[Assessment of mobility/motor skills in old age : Based on the S1 guideline "Geriatric assessment level 2, living guideline"]. / Assessment der Mobilität/Motorik im Alter : Basierend auf der S1-Leitlinie "Geriatrisches Assessment der Stufe 2, Living Guideline".

In addition to locomotion, mobility also includes any motor performance that serves other purposes and movements that are unplanned. This article presents the instruments mentioned in the S1 guideline "Geriatric assessment level 2, living guideline", as well as additional ones that are less known. The classification is into three categories: instruments that focus on the upper extremities, instruments without performance, which mainly focus on the functions and capabilities of the lower extremities, and those that do this using performance tests.

Translocation dynamics of knotted polymers under a constant or periodic external field.

We perform Brownian dynamics simulations to examine how knots alter the dynamics of polymers moving through nanopores under an external field. In the first part of this paper, we study the situation when the field is constant. Here, knots halt translocation above a critical force with jamming occurring at smaller forces for twist topologies compared to non-twist topologies. Slightly below the jamming transition, the polymer's transit times exhibit large fluctuations. This phenomenon is an example of the knot's molecular individualism since the conformation of the knot plays a large role in the chain's subsequent dynamics. In the second part of the paper, we study the motion of the chain when one cycles the field on and off. If the off time is comparable to the knot's relaxation time, one can adjust the swelling of the knot at the pore and hence design strategies to ratchet the polymer in a controllable fashion. We examine how the off time affects the ratcheting dynamics. We also examine how this strategy alters the fluctuations in the polymer's transit time. We find that cycling the force field can reduce fluctuations near the knot's jamming transition, but can enhance the fluctuations at very high forces since knots get trapped in metastable states during the relaxation process. The latter effect appears to be more prominent for non-torus topologies than torus ones. We conclude by discussing the feasibility of this approach to control polymer motion in biotechnology applications such as sequencing.

Origin of metastable knots in single flexible chains.

Recent theoretical progress has explained the physics of knotting of semiflexible polymers, yet knotting of flexible polymers is relatively unexplored. We herein develop a new theory for the size distribution of knots on a flexible polymer and the existence of metastable knots. We show the free energy of a flexible molecule in a tube can be mapped to quantitatively reproduce the free energy distribution of a knot on a flexible chain. The size distribution of knots on flexible chains is expected to be universal and might be observed at a macroscopic scale, such as a string of hard balls.

Stretching self-entangled DNA molecules in elongational fields.

We present experiments of self-entangled DNA molecules stretching under a planar elongational field, and their stretching dynamics are compared to identical molecules without entanglements. Self-entangled molecules stretch in a stage-wise fashion, persisting in an "arrested" state for decades of strain prior to rapidly stretching, slowing down the stretching dynamics by an order of magnitude compared to unentangled molecules. Self-entangled molecules are shown to proceed through a transient state where one or two ends of the molecule are protruding from an entangled, knotted core. This phenomenon sharply contrasts with the wide array of transient configurations shown here and by others for stretching polymers without entanglements. The rate at which self-entangled molecules stretch through this transient state is demonstrably slower than unentangled molecules, providing the first direct experimental evidence of a topological friction. These experimental observations are shown to be qualitatively and semi-quantitatively reproduced by a dumbbell model with two fitting parameters, the values of which are reasonable in light of previous experiments of knotted DNA.

Doping nature of native defects in 1T-TiSe2.

The transition-metal dichalcogenide 1T-TiSe2 is a quasi-two-dimensional layered material with a charge density wave (CDW) transition temperature of T(CDW) ≈ 200 K. Self-doping effects for crystals grown at different temperatures introduce structural defects, modify the temperature-dependent resistivity, and strongly perturbate the CDW phase. Here, we study the structural and doping nature of such native defects combining scanning tunneling microscopy or spectroscopy and ab initio calculations. The dominant native single atom dopants we identify in our single crystals are intercalated Ti atoms, Se vacancies, and Se substitutions by residual iodine and oxygen.

Lateral parabrachial FoxP2 neurons regulate respiratory responses to hypercapnia.

About half of the neurons in the parabrachial nucleus (PB) that are activated by CO2 are located in the external lateral (el) subnucleus, express calcitonin gene-related peptide (CGRP), and cause forebrain arousal. We report here, in male mice, that most of the remaining CO2-responsive neurons in the adjacent central lateral (PBcl) and Kölliker-Fuse (KF) PB subnuclei express the transcription factor FoxP2 and many of these neurons project to respiratory sites in the medulla. PBclFoxP2 neurons show increased intracellular calcium during wakefulness and REM sleep and in response to elevated CO2 during NREM sleep. Photo-activation of the PBclFoxP2 neurons increases respiration, whereas either photo-inhibition of PBclFoxP2 or genetic deletion of PB/KFFoxP2 neurons reduces the respiratory response to CO2 stimulation without preventing awakening. Thus, augmenting the PBcl/KFFoxP2 response to CO2 in patients with sleep apnea in combination with inhibition of the PBelCGRP neurons may avoid hypoventilation and minimize EEG arousals.

Effector memory and central memory NY-ESO-1-specific re-directed T cells for treatment of multiple myeloma.

The cancer-testis antigen NY-ESO-1 is a potential target antigen for immune therapy expressed in a subset of patients with multiple myeloma. We generated chimeric antigen receptors (CARs) recognizing the immunodominant NY-ESO-1 peptide 157-165 in the context of HLA-A*02:01 to re-direct autologous CD8(+) T cells towards NY-ESO-1(+) myeloma cells. These re-directed T cells specifically lysed NY-ESO-1(157-165)/HLA-A*02:01-positive cells and secreted IFNγ. A total of 40% of CCR7(-) re-directed T cells had an effector memory phenotype and 5% a central memory phenotype. Based on CCR7 cell sorting, effector and memory CAR-positive T cells were separated and CCR7(+) memory cells demonstrated after antigen-specific re-stimulation downregulation of CCR7 as sign of differentiation towards effector cells accompanied by an increased secretion of memory signature cytokines such as IL-2. To evaluate NY-ESO-1 as potential target antigen, we screened 78 bone marrow biopsies of multiple myeloma patients where NY-ESO-1 protein was found to be expressed by immunohistochemistry in 9.7% of samples. Adoptively transferred NY-ESO-1-specific re-directed T cells protected mice against challenge with endogenously NY-ESO-1-positive myeloma cells in a xenograft model. In conclusion, re-directed effector- and central memory T cells specifically recognized NY-ESO-1(157-165)/ HLA-A*02:01-positive cells resulting in antigen-specific functionality in vitro and in vivo.

The use of 5-aminolevulinic acid fluorescence guidance in resection of pediatric brain tumors.

INTRODUCTION: Whereas in the adult population 5-Aminolevulinic acid (5-ALA) fluorescence guidance has been widely accepted for improving the extent of tumor resection, the application in children remains an off-label use. Even though most pediatric study protocols require a complete resection for improving outcome parameters, only few pediatric patients have been operated with fluorescence guidance, and it remains questionable, whether and which pediatric tumors show useful fluorescence. We present casuistic reports of application of 5-ALA in children collected from three different neurosurgical departments. PATIENTS AND METHODS: In children with suspected malignant intracerebral tumor or recurrence, individual informed consent was obtained in each case from the parents. 5-ALA was administered according to the adult protocol, with 20 mg/kg, 2 h before induction of anesthesia. We retrospectively analyzed 18 patients (13 male, 5 female; age 3-18 years), using the intraoperative neurosurgical protocol, the postoperative MRI results, and the follow-up clinical examinations. RESULTS: The use of 5-ALA fluorescence guidance proved to be safe in our group of pediatric patients. Fluorescence guidance was most useful for recurrent glioblastoma resection. Medulloblastoma tissue displayed fluorescence only inconsistently, and most pilocytic astrocytoma remained without staining. Ganglioglioma showed partial staining in the central tumor areas, without allowing the use for circumferent resection. CONCLUSION: The off-label use of 5-ALA fluorescence guidance in pediatric patients appears to be most useful in recurrent high-grade gliomas. Fluorescence accumulation in other pediatric brain tumor entities is not predictable and should be evaluated in future clinical studies before being integrated into the current treatment protocols.

Comparing brain tissue oxygen measurements and derived autoregulation parameters from different probes (Licox vs. Raumedic).

We investigated two commercially available probes for measurement of the partial pressure of brain tissue oxygen (PbrO2) and calculation of the index of brain tissue oxygen pressure reactivity (ORx) in 7 patients after aneurysmal subarachnoid hemorrhage (SAH). Simultaneous monitoring of PbrO2 using the Licox(®) probe and the multiparameter Raumedic probe (Neurovent PTO(®)), measuring PbrO2, intracranial pressure (ICP) and brain temperature (Neurovent PTO) was performed for a median of 9 days (range 7-17 days). Both probes provided stable monitoring throughout the desired period. Mean PbrO2 from Licox and Neurovent PTO was 16.1 ± 9.0 mmHg and 17.5 ± 11.9 mmHg respectively. Mean ORx was 0.35 ± 0.44 and 0.31 ± 0.43 respectively. There was a difference in the measurement of PbrO2 of -2.73 ± 10.1 mmHg (Licox - Raumedic). The difference in the two values for the calculated ORx was far smaller (0.03 ± 0.31; Licox - Raumedic) and the correlation coefficient higher than for both values of PbrO2 (0.76 for ORx vs. 0.56 for PbrO2). The calculation of the autoregulation parameter ORx seemed more independent of the measurement process than the measurement of PbrO2 itself and signifies the potential clinical importance of this parameter.

Biomechanical comparisons of three minimally invasive Achilles tendon percutaneous repair suture techniques.

BACKGROUND: While no gold standard exists for the management of Achilles tendon ruptures, surgical repair is common in healthy and active patients. Minimally invasive repair methods have become increasingly popular, while biomechanical equivalency hasn't been proven yet. METHODS: A mid-substance Achilles tendon rupture was created 6 cm proximal to the calcaneal insertion in 27 fresh-frozen cadaveric ankles. Specimens were randomly allocated to 1 of 3 repair techniques: Huttunen et al. (2014) (1) PARS Achilles Jig System, Nyyssönen et al. (2008) (2) Achilles Midsubstance SpeedBridge™, Schipper and Cohen (2017) (3) Dresdner Instrument and subsequently subjected to cyclic loading with 250 cycles each at 1 Hz with 4 different loading ranges (20-100 N, 20-200 N, 20-300 N, and 20-400 N). FINDINGS: After 250 cycles no significant differences in elongation were observed between PARS and Dresdner Instrument(p = 1.0). Furthermore, SpeedBridge™ repairs elongated less than either Dresdner Instrument (p = 0.0006) or PARS (p = 0.102). Main elongation (85%) occurred within the first 10 cycles with a comparable elongation in between 10 and 100 and 100-250 cycles. While all repairs withstood the first 250 cycles of cyclic loading from 20 to 100 N, only the PARS (468 ± 175) and Midsubstance SpeedBridge™ (538 ± 208) survived more cycles. Within all 3 groups suture cut out was seen to be the most common failure mechanism. INTERPRETATION: Within all groups early repair elongation was seen. While this was least obvious within the SpeedBridge™ technique, ultimate strengths of repairs (cycles to failure) were comparable across PARS and SpeedBridge™ with a decline in the Dresdner Instrument group.

Selective intra-arterial chemotherapy with floxuridine as second- or third-line approach in patients with unresectable colorectal liver metastases.

BACKGROUND: An outcome assessment was performed of patients with unresectable colorectal liver metastases (CRLM) treated in second or third line with floxuridine (FUDR)-based hepatic artery infusion (HAI). METHODS: Twenty-three patients who were pretreated with systemic (immuno)chemotherapy received FUDR-HAI alone or combined with systemic chemotherapy. We reviewed patient charts and our prospective patient database for survival and associated risk factors. RESULTS: Patients received FUDR-HAI for unresectable CRLM from January 2000 to September 2010. Twelve patients (52%) received concurrent systemic chemotherapy. Median overall survival (OS), progression-free survival (PFS), and hepatic PFS were 15.6 months (range, 2.5-55.7 months), 3.9 months (range, 0.7-55.7 months), and 5.5 months (range, 1.6-55.7 months), respectively. The liver resection rate after HAI was 35%. PFS was better in patients undergoing secondary resection than in patients without resection (hazard ratio [HR] 0.21; 95% confidence interval [95% CI] 0.07-0.66; P = 0.0034), while OS showed a trend toward improvement (HR 0.4; 95% CI 0.13-1.2; P = 0.09). No differences were observed in OS (P = 0.69) or PFS (P = 0.086) in patients who received FUDR-HAI alone compared with patients treated with combined regional and systemic chemotherapy. No statistically significant differences were seen in patients previously treated with one chemotherapy line compared with patients treated with two lines. Presence of extrahepatic disease was a negative risk factor for PFS (liver-only disease: HR 0.03; 95% CI 0.0032-0.28; P < 0.0001). Toxicities were manageable with dose modifications and supportive measures. CONCLUSIONS: FUDR-HAI improves PFS and results in a trend toward improved OS in selected patients able to undergo liver resection after tumor is downsized.

Risk-adapted FDG-PET/CT-based follow-up in patients with diffuse large B-cell lymphoma after first-line therapy.

BACKGROUND: The purpose of this study was to evaluate the impact of 2-[fluorine-18]fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography (FDG-PET/CT) during follow-up of patients with diffuse large B-cell lymphoma (DLBCL) being in complete remission or unconfirmed complete remission after first-line therapy. PATIENTS AND METHODS: DLBCL patients receiving FDG-PET/CT during follow-up were analyzed retrospectively. Confirmatory biopsy was mandatory in cases of suspected disease recurrence. RESULTS: Seventy-five patients were analyzed and 23 (30%) had disease recurrence. The positive predictive value (PPV) of FDG-PET/CT was 0.85. Patients >60 years [P = 0.036, hazard ratio (HR) = 3.82, 95% confidence interval (CI) 1.02-7.77] and patients with symptoms indicative of a relapse (P = 0.015; HR = 4.1; 95% CI 1.20-14.03) had a significantly higher risk for relapse. A risk score on the basis of signs of relapse, age >60 years, or a combination of these factors identified patients at high risk for recurrence (P = 0.041). CONCLUSIONS: FDG-PET/CT detects recurrent DLBCL after first-line therapy with high PPV. However, it should not be used routinely and if only in selected high-risk patients to reduce radiation burden and costs. On the basis of our retrospective data, FDG-PET/CT during follow-up is indicated for patients <60 years with clinical signs of relapse and in patients >60 years with and without clinical signs of relapse.

Hodgkin's lymphoma in remission after first-line therapy: which patients need FDG-PET/CT for follow-up?

BACKGROUND: The purpose of the study was to evaluate the impact of 2-[fluorine-18]fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET)/computed tomography (CT) during follow-up of patients with Hodgkin's lymphoma. PATIENTS AND METHODS: Patients in complete remission or an unconfirmed complete remission after first-line therapy who received FDG-PET/CT during their follow-up were analyzed retrospectively. Confirmatory biopsy was mandatory in case of recurrence. RESULTS: Overall, 134 patients were analyzed. Forty-two (31.3%) patients had a recurrence. The positive predictive value of FDG-PET/CT was 0.98. Single-factor analysis identified morphological residual mass [P = 0.0005, hazard ratio (HR) 3.4, 95% confidence interval (CI) 1.7-6.6] and symptoms (P < 0.0001, HR 4.9, 95% CI 2.4-9.9) as significant risk factors for relapse. By multivariate analysis, morphological residual mass was the only significant risk factor for early follow-up (<24 months) (P = 0.0019, HR 7.6, 95% CI 2.1-27.3). Advanced stage (P = 0.0426, HR 3.6, 95% CI 1.1-12.3) and the presence of symptoms (P = 0.0009, HR = 14.6, 95% CI 3.0-69.7) were found to be significant risk factors for later follow-up (>24 months). CONCLUSIONS: Asymptomatic patients without morphological residues and an early stage of disease do not need a routine FDG-PET/CT for follow-up. Asymptomatic patients with morphological residues should receive routine follow-up FDG-PET/CT for the first 24 months. Only patients with advanced initial stage do need a routine follow-up FDG-PET/CT beyond 24 months.

Role of serotonergic dorsal raphe neurons in hypercapnia-induced arousals.

During obstructive sleep apnea, elevation of CO2 during apneas contributes to awakening and restoring airway patency. We previously found that glutamatergic neurons in the external lateral parabrachial nucleus (PBel) containing calcitonin gene related peptide (PBelCGRP neurons) are critical for causing arousal during hypercapnia. However, others found that genetic deletion of serotonin (5HT) neurons in the brainstem also prevented arousal from hypercapnia. To examine interactions between the two systems, we showed that dorsal raphe (DR) 5HT neurons selectively targeted the PBel. Either genetically directed deletion or acute optogenetic silencing of DRSert neurons dramatically increased the latency of mice to arouse during hypercapnia, as did silencing DRSert terminals in the PBel. This effect was mediated by 5HT2a receptors which are expressed by PBelCGRP neurons. Our results indicate that the serotonergic input from the DR to the PBel via 5HT2a receptors is critical for modulating the sensitivity of the PBelCGRP neurons that cause arousal to rising levels of blood CO2.

Cure of xenografted human tumors by bispecific monoclonal antibodies and human T cells.

Tumor immunotherapy should increase both the number of T cells that kill the tumor and the likelihood that those cells are activated at the tumor site. Bispecific monoclonal antibodies (Bi-mAbs) were designed that bound to a Hodgkin's tumor-associated antigen (CD30) on the tumor and to either CD3 or CD28 on the T cell. Immunodeficient mice were cured of established human tumors when mice were treated with both the CD3-CD30 and the CD28-CD30 Bi-mAbs and then given human peripheral blood lymphocytes that had been incubated with the CD3-CD30 Bi-mAb and cells that expressed CD30. The enrichment of human T cells within the tumor and the fact that established tumors can be cured may indicate in situ activation of both the T cell receptor and the costimulatory pathway.

MAGE-C1/CT-7 expression in plasma cell myeloma: sub-cellular localization impacts on clinical outcome.

Plasma cell myelomas (PMs) have a poor prognosis. Cancer-testis (CT) antigens are immunogenic proteins, representing potential targets for tumor vaccination strategies. The expression of the CT antigens GAGE, MAGE-A4, MAGE-C1/CT-7, and NY-ESO-1 was investigated on paraffin-embedded bone marrow biopsies from 219 PM and 8 monoclonal gammopathy of undetermined significance (MGUS) patients. The frequency and prognostic impact of these CT antigens were compared with known morphological prognostic markers (i.e. Mib1 labeling index) and the presence of the translocations t(4;14)(p16.3; q32) and t(11;14)(q13;q32). We show that MAGE-C1/CT-7 is the most prevalent CT antigen, expressed in 57% of PMs in a high percentage of tumor cells. While MAGE-C1/CT-7 was absent in non-malignant plasma cells, plasma cells of patients with MGUS did express MAGE-C1/CT-7, but no other CT antigens. MAGE-C1/CT-7 was more frequently expressed in PMs with an elevated proliferation rate (Mib1 >10%) compared to PMs with a low proliferation rate (Mib1

Scrubbing intensification for sulphur and ammonia compounds removal.

Operating conditions were optimised in a new compact scrubber in order to remove odorous sulphur (H(2)S and CH(3)SH) and ammonia compounds. The influence of the superficial gas and liquid velocities, pH, contactor length, inlet concentrations (sulphur compounds, ammonia, chlorine), and the mixing effects was characterised. Whereas abatement increased with velocities, pH and the chlorine concentration, an increase of inlet CH(3)SH concentration drove to a worse efficiency of process. Moreover, the contactor length and the presence of another pollutant in the gas phase only played a role on the methylmercaptan removal. Finally, the reactive consumptions were estimated at the outlet of the reactor. The chlorination by-product quantification permitted to understand the under-stoichiometry.

Expression of RHAMM/CD168 and other tumor-associated antigens in patients with B-cell chronic lymphocytic leukemia.

Antigen targeted immunotherapies might represent a novel treatment for B-cell chronic lymphocytic leukemia (B-CLL). We screened the mRNA expression of tumor-associated antigens (TAAs) from the literature (fibromodulin, survivin, OFA-iLRP, BAGE, G250, MAGE1, PRAME, proteinase, syntaxin, hTERT, WT-1) and TAAs defined previously by serological analysis of cDNA expression libraries from leukemic cells (PINCH, HSJ2, MAZ, MPP11, RHAMM/CD168, NY-Ren60). Peripheral blood mononuclear cells from 43 B-CLL patients and 20 healthy volunteers (HVs) were examined by conventional and quantitative RT-PCR. mRNA of RHAMM/CD168, fibromodulin, syntaxin and NY-Ren60 was expressed in 55-90%, and mRNA of HSJ2, MAZ and OFAiLRP was expressed in 90-100% of the patients. No expression of WT-1, hTERT, BAGE, G250, MAGE1 or survivin was observed. Low (2-20%) expression frequencies of MPP11, PINCH, PRAME and proteinase were detected. RHAMM/CD168, fibromodulin, PRAME and MPP11 showed expression in B-CLL patients, but not in HVs. Because of the exquisite tissue expression of RHAMM/CD168 and its high expression frequency in CLL patients, mixed lymphocyte peptide culture (MLPC), enzyme-linked immunosorbent spot (ELISPOT) and flow cytometry were performed for antigen specific T-cells. In MLPC, RHAMM specific responses by CD8+HLA-A2/R3tetramer+CCR7-CD45RAhigh effector T-cells were detected. RHAMM/CD168 might be a possible target for future immunotherapies in both ZAP-70(+) and ZAP-70(-) B-CLL patients.

Solution structure of PCP, a prototype for the peptidyl carrier domains of modular peptide synthetases.

BACKGROUND: Nonribosomal peptide synthetases (NRPSs) are large modular enzymes responsible for the synthesis of a variety of microbial bioactive peptides. They consist of modules that each recognise and incorporate one specific amino acid into the peptide product. A module comprises several domains, which carry out the individual reaction steps. After activation by the adenylation domain, the amino acid substrate is covalently tethered to a 4'-phosphopantetheinyl cofactor of a peptidyl carrier domain (PCP) that passes the substrate to the reaction centres of the consecutive domains. RESULTS: The solution structure of PCP, a distinct peptidyl carrier protein derived from the equivalent domain of an NRPS, was solved using NMR techniques. PCP is a distorted four-helix bundle with an extended loop between the first two helices. Its overall fold resembles the topology of acyl carrier proteins (ACPs) from Escherichia coli fatty acid synthase and actinorhodin polyketide synthase from Streptomyces coelicolor; however, the surface polarity and the length and relative alignment of the helices are different. The conserved serine, which is the cofactor-binding site, has the same location as in the ACPs and is situated within a stretch of seven flexible residues. CONCLUSIONS: The structure of PCP reflects its character as a protein domain. The fold is well defined between residues 8 and 82 and the structural core of the PCP domain can now be defined as a region spanning 37 amino acids in both directions from the conserved serine. The flexibility of the post-translationally modified site might have implications for interactions with the cooperating proteins or NRPS domains.