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The treatment of multiple myeloma (MM) is evolving rapidly. In recent years, T-cell-based novel immunotherapies emerged as new treatment strategies for patients with relapsed/refractory MM, including highly effective new options like chimeric antigen receptor (CAR)-modified T cells and bispecific antibodies (bsAbs). Currently, B-cell maturation antigen is the most commonly used target antigen for CAR T-cell and bsAb therapies in MM. Results from different clinical trials have demonstrated promising efficacy and acceptable safety profile of bsAb in RRMM.

Despite technical advances, day surgery still accounts for <1 % of adrenal procedures. We investigated feasibility and safety of same day adrenalectomy (SDA).

The new XR-Series haematology analyser from Sysmex provides increased throughput and automation, along with a new reagent in WDF channel for optimised WBC differential.

Kidney fibrosis is the hallmark of chronic kidney disease progression; however, at present no antifibrotic therapies exist1–3. The origin, functional heterogeneity and regulation of scar-forming cells that occur during human kidney fibrosis remain poorly understood1,2,4. Here, using single-cell RNA sequencing, we profiled the transcriptomes of cells from the proximal and non-proximal tubules of healthy and fibrotic human kidneys to map the entire human kidney. This analysis enabled us to map all matrix-producing cells at high resolution, and to identify distinct subpopulations of pericytes and fibroblasts as the main cellular sources of scar-forming myofibroblasts during human kidney fibrosis. We used genetic fate-tracing, time-course single-cell RNA sequencing and ATAC–seq (assay for transposase-accessible chromatin using sequencing) experiments in mice, and spatial transcriptomics in human kidney fibrosis, to shed light on the cellular origins and differentiation of human kidney myofibroblasts and their precursors at high resolution. Finally, we used this strategy to detect potential therapeutic targets, and identified NKD2as a myofibroblast-specific target in human kidney fibrosis.

F0B7Gasdermin D contributes to focal crystalline thrombotic angiopathy and its consequences: ischemic tissue infarction and organ failure.F0B7Gasdermin D drives neutrophil necrosis, maturation, and tissue recruitment during focal crystalline thrombotic angiopathy.

Corneal confocal laser scanning microscopy is a promising method for in vivoinvestigation of cellular structures, e. g., of nerve fibers in the sub-basal nerve plexus. During recording, even slight displacements of the focal plane lead to images of adjacent tissue layers. In this work, we propose a closed-loop control of the focal plane. To detect and evaluate the visible tissues, we utilize the Bag of Visual Words approach to implement a customizable image processing pipeline for real-time applications. Furthermore, we show that the proposed model can be trained with small classification datasets and can be applied as a segmentation method. The proposed control loop, including tissue detection, is implemented in a proof-of-concept setup and shows promising results in a first evaluation with a human subject.

Printed electronics offer great potential for new applications such as Internet of Things devices and wearables. A methodology for integration of design and process assessment based on a stepwise transfer of the circuit to be printed from printed circuit board test vehicles to the final printed substrate is introduced. A multi-layer vector ink-jet printing process with three functional inks is presented using the example of the fabrication of a demonstrator circuit. This fabrication is realized using a newly set up printing system as enabling technology: Integration of a piezo print head into the path planning of the printing system and its control as virtual stepper axis enable highly precise vector printing yielding printed functional elements with low tolerances. Finally, process improvements for assembly of surface mounted devices on printed foil substrates are outlined.

We present an in vivo confocal laser scanning microscopy based method for large 3D reconstruction of the cornea on a cellular level with cropped volume sizes up to 266 x 286 x 396 µm^3. The microscope objective used is equipped with a piezo actuator for automated, fast and precise closed-loop focal plane control. Furthermore, we present a novel concave surface contact cap, which significantly reduces eye movements by up to 87%, hence increasing the overlapping image area of the whole stack. This increases the cuboid volume of the generated 3D reconstruction significantly. The possibility to generate oblique sections using isotropic volume stacks opens the window to slit lamp microscopy on a cellular level.

Purpose To identify the variant features encountered in parathyroid abnormalities and document those suggesting malignant change.Materials and methods Data were collected from a cohort of patients who underwent investigation for primary hyperparathyroidism over a 10-year period. Ultrasonographic features: shape, presence of calcification, cystic changes, heterogeneous echogenicity, vascularity, capsular thickening, local invasion, and vascularity were reviewed retrospectively and were used to correlate with final histological findings.Results One hundred forty-seven patients with histology and concurrent ultrasonographic scans were reviewed, and divided into benign parathyroid lesions (nodular hyperplasia (n= 44), adenoma (n= 93)) and parathyroid carcinoma (n= 10). Parathyroid carcinomas were significantly larger than benign parathyroid lesions (P= 0.030). Benign parathyroid lesions showed variant sonographic features: irregular shape (16.8%), heterogenous echogenicity (24.1%), calcification (1.5%), capsular thickening (1.5%), and cystic change (19.7%). A significantly higher proportion of parathyroid carcinomas demonstrated heterogenous echogenicity (P= 0.022), capsular thickening (P= 0.023), and infiltrative margin (P< 0.0001) than benign parathyroid lesions. Of the 137 benign parathyroid lesions, 38 (27.7%), 76 (55.5%), 23 (16.8%) were avascular, vascular, and hypervascular, respectively. Of the 10 parathyroid carcinomas, 4 (40%), 3 (30%), and 3 (30%) of lesions were avascular, vascular, and hypervascular, respectively. The vascularity of the lesions did not differ significantly between the parathyroid carcinoma and benign parathyroid lesions (P= 0.281).Conclusion Ultrasonographic features such as irregular shape, heterogeneous echogenicity, cystic change, and vascularity are nondiscriminatory features between benign or malignant lesions. Large lesion size together with the presence of calcification, capsular thickening, or infiltrative margin strongly raises the suspicion of a malignant parathyroid lesion, and management should be altered.

We demonstrate a 60 mg light video-endomicroscope with a cylindrical shape of the rigid tip of only 1.6 mm diameter and 6.7 mm length. A novel implementation method of the illumination unit in the endomicroscope is presented. It allows for the illumination of the biological sample with fiber-coupled LED light at 455 nm and the imaging of the red-shifted fluorescence light above 500 nm in epi-direction. A large numerical aperture of 0.7 leads to a sub-cellular resolution and yields to high-contrast images within a field of view of 160 μm. A miniaturized chip-on-the-tip CMOS image sensor with more than 150,000 pixels captures the multicolor images at 30 fps. Considering size, plug-and-play capability, optical performance, flexibility and weight, we hence present a probe which sets a new benchmark in the field of epifluorescence endomicroscopes. Several ex-vivo and in-vivo experiments in rodents and humans suggest future application in biomedical fields, especially in the neuroscience community, as well as in medical applications targeting optical biopsies or the detection of cellular anomalies.

The article presents the author's views on the diversity seen in church music concerts. Various topics discussed include dramaturgy seen in diversity, practice of choral music, revaluation of language used in music, cantatas written by composer Johann Sebastian Bach and role of symbols in church music texts.

To identify molecular targets that modify sensitivity to lenalidomide, we measured proliferation in multiple myeloma (MM) cells transfected with 27 968 small interfering RNAs in the presence of increasing concentrations of drug and identified 63 genes that enhance activity of lenalidomide upon silencing. Ribosomal protein S6 kinase (RPS6KA3 or RSK2) was the most potent sensitizer. Other notable gene targets included 5 RAB family members, 3 potassium channel proteins, and 2 peroxisome family members. Single genes of interest included I-κ-B kinase-α (CHUK), and a phosphorylation dependent transcription factor (CREB1), which associate with RSK2 to regulate several signaling pathways. RSK2 knockdown induced cytotoxicity across a panel of MM cell lines and consistently increased sensitivity to lenalidomide. Accordingly, 3 small molecular inhibitors of RSK2 demonstrated synergy with lenalidomide cytotoxicity in MM cells even in the presence of stromal contact. Both RSK2 knockdown and small molecule inhibition downregulate interferon regulatory factor 4 and MYC, and provides an explanation for the synergy between lenalidomide and RSK2 inhibition. Interestingly, RSK2 inhibition also sensitized MM cells to bortezomib, melphalan, and dexamethasone, but did not downregulate Ikaros or influence lenalidomide-mediated downregulation of tumor necrosis factor-α or increase lenalidomide-induced IL-2 upregulation. In summary, inhibition of RSK2 may prove a broadly useful adjunct to MM therapy.

To identify molecular targets that modify sensitivity to lenalidomide, we measured proliferation in multiple myeloma (MM) cells transfected with 27 968 small interfering RNAs in the presence of increasing concentrations of drug and identified 63 genes that enhance activity of lenalidomide upon silencing. Ribosomal protein S6 kinase (RPS6KA3 or RSK2) was the most potent sensitizer. Other notable gene targets included 5 RAB family members, 3 potassium channel proteins, and 2 peroxisome family members. Single genes of interest included I-κ-B kinase-α (CHUK), and a phosphorylation dependent transcription factor (CREB1), which associate with RSK2 to regulate several signaling pathways. RSK2 knockdown induced cytotoxicity across a panel of MM cell lines and consistently increased sensitivity to lenalidomide. Accordingly, 3 small molecular inhibitors of RSK2 demonstrated synergy with lenalidomide cytotoxicity in MM cells even in the presence of stromal contact. Both RSK2 knockdown and small molecule inhibition downregulate interferon regulatory factor 4 and MYC, and provides an explanation for the synergy between lenalidomide and RSK2 inhibition. Interestingly, RSK2 inhibition also sensitized MM cells to bortezomib, melphalan, and dexamethasone, but did not downregulate Ikaros or influence lenalidomide-mediated downregulation of tumor necrosis factor-α or increase lenalidomide-induced IL-2 upregulation. In summary, inhibition of RSK2 may prove a broadly useful adjunct to MM therapy.

Gestures accompany speech and enrich human communication. When aphasia interferes with verbal abilities, gestures become even more relevant, compensating for and/or facilitating verbal communication. However, small-scale clinical studies yielded diverging results with regard to a therapeutic gesture benefit for lexical retrieval. Based on recent functional neuroimaging results, delineating a speech-gesture integration network for lexical learning in healthy adults, we hypothesized that the commonly observed variability may stem from differential patholinguistic profiles in turn depending on lesion pattern. Therefore we used a controlled novel word learning paradigm to probe the impact of gestures on lexical learning, in the lesioned language network.

Meaningful gestures enhance speech comprehensibility. However, their role during novel-word acquisition remains elusive. Here we investigate how meaningful versus meaningless gestures impact on novel-word learning and contrast these conditions to a purely verbal training. After training, neuronal processing of the novel words was assessed by blood-oxygen-level-dependent functional magnetic resonance imaging (BOLD-fMRI), disclosing that networks affording retrieval differ depending on the training condition. Over 3 days participants learned pseudowords for common objects (e.g., /klira/ -cap). For training they repeated the novel word while performing (i) an iconic, (ii) a grooming or (iii) no gesture. For the two conditions involving gestures, these were either actively repeated or passively observed during training. Behaviorally no substantial differences between the five different training conditions were found while fMRI disclosed differential networks affording implicit retrieval of the learned pseudowords depending on the training procedure. Most notably training with actively performed iconic gestures yielded larger activation in a semantic network comprising left inferior frontal (BA47) and inferior temporal gyri. Additionally hippocampal activation was stronger for all trained compared to unknown pseudowords of identical structure. The behavioral results challenge the generality of an ‘enactment-effect’ for single word learning. Imaging results, however, suggest that actively performed meaningful gestures lead to a deeper semantic encoding of novel words. The findings are discussed regarding their implications for theoretical accounts and for empirical approaches of gesture-based strategies in language (re)learning.

Cervical lymph nodes (CLNs) are the most common site of metastases in papillary thyroid cancer (PTC). Ultrasound scan (US) is the most commonly used imaging modality in the evaluation of CLNs in PTC. Computerised tomography (CT) and 18fluorodeoxyglucose positron emission tomography (18FDG PET–CT) are used less commonly. It is widely believed that the above imaging techniques should guide the surgical approach to the patient with PTC.

Parathyroid cancer is a rare cause of primary hyperparathyroidism, but a missed diagnosis is often fatal. This Review highlights genetic, imaging and laboratory findings that can generate a preoperative diagnosis (or strong suspicion) of parathyroid cancer. The authors describe the management of these patients, which should include oncological resection and histological disease staging to predict prognosis and the need for adjuvant treatment.

Objective: When a stereotactic biopsy is taken to enable histopathological diagnosis of a suspected brain tumor, it is essential to i) do this safely, that is not injure a major blood vessel and ii) to obtain relevant vital material from the tumor. We are investigating the suitability of Indocyanine Green (ICG) fluorescence for blood vessel recognition and 5- Aminolevulinic acid (5-ALA) induced Protoporphyrin IX (PpIX) fluorescence for identification of proliferative brain tumor tissue. Methods: A fiber-optic endoscopic approach was studied to generate and detect both fluorescence signals. PpIX concentrations in brain tumors have been measured by chemical extraction. Preliminary equipment was studied in a mouse model. Results: PpIX-concentrations in glioblastoma tissue showed high inner- and inter-patient variability, but each patient out of 15 with interpretable data showed at least one sample with a PpIX-concentration exceeding 2.4 mol/l, which is easily detectable by state-of-the-art fiberoptic fluorescence spectroscopy and imaging. The imaging fluoroscope with 30,000 pixels resolution could be introduced through a position controlled stereotactic needle. ICG-fluorescence from vessels with diameters ≥ 0.1 mm can be detected with a contrast of 2-2.5 against surrounding tissue. Conclusion: Fluorescence detection during stereotactic biopsy might increase safety and precision of the procedure significantly.

Castleman's disease is an infectious disease of the lymph node that causes either local symptoms or a systemic inflammatory syndrome. This Review discusses the viral causes of the disease and the mechanisms of its subsequent progression. The efficacy of established treatment options for this disease and of potential novel therapies is outlined.

The establishment of the dies solisas a regular day of rest by Constantine is absolutely a novum in antiquity. The text of the law is not preserved, but two texts of the year 321 (Codex TheodosianusII,8,1 and Codex IustinianusIII 12,2 [3]) hint to the fact that Constantine established the dies solisin connection to the laws about the clergy and the building of churches in 312/313. So, the character of the dies soliscannot be considered as a pagan or syncretistic one, but as an early step towards a Christianisation of the Roman Empire. Even the Roman army had to observe the dies solisin a Christian manner (cf. the oration in Eus., v.C. IV 19f.) from 311/312 onwards. In this early time, of course, the new rules are only realised in the Western part of the Empire, only from 324 onwards even the Eastern part accepted the new rhythm of time. Early Egyptian papyri show that the Christian name of the day (dies dominicus, dominica) is used even in documents written by pagan administrators from 325 onwards.

The article presents evidence of Beethoven as a composer for the musical instrument Viennese orphica. In a letter to Anton Schindler, Beethoven's childhood friend Franz Gerhard Wegeler wrote that he could supply him with letters from Beethoven for Schindler's planned Beethoven biography and two little pieces for the orphica, which Beethoven composed for his wife, Eleonore von Breuning, who had belonged to Beethoven's circle of friends in Bonn, in 1802. Wegeler referred to the two pieces, WoO 51, an Allegro in C Major and an Adagio in F Major.

To determine the clinical incidence and characteristics of symptomatic choroidal metastasis (CM) in breast cancer.

Abstract: Background: To determine the effectiveness and risk profile of combined ruthenium- (Ru)-106-brachytherapy and transpupillary thermotherapy (TTT) of the tumour apex for the treatment of large choroidal melanoma.Methods: A consecutive series of 31 large choroidal melanoma treated by Ru-106-brachytherapy and adjuvant TTT was studied. TTT was performed 1 day prior to plaque removal and up to 3 times (mean: 1.8) during follow-up. Evaluation comprised tumour regression, treatment-related adverse events, necessity of additional treatment and visual results.Results: Mean follow-up was 21.6±7.8 (10.8–38.3) months. Mean tumour thickness was 6.8±1.0 (5.0–8.9) mm prior to treatment. Mean residual tumour thickness at the end of follow-up was 2.5±1.0 mm. Relevant adverse treatment effects were exudative maculopathy or macula oedema (22.6%), vitreous haemorrhage (16.1%), optic neuropathy (16.1%) and retinal detachment (9.7%). One tumour recurrence occurred during follow-up, and was treated by enucleation.Conclusions: The combination of Ru-106-brachytherapy with TTT allows for the treatment of large posterior choroidal melanoma. The rate of treatment-related adverse events appears to be acceptable.

Abstract: Background: Primary pars plana vitrectomy (PPPV) has gained widespread popularity in the treatment of rhegmatogenous retinal detachments (RRD). However, the surgical procedure is still flawed by a significant rate of anatomical and functional failures. The study was conducted to analyse the risk factors for a dissatisfying postoperative outcome. Methods: We carried out a retrospective study of 512 cases of PPPV with a minimum follow-up of 3 months from one institution over a 9-year period. Preoperatively, 24.8% of patients (127 out of 512) were pseudophakic, 16.4% (84 out of 512) highly myopic, 19.9% (102 out of 512) had preoperative proliferative vitreoretinopathy (PVR) and 14.6% (75 out of 512) had vitreous haemorrhage. Results: The follow-up period ranged from 3 to 108 months (median 14.8). Retinal reattachment was achieved with one operation in 70.7% (362 out of 512) and after one or more operations in 97.5% of cases (499 out of 512). The major reasons for redetachments were new retinal breaks, followed by a combination of new breaks and PVR, and PVR without apparent breaks. Postoperative visual acuities of ≥0.1 and ≥0.4 were achieved in 82.8% (424 out of 512) and 48.2% (247 out of 512) respectively. Out of 376 phakic patients at study entry, 66.4% (250 out of 376) underwent cataract surgery either in combination with PPPV or during the postoperative course. Factors that were significantly associated with either anatomical or functional failure included duration of symptoms, low preoperative visual acuity, myopia, amblyopia, hypotony, macular detachment, preoperative PVR, extent of detachment, involvement of inferior quadrants, no detectable breaks, large breaks, breaks posterior to the equator, surgeon, level of surgical training, endocryotherapy, and combined scleral buckling surgery. Conclusion: Primary pars plana vitrectomy is still flawed by a relatively high primary redetachment rate following the initial procedure. The advantages of the technique are a high final reattachment rate and relatively good functional results in a subset of patients with more complicated types of RRD. The risk factors for postoperative failures following PPPV for RRD match to a large extent those following scleral buckling surgery (SBS). Future improvements of the technique will have to focus on modifiable risk factors, such as details of the surgical procedures, surgical training and case selection, to distinguish it from SBS.

Abstract

Abstract Von Hippel–Lindau disease (VHL) and neurofibromatosis type 1 (NF 1) are hereditary multitumor syndromes that show associated ocular manifestations. Capillary retinal angioma, a benign vascular tumor, is the classical ocular lesion in VHL. It often appears as the first manifestation of the disease and may thus lead to the diagnosis of VHL. Since small angiomas can be treated easily by laser photocoagulation, a regular ocular screening of VHL patients is recommended. Ocular manifestations of NF 1 are more diverse as compared to VHL. Lisch nodules of the iris are an important diagnostic criteria of NF 1 since they can be found in almost every affected patient. Optic glioma can occur both intraorbitally and intracranially. The intraorbital form causes progressive protrusion of the globe and eventually blindness. Extension of the tumor beyond the chiasm worsens the prognosis quoad vitam. The hallmark of NF 1, namely cutaneous neurofibroma can cause visual impairment when affecting the skin of the eyelids. The rare intraorbital pexiform neurofibroma is associated with abnormal development of the orbital bones and infantile glaucoma. It may result in orbital mass effects and therefore may need surgical excision.

In June 1998, proton-beam therapy of ocular tumors started at the Hahn-Meitner Institute Berlin, Germany. The purpose of the present study is to evaluate treatment outcome for uveal melanomas. 245 consecutive patients with primary melanoma of the uvea were treated from June 1998 to April 2003 with a 68-MeV proton beam. In 96.2% of all patients, a uniform fractionation scheme was applied: single dose 15 CGE (cobalt gray equivalent), total dose 60 CGE on 4 consecutive days. Follow-up is available in 229 patients. At the time of median follow-up (18.4 months), local control is 96.4% and 95.5% at 3 years. Eye retention rate is 92.6% at 20 months (median follow-up) and 87.5% at 3 years. Proton-beam irradiation of uveal melanomas at the Hahn-Meitner Institute after the first 5 years of its initiation reveals local tumor control and eye retention rates in the range of other centers with larger experience. Delivering high treatment quality in hadron therapy from the beginning has been achieved. Im Juni 1998 wurde am Hahn-Meitner-Institut in Berlin mit der Protonentherapie von Augentumoren begonnen. In der vorliegenden Arbeit werden die ersten Ergebnisse der Behandlung des primären Aderhautmelanoms vorgestellt. Zwischen Juni 1998 und April 2003 wurden 245 Patienten mit 68-MeV-Protonen bestrahlt. Bei 96,2% der Behandelten kam ein einheitliches Fraktionierungsschema zur Anwendung: Einzeldosis 15 CGE (Cobalt-Gray-Äquivalent), Gesamtdosis 60 CGE an 4 aufeinander folgenden Tagen. Von 229 Patienten stehen Verlaufsdaten zur Verfügung. Die lokale Tumorkontrolle liegt zum Zeitpunkt der medianen Nachbeobachtung (18,4 Monate) bei 96,4% und bei 95,5% nach 3 Jahren. Nach 3 Jahren können 87,5% der Augen erhalten werden, zum Zeitpunkt der medianen Nachbeobachtung für diesen Parameter (20 Monate) sind es 92,6%. Die Ergebnisse für die lokale Tumorkontrolle und den Augenerhalt sind vergleichbar mit denen anderer Zentren. Damit ist es gelungen, in der Hadronentherapie von Beginn an eine Behandlung auf hohem qualitativem Niveau zu etablieren.

A dysbalanced immune response is thought to account for a substantial part of the morbidity and mortality after severe trauma. The cytokine interleukin-10 (IL-10) suppresses the transcription of proinflammatory cytokines, mainly in macrophages and monocytes. The objectives of this prospective study in a level I trauma center in Germany were to examine the distribution of IL-10 promoter polymorphisms in a cohort of severely injured patients, to measure IL-10 cytokine levels and relate these to the genotype, and to identify associations of IL-10 polymorphisms with the incidence of severe multiple organ dysfunction syndrome (MODS). The genotypes of polymorphisms −592 and −1082 were determined by polymerase chain reaction (PCR) and restriction cleavage with Rsa 1 or Mnl I, respectively. We analyzed 119 severely injured trauma patients [mean Injury Severity Score (ISS) 38.0 ± 13.2]. The frequency of the −1082A allele was 0.542, and that of the −592C allele was 0.807. IL-10 polymorphisms were not significantly associated with mean systemic IL-10 cytokine levels 6, 12, and 18 h after admission to the ICU. Carriers of the genotype −592AC had significantly higher overall MOD scores than non-AC carriers (P= 0.018; Pcorr= 0.036). The genotypes of the IL-10 SNP −1082 were not significantly associated with MOD scores. A multivariate Cox hazard regression analysis including important factors of the patients’ anatomic and physiological trauma impact revealed only the shock index, the severity of the head injury, and the IL-10 −592 genotype AC as significant independent risk factors for the development of MODS. In this multivariate analysis, carriers of the genotype −592AC displayed a 3.3-fold increase in the relative risk of developing a MODS (P= 0.008, hazard ratio 3.29, 95% CI 1.36–7.97). Our data suggest a possible link between the AC genotype of the −592 single nucleotide polymorphism and significantly higher mean MOD scores. The AC genotype was associated in multivariate analysis with a higher relative risk of MODS in multiply injured patients. Further investigations in larger cohorts need to focus on the potential diagnostic and therapeutic options of this SNP.

Dysbalance in the immune system is perceived as a major factor for adverse outcome after trauma. Transforming growth factor-1 (TGF-1) is a multifunctional cytokine that regulates proliferation, differentiation of cells, wound healing, and angiogenesis. The influence of TGF-1 on trauma patients outcome is still unclear. Injury patterns and clinical outcome parameters of 99 consecutive patients with life-threatening injury and an injury severity score (ISS) > 15 were assessed in a prospective, single-center study at a Level I trauma center. Levels of TGF-1 in plasma were measured over a 5-day period by an enzyme-linked immunoabsorbant assay (ELISA). TGF-1 plasma levels rise shortly after trauma and gradually drop as the 5th day approaches. Mean and maximal TGF-1 plasma levels were significantly higher in patients who developed sepsis and were significantly lower in patients with renal or hepatic failure. Receiver operating characteristics-curve analysis of liver failure shows an area under the curve (AUC) of 0.68 (95 0.55–0.81, P0.02) and of an AUC of 0.63 (95 0.52–0.75, P0.03) for renal failure for maximal TGF-1 plasma (initial until day 2) levels if lower values represent a more positive test. The data indicate that the increase and decrease of TGF-1 plasma levels may contribute to clinical outcome after severe injury. Lower TGF-1 levels are associated with liver and renal insufficiency. Higher TGF-1 levels 6 h after ICU admission increase the risk of sepsis. TGF-1 seems to be an early onset reactant and not a second-line responsive cytokine.

Bone loss in inflammatory bowel disease (IBD) is presumed to be mediated by inflammation. Increased levels of the multifunctional cytokine IL-6 in inflammatory diseases have been proposed to be the link in such “inflammation-mediated osteopenia.” A recently described G/C polymorphism with an effect on transcription rate and plasma levels of IL-6 suggests a genetically determined difference in the degree of the IL-6 response to stressful stimuli between individuals. This study aimed to assess the frequency of genotypes and haplotypes of the G/C polymorphism of IL-6 in IBD patients. A further aim was to assess whether carriage of the potentially protective CC genotype is favorable with respect to the development of bone disease in IBD. The IL-6 polymorphism was typed in 105 IBD patients and 113 healthy controls. Bone mineral density was evaluated at baseline and after a prospective 2-year-follow-up. The favorable CC genotype with decreased IL-6 release was not underrepresented in IBD patients compared to healthy controls. Carriage of this genotype was not protective with respect to the development of bone disease, either for the bone mineral density at baseline or for the prospectively observed bone loss. Within the subgroup of patients who did not receive steroids during follow-up, the prospectively observed bone loss was even slightly higher in CC carriers, but differences did not reach significance. Genetically determined differences in the degree of the IL-6 response to stressful stimuli are no major predictors for the degree of bone disease in IBD patients.

The one-dimensional Schrodinger equation is considered when the potential is real valued and integrable and has a finite first moment. The small-energy asymptotics of the logarithmic spatial derivative of the Jost solutions are established. Some consequences of these asymptotics are presented, such as the small-energy limits of the scattering coefficients and a simplified characterization of the scattering data for the inverse scattering problem. When the potential also has a finite second moment, some improved results are given on the small-energy asymptotics of the scattering coefficients and the logarithmic spatial derivatives of the Jost solutions.

Lysophosphatidic acid (LPA) is a small lipid mediator with pleiotropic biological activities, e.g., the regulation of cellular proliferation and various aspects of cellular physiology. Signal transduction is achieved by binding to 2 high-affinity receptors, EDG2 and EDG4, and a group of low-affinity receptors, EDG1–7, all belonging to the superfamily of G protein–coupled receptors. We examined the growth-regulatory effects of LPA in primary cultures of 8 goiters and 1 papillary thyroid cancer. We further assessed mRNA expression of high-affinity receptors EDG2 and EDG4 in 14 normal thyroids, 29 papillary thyroid cancers, 7 follicular thyroid cancers and 13 goiters by quantitative RT-PCR. We also identified mRNA expression of phospholipase A2 and LPA acyltransferase in fresh thyroid tissues derived from various sources. At concentrations of 10, 50 and 150 μM, LPA induced a 2-fold rise of proliferation (p &lt; 0.001) and acted as strongly as thyrotropin. The combination of LPA and TSH produced significant synergistic effects compared with each substance alone (p &lt; 0.05). Normal thyroid, goiter and papillary or follicular thyroid cancer expressed 2 high-affinity cognate LPA receptors, EDG2 and EDG4. EDG4 receptor mRNA expression was increased 3-fold in differentiated thyroid cancer (p &lt; 0.01), both papillary (p &lt; 0.01) and follicular (p &lt; 0.05), compared to normal thyroid or goiter. Overall expression of EDG2 receptor was unchanged in malignancy; however, increased EDG2 expression in individual samples correlated with lymphonodular metastasis (p = 0.01). Thus, lipid mediators are a novel class of factors involved in the control of proliferation in the human thyroid. Altered mRNA expression of the high-affinity LPA receptor EDG4 suggests a role in the pathogenesis of differentiated thyroid cancer. © 2001 Wiley-Liss, Inc.

: Hitzeschockproteine (HSP) sind bedeutsame Mediatoren der Stressreaktion, die als Chaperone bei der Zellprotektion mitwirken. Sie induzieren die Expression proinflammatorischer Zytokine wie Interleukin-6 (IL-6) und Tumornekrosefaktor α (TNF-α). Die wichtigsten Vertreter aus der Familie der HSP sind HSP70, HSP70hom und HSP90. Polymorphismen der HSP70-Gene sind mit dem Ausmaß und dem Erfolg der Immunantwort signifikant assoziiert. Für die Morbidität und die Mortalität des Polytraumapatienten wird u. a. eine fehlregulierte Immunantwort verantwortlich gemacht. Deshalb wurde im Rahmen einer prospektiven, monozentrischen Polytraumastudie untersucht, ob und in welcher Ausprägung der A1538G-PstI-Polymorphismus in Position des HSP70-2-Gens Einfluss auf den Verlauf nach Polytrauma hat. Bei 80 konsekutiven Polytraumapatienten wurden insgesamt > 100.000 Datenpunkte erfasst. Der HSP70-2-Polymorphismus wurde nach DNA-Amplifikation durch Polymerasekettenreaktion und Restriktionsverdau mit PstI bestimmt. Die Plasmaspiegel von IL-6 und TNF-α wurden 30 min nach Eintreffen im Schockraum, unmittelbar präoperativ sowie 6 h, 12 h, 18 h, 2 Tage und 5 Tage nach der stationären Aufnahme durch Chemilumineszenzimmunoassay gemessen. Bei biallelischem Vorliegen des HSP70-2-PstI-Polymorphismus fanden sich erniedrigte Plasmaspiegel von TNF-α, wobei der Unterschied nur präoperativ (P < 0,01) und an Tag 5 (P > 0,001) signifikant war. Bezüglich der IL-6-Expression fanden sich gleichfalls erniedrigte Werteunterschiede, wobei präoperativ ein Signifikanzniveau erreicht wurde. Bezüglich der Verlaufsparameter Überleben, Eintritt einer Sepsis oder Pneumonie, Dialysepflicht, Leberversagen, Lungenversagen oder Erreichen von mindestens einem Punkt aus der Denver-Multiorganversagenklassifikation fand sich weder für den P1P1- noch den P1P2-Genotyp ein signifikant erhöhtes Risiko mit Bezug auf den Eintritt eines der vorgenannten widrigen Ereignisse. Folglich beeinflusst die genetische Konstellation eines genetisch polymorphen Locus im HSP70-2-Gen anscheinend die Immunantwort auf ein schwerstes Trauma, zumindest im Hinblick auf die Produktion von IL-6 oder TNF-α. Bei der Analyse harter Erfolgsparameter zeigt sich kein alleltypspezifischer Einfluss von Varianten des Hitzeschockproteins HSP70-2.

Proliferation is controlled by a network of mitogenic and growth inhibitory factors. Transforming growth factor-β1 (TGF-β1) and activin A are the most important growth inhibitors of benign follicular epithelial cells of the human thyroid. The effects of these substances on malignant primary thyrocytes are not known. We have examined the growth regulatory effects of activin A and TGF-β1 in primary cultures derived from four papillary cancers, two follicular thyroid cancers, and three benign thyroid tissues. Malignant cells demonstrated resistance to activin and TGF-β1 or reversal to a weak but significant mitogenic effect (p< 0.001). We also evaluated the activin receptor transcription pattern. Isoforms alk4-1, 4-2, and 4-3 were found in benign (n= 12) and malignant (n= 22) tissues. Two subtypes of type I and type II activin receptors were demonstrated. Semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) demonstrated a significant threefold downregulation of alk4-1 receptors in papillary (n= 25) and follicular (n= 18) thyroid cancers as compared to normal thyroids (n= 12) (p< 0.001). To our knowledge these are the first data to demonstrate reversal of activin and TGF-β1 effects in thyroid malignancy and to demonstrate changes of the type Ib activin receptor expression in thyroid malignancy.

Broca's region in the dominant cerebral hemisphere is known to mediate the production of language but also contributes to comprehension. Here, we report the differential participation of Broca's region in imagery of motion in humans. Healthy volunteers were studied with functional magnetic resonance imaging (fMRI) while they imagined movement trajectories following different instructions. Imagery of right‐hand finger movements induced a cortical activation pattern including dorsal and ventral portions of the premotor cortex, frontal medial wall areas, and cortical areas lining the intraparietal sulcus in both cerebral hemispheres. Imagery of movement observation and of a moving target specifically activated the opercular portion of the inferior frontal cortex. A left‐hemispheric dominance was found for egocentric movements and a right‐hemispheric dominance for movement characteristics in space. To precisely localize these inferior frontal activations, the fMRI data were coregistered with cytoarchitectonic maps of Broca's areas 44 and 45 in a common reference space. It was found that the activation areas in the opercular portion of the inferior frontal cortex were localized to area 44 of Broca's region. These activations of area 44 can be interpreted to possibly demonstrate the location of the human analogue to the so‐called mirror neurones found in inferior frontal cortex of nonhuman primates. We suggest that area 44 mediates higher‐order forelimb movement control resembling the neuronal mechanisms subserving speech. Hum. Brain Mapping 11:273–285, 2000. © 2000 Wiley‐Liss, Inc.