the lpxM mutation in Yersinia pestis resulting in modification of the biosynthesis of major immunoreactive antigens.

Deletion mutants in the lpxM gene in two Yersinia pestis strains, the live Russian vaccine strain EV NIIEG and a fully virulent strain, 231, synthesise a less toxic penta-acylated lipopolysaccharide (LPS). Analysis of these mutants revealed they possessed marked reductions in expression and immunoreactivity of numerous major proteins and carbohydrate antigens, including F1, Pla, Ymt, V antigen, LPS, and ECA. Moreover, both mutants demonstrated altered epitope specificities of the antigens as determined in immunodot-ELISAs and immunoblotting analyses using a panel of monoclonal antibodies. The strains also differed in their susceptibility to the diagnostic plague bacteriophage L-413C. These findings indicate that the effects of the lpxM mutation on reduced virulence and enhanced immunity of the Y. pestis EV DeltalpxM is also associated with these pleiotropic changes and not just to changes in the lipid A acylation.

T-cell precursor frequencies and long-term outcome following unrelated hematopoietic stem cell transplantation.

Functional assays measuring alloreactivity of donor cells are desired to detect either cryptic epitopes inducing graft-vs.-host disease (GvHD) after human leukocyte antigen (HLA)-identical hematopoietic stem cell transplantation (HSCT) or permissible HLA mismatches. However, their value in predicting GvHD and survival is still limited. We determined the cytotoxic and helper T-cell precursor (CTLp and HTLp) frequencies by limiting dilution analysis (LDA) in 40 unrelated recipient/donor combinations. The median observation period at the time of this writing was 4.44 years (range from 0.1 to 11.28). Better overall survival was observed in patients with rather low host-specific CTLp and HTLp frequencies, whereas a trend toward high CTLp frequencies was seen in patients with higher incidence of acute GvHD, especially in patients mismatched in HLA-C. CTLp and HTLp frequencies did not correlate with the incidence of chronic GvHD and relapse. In conclusion, we detected a trend toward better overall survival of patient/donor pairs with low CTLp and HTLp frequencies, however, recommend to use LDA as an additional tool for identifying the most suitable donor when more than one fully HLA-matched stem cell donor is available.

Structural diversity and endotoxic activity of the lipopolysaccharide of Yersinia pestis.

The endotoxic activity of the lipopolysaccharides (LPS) with defined chemical structure from Yersinia pestis strains of various subspecies differing in their epidemic potential was studied. The LPS of two strains of Y. pestis ssp. caucasica and ssp. altaica, whose structures have not been studied earlier, were analyzed by high-resolution mass spectrometry. In addition to reported structural changes, an increase in the degree of LPS phosphorylation was observed when strain I-2377 (ssp. altaica) was cultivated at an elevated temperature. A high tumor necrosis factor alpha(TNF-alpha)-inducing activity observed for LPS samples from Y. pestis cultures grown at 25 degrees C correlated with an increased degree of lipid A acylation, particularly, with the presence of the hexaacyl form of lipid A, which was absent from the LPS when bacteria were cultivated at 37 degrees C. No correlation was found between the lethal toxicity of the LPS in vivo and its ability to induce TNF-alpha production in vitro.

A Yersinia pestis lpxM-mutant live vaccine induces enhanced immunity against bubonic plague in mice and guinea pigs.

The lpxM mutant of the live vaccine Yersinia pestis EV NIIEG strain synthesising a less toxic penta-acylated lipopolysaccharide was found to be avirulent in mice and guinea pigs, notably showing no measurable virulence in Balb/c mice which do retain some susceptibility to the parental strain itself. Twenty-one days after a single injection of the lpxM-mutant, 85-100% protection was achieved in outbred mice and guinea pigs, whereas a 43% protection rate was achieved in Balb/c mice given single low doses (10(3) to 2.5 x 10(4) CFU) of this vaccine. A subcutaneous challenge with 2000 median lethal doses (equal to 20,000 CFU) of fully virulent Y. pestis 231 strain, is a 6-10-fold higher dose than that which the EV NIIEG itself can protect against.

Endotoxin: physical requirements for cell activation.

Lipopolysaccharide (LPS) is the eminent lipid component of the outer leaflet of the outer membrane of Gram-negative bacteria and the major initiator of innate immune response to bacterial infection. Below the critical micellar concentration (CMC), LPS is exclusively present as a monomer. Above this concentration, aggregates are formed. Increasing the concentration beyond the CMC leads to an increase in aggregate concentration, whereas the concentration of monomers remains constant or even decreases. The question how LPS activates immune cells and whether the aggregate or the monomer is the biologically active unit has been and still is controversial. To prepare clearly defined monomeric solutions, we utilized a dialysis set-up consisting of a donor and an acceptor chamber, separated by a dialysis diaphragm with a cut-off of 5 kDa, thus allowing only monomers to pass. Human mononuclear cells (MNCs) were then stimulated with equal concentrations of aggregates and monomers, respectively, of deep rough mutant LPS from Escherichia coli strain F515 (Re LPS) and TNF-alpha release was determined. In contrast to earlier and very recent work of others, we started with a preparation of aggregate-suspensions and pure monomer-solutions and show that monomers are significantly less active than aggregates in the absence and presence of serum proteins at identical concentrations. In our model, we propose that LPS aggregates are detected by membrane-associated LBP and intercalated into the cell membrane to bring LPS into close proximity to signaling proteins in the membrane, thus finally leading to cell activation. To support this model, we present data showing that LBP is indeed present in or at the cell membrane of human macrophages.

Sinorhizobium meliloti strain 1021 produces a low-molecular-mass capsular polysaccharide that is a homopolymer of 3-deoxy-D-manno-oct-2-ulosonic acid harboring a phospholipid anchor.

Sinorhizobium meliloti strain 1021 possesses the particularity to synthesize biologically inefficient capsular polysaccharides (KPS). It has been assumed that this class of compounds is not produced in high-molecular-mass (HMM) forms, even if many genetic analyses show the existence of expression of genes involved in the biosynthesis of capsular polysaccharides. The expression of these genes that are involved in the export of a KPS throughout the membrane and in the attachment of a lipid moiety has never been related to a structurally characterized surface polysaccharide. It is now reported that S. meliloti strain 1021 produces low-molecular-mass polysaccharides (4-4.5 kDa) that are exclusively composed of beta-(2-->7)-linked 3-deoxy-d-manno-oct-2-ulopyranosonic acid (Kdo) residues. These compounds are considered precursor molecules of HMM KPS, whose biosynthesis is arrested in the case of S. meliloti strain 1021. For the first time, the phospholipid anchor of a rhizobial KPS has been found, and its structure could be partially identified-namely, a phosphoglycerol moiety bearing a hydroxy-octacosanoic acid. When compared to other rhizobial KPS (composed of dimeric hexose-Kdo-like sugar repeating units), the Kdo homopolymer described here may explain why a complementation of S. meliloti strain 1021 Exo B mutant with an effective rkpZ gene restoring an active higher KPS size does not completely lead to the fully effective nitrogen fixing phenotype.

The pmrF polymyxin-resistance operon of Yersinia pseudotuberculosis is upregulated by the PhoP-PhoQ two-component system but not by PmrA-PmrB, and is not required for virulence.

The Yersinia pseudotuberculosis chromosome contains a seven-gene polycistronic unit (the pmrF operon) whose products share extensive homologies with their pmrF counterparts in Salmonella enterica serovar Typhimurium (S. typhimurium), another Gram-negative bacterial enteropathogen. This gene cluster is essential for addition of 4-aminoarabinose to the lipid moiety of LPS, as demonstrated by MALDI-TOF mass spectrometry of lipid A from both wild-type and pmrF-mutated strains. As in S. typhimurium, 4-aminoarabinose substitution of lipid A contributes to in vitro resistance of Y. pseudotuberculosis to the antimicrobial peptide polymyxin B. Whereas pmrF expression in S. typhimurium is mediated by both the PhoP-PhoQ and PmrA-PmrB two-component regulatory systems, it appears to be PmrA-PmrB-independent in Y. pseudotuberculosis, with the response regulator PhoP interacting directly with the pmrF operon promoter region. This result reveals that the ubiquitous PmrA-PmrB regulatory system controls different regulons in distinct bacterial species. In addition, pmrF inactivation in Y. pseudotuberculosis has no effect on bacterial virulence in the mouse, again in contrast to the situation in S. typhimurium. The marked differences in pmrF operon regulation in these two phylogenetically close bacterial species may be related to their dissimilar lifestyles.