Synergies of THESEUS with the large facilities of the 2030s and guest observer opportunities.

The proposed THESEUS mission will vastly expand the capabilities to monitor the high-energy sky. It will specifically exploit large samples of gamma-ray bursts to probe the early universe back to the first generation of stars, and to advance multi-messenger astrophysics by detecting and localizing the counterparts of gravitational waves and cosmic neutrino sources. The combination and coordination of these activities with multi-wavelength, multi-messenger facilities expected to be operating in the 2030s will open new avenues of exploration in many areas of astrophysics, cosmology and fundamental physics, thus adding considerable strength to the overall scientific impact of THESEUS and these facilities. We discuss here a number of these powerful synergies and guest observer opportunities.

Implications of Dedicated Seismometer Measurements on Newtonian-Noise Cancellation for Advanced LIGO.

Newtonian gravitational noise from seismic fields will become a limiting noise source at low frequency for second-generation, gravitational-wave detectors. It is planned to use seismic sensors surrounding the detectors' test masses to coherently subtract Newtonian noise using Wiener filters derived from the correlations between the sensors and detector data. In this Letter, we use data from a seismometer array deployed at the corner station of the Laser Interferometer Gravitational Wave Observatory (LIGO) Hanford detector combined with a tiltmeter for a detailed characterization of the seismic field and to predict achievable Newtonian-noise subtraction levels. As was shown previously, cancellation of the tiltmeter signal using seismometer data serves as the best available proxy of Newtonian-noise cancellation. According to our results, a relatively small number of seismometers is likely sufficient to perform the noise cancellation due to an almost ideal two-point spatial correlation of seismic surface displacement at the corner station, or alternatively, a tiltmeter deployed under each of the two test masses of the corner station at Hanford will be able to efficiently cancel Newtonian noise. Furthermore, we show that the ground tilt to differential arm-length coupling observed during LIGO's second science run is consistent with gravitational coupling.

[5-Year-Follow-up of the MEmbeR Multicenter Study on Medical-Occupational Rehabilitation]. / 5-Jahres-Follow-Up der multizentrischen Evaluationsstudie zur medizinisch-beruflichen Rehabilitation (MEmbeR).

In Germany, medical-occupational rehabilitation represents an essential link between rehabilitation programs focusing either on medical or occupational rehabilitation. Its main objective is return to work. The current study presents the vocational integration 5 years after medical-occupational rehabilitation and determines possible prognostic factors for long-term occupational integration. To evaluate the effectiveness of medical-occupational rehabilitation, a 5-year-follow-up interview was conducted with participants (n=105) of the multicenter study on medical-occupational rehabilitation (MEmbeR). As a main result, 76% of the participants were still employed 5 years after medical-occupational rehabilitation and the return to work rate was 57%. Prognostic factors for long-term occupational integration could not be identified. However, a low degree of disability, an unrestricted capacity for teamwork as well as an unrestricted ability to judge might be beneficial factors for a successful reintegration. The high amount of participants who returned to work 5 years after medical-occupational rehabilitation, supports the concept of medical-occupational rehabilitation. However, more studies are needed to identify further factors influencing the outcome.

[Interbody fusion procedures. Development from a historical perspective]. / Interkorporelle Fusionsverfahren an der Wirbelsäule. Die Entwicklung aus historischer Sicht.

BACKGROUND: The development of interbody fusion now stretches over many decades and is still not complete. DISCUSSION: Due to the lack of appropriate implants, the initial fusions were performed via decortication of the dorsal and lateral structures of the spine, followed by placement of an autograft. Despite acceptable fusion results, better primary stability and higher fusion rates were desired. In addition, it became known that the primary load-bearing of the spine is located ventrally in the area of the corpus of the vertebrae. These considerations led to the development of the PLIF technique that was introduced by Cloward in 1953 and gained significantly in popularity. After removal of the intervertebral disc, he positioned iliac crest bone blocks between the vertebral bodies. Based on this technique and these considerations, intervertebral implants were developed in the 1970s. The so-called Bagby Basket was the first intervertebral cage that was initially used in horses with wobbler syndrome. Other milestones in the improvement of the cage designs followed, resulting in the production of different implant shapes and materials. The elastic modulus of the interbody implants approached by modern materials became more and more similar to bone, so that subsidence of cages reduced and the fusion rate could be further increased. The primary stability could be further increased with screw-rod systems, so that dorsal instrumentation became the standard in the context of PLIF and TLIF procedures today. The TLIF procedure described by Harms was a new modification and minimized complications of lumbar fusions and reduced the invasiveness of the procedure. CONCLUSION: Nowadays a wide variety of implants and implantation techniques are available, making interbody fusions in PLIF and TLIF techniques safe and successful procedures.

[Therapy of scoliosis from a historical perspective]. / Therapie der Skoliose aus historischer Sicht.

Scoliosis can be considered as one of the classical orthopedic diseases of the spine. The history of orthopedics is closely connected to the development of the therapy of scoliosis. In the eighteenth and the beginning of the nineteenth centuries the therapy of scoliosis was mainly a conservative corrective orthopedic treatment with a variety of corset forms and extension bed treatment. In the middle of the nineteenth century physiotherapy (movement therapy) became established as an supplementary active treatment. The first operations for treatment of scoliosis were carried out in 1839. The real success with surgical procedures for improvement in corrective options was connected to the introduction of metal spinal implants in the early 1960s.

Visual generalization in honeybees: evidence of peak shift in color discrimination.

In the present study, we investigated color generalization in the honeybee Apis mellifera after differential conditioning. In particular, we evaluated the effect of varying the position of a novel color along a perceptual continuum relative to familiar colors on response biases. Honeybee foragers were differentially trained to discriminate between rewarded (S+) and unrewarded (S-) colors and tested on responses toward the former S+ when presented against a novel color. A color space based on the receptor noise-limited model was used to evaluate the relationship between colors and to characterize a perceptual continuum. When S+ was tested against a novel color occupying a locus in the color space located in the same direction from S- as S+, but further away, the bees shifted their stronger response away from S- toward the novel color. These results reveal the occurrence of peak shift in the color vision of honeybees and indicate that honeybees can learn color stimuli in relational terms based on chromatic perceptual differences.

[The MEmbeR Multicenter Study on medical-occupational rehabilitation]. / Multizentrische Evaluationsstudie zur medizinisch-beruflichen Rehabilitation (MEmbeR).

INTRODUCTION: MEmbeR is a prospective multi-center study on medical-occupational rehabilitation in Germany. METHODS: 196 neurological, psychiatric, orthopaedic, and internal medicine patients from 21 rehabilitation centres all across Germany have been enrolled and followed-up for 2 years after discharge. Primary outcome parameter was defined as return to work. Further, the SF-12 and a Mini-ICF-Rating have been used. RESULTS: Mean age was 34.1 (9.9) years, length of stay 150.0 (223.5) days. Prior to occupational rehabilitation, 69.9% were unable to work, 2 years after discharge only 5.6%. Rate of participants seeking a job was reduced from 19.7% to 3.1%. In summary, 78.1% returned to work. Employed participants were younger (32.8 [9.7] vs. 38.5 [9.4] years, p=0.001) and less disabled (Degree of Disablement [GdB]: 20.0 [31.2] vs. 36.1 [33.7], p<0.05). CONCLUSION: The multicenter cohort study MEmbeR provides further knowledge about the outcome of medical-occupational rehabilitation in Germany.

Evidence of red sensitive photoreceptors in Pygopleurus israelitus (Glaphyridae: Coleoptera) and its implications for beetle pollination in the southeast Mediterranean.

A very well-documented case of flower-beetle interaction is the association in the Mediterranean region between red bowl-shaped flowers and beetles of the family Glaphyridae. The present study examines the visual mechanisms by which Pygopleurus israelitus (Glaphyridae: Scarabaeoidea: Coleoptera) would perceive the colors of flowers they visit by characterizing the spectral sensitivity of its photoreceptors. Our measurements revealed the presence of three types of photoreceptors, maximally sensitive in the UV, green and red areas of the spectrum. Using color vision space diagrams, we calculated the distribution of beetle-visited flower colors in the glaphyrid and honeybee color space and evaluated whether chromatic discrimination differs between the two types of pollinators. Respective color loci in the beetle color space are located on one side of the locus for green foliage background, whereas in the honeybee the flower color loci surround the locus occupied by green foliage. Our results represent the first evidence of a red sensitive photoreceptor in a flower-visiting coleopteran species, highlighting Glaphyridae as an interesting model group to study the role of pollinators in flower color evolution.

Can red flowers be conspicuous to bees? Bombus dahlbomii and South American temperate forest flowers as a case in point.

It has been argued that trichromatic bees with photoreceptor spectral sensitivity peaks in the ultraviolet (UV), blue and green areas of the spectrum are blind to long wavelengths (red to humans). South American temperate forests (SATF) contain a large number of human red-looking flowers that are reported to be visited by the bumblebee Bombus dahlbomii. In the present study, B. dahlbomii's spectral sensitivity was measured through electroretinogram (ERG) recordings. No extended sensitivity to long wavelengths was found in B. dahlbomii. The spectral reflectance curves from eight plant species with red flowers were measured. The color loci occupied by these flowers in the bee color space was evaluated using the receptor noise-limited model. Four of the plant species have pure red flowers with low levels of chromatic contrast but high levels of negative L-receptor contrast. Finally, training experiments were performed in order to assess the role of achromatic cues in the detection and discrimination of red targets by B. dahlbomii. The results of the training experiments suggest that the bumblebee relies on achromatic contrast provided by the L-receptor to detect and discriminate red targets. These findings are discussed in the context of the evolutionary background under which the relationship between SATF species and their flower visitors may have evolved.

Review of metastatic spine tumour classification and indications for surgery: the consensus statement of the Global Spine Tumour Study Group.

Choosing the right operation for metastatic spinal tumours is often difficult, and depends on many factors, including life expectancy and the balance of the risk of surgery against the likelihood of improving quality of life. Several prognostic scores have been devised to help the clinician decide the most appropriate course of action, but there still remains controversy over how to choose the best option; more often the decision is influenced by habit, belief and subjective experience. The purpose of this article is to review the present systems available for classifying spinal metastases, how these classifications can be used to help surgical planning, discuss surgical outcomes, and make suggestions for future research. It is important for spinal surgeons to reach a consensus regarding the classification of spinal metastases and surgical strategies. The authors of this article constitute the Global Spine Tumour Study Group: an international group of spinal surgeons who are dedicated to studying the techniques and outcomes of surgery for spinal tumours, to build on the existing evidence base for the surgical treatment of spinal tumours.

Nondividing but metabolically active gamma-irradiated Brucella melitensis is protective against virulent B. melitensis challenge in mice.

Brucella spp. are gram-negative bacteria that cause the most frequent zoonotic disease worldwide, with more than 500,000 human infections yearly; however, no human vaccine is currently available. As with other intracellular organisms, cytotoxic mechanisms against infected cells are thought to have an important role in controlling infection and mediating long-term immunity. Live attenuated strains developed for use in animals elicit protection but retain unacceptable levels of virulence. Thus, the optimal design for a brucellosis vaccine requires a nonliving vaccine that confers effective immunity. Historically, inactivation methods such as chemical or heat treatment successfully impair Brucella reproductive capacity; nevertheless, metabolically inactive vaccines (subunit or killed) present very limited efficacy. Hence, we hypothesized that bacterial metabolism plays a major role in creating the proper antigenic and adjuvant properties required for efficient triggering of protective responses. Here, we demonstrate that inactivation of Brucella melitensis by gamma-irradiation inhibited its replication capability and yet retained live-Brucella protective features. Irradiated Brucella possessed metabolic and transcriptional activity, persisted in macrophages, generated antigen-specific cytotoxic T cells, and protected mice against virulent bacterial challenge, without signs of residual virulence. In conclusion, pathogen metabolic activity has a positive role in shaping protective responses, and the generation of inactivated and yet metabolically active microbes is a promising strategy for safely vaccinating against intracellular organisms such as B. melitensis.

Preclinical characterization of selective phosphodiesterase 10A inhibitors: a new therapeutic approach to the treatment of schizophrenia.

We have recently proposed the hypothesis that inhibition of the cyclic nucleotide phosphodiesterase (PDE) 10A may represent a new pharmacological approach to the treatment of schizophrenia (Curr Opin Invest Drug 8:54-59, 2007). PDE10A is highly expressed in the medium spiny neurons of the mammalian striatum (Brain Res 985:113-126, 2003; J Histochem Cytochem 54:1205-1213, 2006; Neuroscience 139:597-607, 2006), where the enzyme is hypothesized to regulate both cAMP and cGMP signaling cascades to impact early signal processing in the corticostriatothalamic circuit (Neuropharmacology 51:374-385, 2006; Neuropharmacology 51:386-396, 2006). Our current understanding of the physiological role of PDE10A and the therapeutic utility of PDE10A inhibitors derives in part from studies with papaverine, the only pharmacological tool for this target extensively profiled to date. However, this agent has significant limitations in this regard, namely, relatively poor potency and selectivity and a very short exposure half-life after systemic administration. In the present report, we describe the discovery of a new class of PDE10A inhibitors exemplified by TP-10 (2-{4-[-pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenoxymethyl}-quinoline succinic acid), an agent with greatly improved potency, selectivity, and pharmaceutical properties. These new pharmacological tools enabled studies that provide further evidence that inhibition of PDE10A represents an important new target for the treatment of schizophrenia and related disorders of basal ganglia function.

Comparison of histidine-tryptophan-ketoglutarate solution and University of Wisconsin solution in adult liver transplantation.

BACKGROUND: A safe and effective preservation solution is a precondition for successful orthotopic liver transplantation (OLT). This study compared University of Wisconsin (UW) and histidine-tryptophan-ketoglutarate (HTK) solutions in OLT. PATIENTS AND METHODS: We retrospectively reviewed the medical records of 137 primary cadaveric. OLT performed between January 2003 and December 2006 at our institution. Sixty-eight grafts were harvested using UW and 69 using HTK. Recipients were managed similarly in regard to operative techniques and immunosuppression. We collected donor data including serum transaminases, serum sodium, ICU stay and assessed macroscopic liver quality. Recipient serum transaminases were collected on postoperative days 1, 7, 14, and 30. We compared biliary and vascular complications, as well as patient and graft survivals. RESULTS: Mean serum bilirubin levels were slightly higher in the HTK group at 1,7,14, and 30 days after transplantation, whereas transaminases were higher in the UW group. Primary nonfunction occurred in 1 patient in each group. Retransplantation was performed in 5 patients in the UW and in 9 patients in the HTK group. Biliary complication rates were similar in the UW and HTK groups (22% and 17%, respectively). Six arterial complications occurred in the HTK (8.7%) and 2 in the UW group (2.9%; P < .05). Mean follow-up was 25 months. Graft survival at 1, 12, and 36 months was 90%, 78%, and 75% versus 90%, 71%, and 71% in the UW versus HTK groups, respectively. One-, 12-, and 36-month patient survival rates were 93%, 78%, and 75% versus 93%, 78%, and 78% in the UW versus HTK groups, respectively. CONCLUSIONS: There were no significant differences in graft and patient survivals between the 2 groups. Whereas the biliary complication rates were comparable in both groups, the arterial complications were clearly higher in the UW group (8.7% vs 2.9%; P < .05%). UW and HTK solutions seemed to be equally safe and effective in the preservation of liver grafts. The high incidence of arterial complications in the UW group requires further prospective studies.

Results of resection and transplantation for hepatocellular carcinoma in cirrhosis and noncirrhosis.

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Both liver resection (LR) and orthotopic liver transplantation (OLT) are surgical treatment options depending on the size of the tumor and the presence of cirrhosis. Liver cirrhosis is the main reason for the high early postoperative mortality after resection. Even in the Child A stage, extensive resections are not recommended. This study presented the results of surgical treatment (LR or OLT) for HCC in cirrhotic and noncirrhotic livers. We analyzed the data of 76 patients who underwent LR or OLT for HCC from January 2001 to December 2006. In noncirrhotic livers the following resections were performed: 30 right and extended right hemihepatectomies (54.5%); 11 left hemihepatectomies (20%); and 14 mono- or bisegmentectomies (25.5%). In cirrhotic livers the following procedures were performed: in Child A stage 1 right hemihepatectomy, 1 extended right hemihepatectomy, 1 extended left hemihepatectomy, and 4 mono- or bisegmentectomies; and in Child B stage, 3 mono- or bisegmentectomies. Among 11 patients who underwent transplantation, tumors in 2 patients exceeded the Milan criteria. Five patients in the LR group were treated with transarterial chemoembolization before transplantation. LR for HCC in cirrhosis should be performed with caution; there were no long-term survivors in our data. Our study confirmed that OLT shows good long-term survival in early HCC stages. However, this may also be true for stages above the Milan criteria. For HCC in noncirrhotic livers, LR remains the treatment of choice, justifying an extensive surgical approach. Such an approach achieved favorable long term survivals.

[Oncological surgery of the spine]. / Onkologische Chirurgie der Wirbelsäule.

Spine surgery has been significantly influenced during the past 20 years by improvements in anaesthesia and radiology. This progress has also been promoted by technical developments in spinal instrumentation, mainly the introduction of pedicle screws and anterior support with cages. Both techniques allow correction and stabilisation methods that have had a major effect on tumour surgery. These advancements have allowed less experienced spine surgeons to perform tumour surgery, which may have a negative effect on the outcome. From our point of view, it should be required that tumour surgery be performed only in hospitals managing a certain number of tumours annually. For optimal results, en bloc resection and intralesional marginal resection in particular are highly demanding of the surgeon's technical skills and experience. Second and third operations complicate the intervention unnecessarily. Normally, R0 resection can not be achieved by a second or third revision. For this reason tumour surgery requires a standardised overall concept which must be suited to individual problems. This can be best decided in a tumour board meeting for choosing the options for adjuvant therapy. Only by such a coordinated effort may good mid- and long-term results be achieved.It must be pointed out that en bloc resection is the only surgical therapy that makes a curative approach possible. On the other hand it can also be demonstrated that by making extended, intralesional marginal resections as radical as possible, good mid-term results can be achieved. Here the adjuvant chemo- and radiotherapy play an important role.

Characterization of dendritic cell subsets in patients undergoing renal transplantation.

Dendritic cells (DCs) play a key role in transplantation tolerance and immune reactions to transplants. In order to ascertain whether DC levels are predictive for rejection, we examined the levels and expression patterns of DCs of renal transplant patients following immunosuppressive and/or surgical interventions. Myeloid (HLA-DR+/CD11c+) and plasmacytoid (HLA-DR+/CD123+) DCs were characterized by flow cytometry over 28 days. We demonstrated that myeloid DCs and plasmacytoid DCs in peripheral blood were discernable and dramatically decreased following renal transplantation and immunosuppression. Furthermore, the expression of CD62L was significantly up-regulated (P=.032), while CD86 was significantly down-regulated (P=.008) on myeloid but not plasmacytoid DCs. Although DC levels alone were not predictive for the occurrence of a rejection episode, in combination with other factors they may be indicative of rejection, thereby sparing the patient a biopsy.

Elucidating the medium-resolution structure of ribosomal particles: an interplay between electron cryo-microscopy and X-ray crystallograhy.

BACKGROUND: Ribosomes are the universal cellular organelles that accomplish the translation of the genetic code into proteins. Electron cryo-microscopy (cryo-EM) has yielded fairly detailed three-dimensional reconstructions of ribosomes. These were used to assist in the determination of higher resolution structures by X-ray crystallography. RESULTS: Molecular replacement studies using cryo-EM reconstructions provided feasible packing schemes for crystals of ribosomes and their two subunits from Thermus thermophilus, and of the large subunits from Haloarcula marismortui. For the large subunits, these studies also confirmed the major heavy-atom sites obtained by single isomorphous replacement combined with anomalous diffraction (SIRAS) and by multiple isomorphous replacement combined with anomalous diffraction (MIRAS) at approximately 10 A. Although adequate starting phases could not be obtained for the small subunits, the crystals of which diffract to 3.0 A, cryo-EM reconstructions were indispensable for analyzing their 7.2 A multiple isomorphous replacement (MIR) map. This work indicated that the conformation of the crystallized small subunits resembles that seen within the 70S ribosomes. Subsequently, crystals of particles trapped in their functionally active state were grown. CONCLUSIONS: Single-particle cryo-EM can contribute to the progress of crystallography of non-symmetrical, large and flexible macromolecular assemblies. Besides confirming heavy-atom sites, obtained from flat or overcrowded difference Patterson maps, the cryo-EM reconstructions assisted in elucidating packing arrangements. They also provided tools for the identification of the conformation within the crystals and for the estimation of the level of inherent non-isomorphism.

Reversal of neurobehavioral social deficits in dystrophic mice using inhibitors of phosphodiesterases PDE5A and PDE9A.

Duchenne muscular dystrophy is caused by mutations in the DYSTROPHIN gene. Although primarily associated with muscle wasting, a significant portion of patients (approximately 25%) are also diagnosed with autism spectrum disorder. We describe social behavioral deficits in dystrophin-deficient mice and present evidence of cerebellar deficits in cGMP production. We demonstrate therapeutic potential for selective inhibitors of the cGMP-specific PDE5A and PDE9A enzymes to restore social behaviors in dystrophin-deficient mice.

Changes in quality of life after renal transplantation.

Quality of life is becoming an increasingly important concept in the evaluation of different therapeutic interventions. In this cross-sectional study, quality of life analyzed in 76 renal transplant patients was compared with 65 patients with end-stage renal disease (ESRD) awaiting transplantation. Both groups were asked to estimate their subjective quality of life by responding to a multidimensional questionnaire that sought information in the following areas: (1) sociodemographic data, (2) a personality test (Giessen-Test), (3) information about employment, (4) assessment of anxiety and depression (GHQ-28), (5) the SF-36 as an important measurement for quality of life, and (6) the ESRD symptom checklist-transplantation module. The sociodemographic profiles of both groups were similar. The SF-36 revealed significantly higher values for transplant recipients in terms of physical functioning (P < or = .001), general health perceptions (P < or = .01), social functioning (P < or = .01), and physical summary value (P < or = .001). The other tests (Giessen-Test and GHQ-28) and employment data showed no significant differences between the two samples. Collectively, the data demonstrate a considerable improvement in quality of life in renal transplant patients. Despite good physical recovery and higher quality of life after transplantation, the rate of vocational rehabilitation remained low, partially explained by the currently high levels of unemployment.