QOL-04. Histology, treatment, and extent of pretreatment hydrocephalus are major determents of neurocognitive outcome for survivors of pediatric posterior fossa tumors - report from the German HIT-studies [Abstract]

BACKGROUND: Cognitive impairments following pediatric brain tumors are generally attributed to tumor site, surgical intervention, complications as well as to nonsurgical treatment. We investigated impairments for patients with medulloblastoma (MB), ependymoma (EP) and low-grade glioma (LGG) of the cerebellum treated within the German pediatric brain tumor network to compare and rank major determents. PATIENTS+METHODS: Following protocol treatment, 245 patients with MB (n=106), EP (n=32), and cerebellar LGG (n=107, surgery only) were examined 2 + 5 years after diagnosis using the German “Neuropsychological-Basic-Diagnostic” (NBD) tool based on the Cattell-Horn-Carroll model for intelligence. Within this retrospective study, multiple linear regression models were applied. RESULTS: The MB+EP vs. LGG-cohort differed slightly in median age at diagnosis (8.7/6.1 years) and location (cerebellar hemispheres: 8%MB+EP/49.5%LGG), while sex-ratio, grade of resection, extent of pre-operative hydrocephalus were comparable. With smaller median tumor-volume in the MB+EP vs. LGG-cohort (34.1/44.1cm3), ranges broadly overlapped. Median scores of age-appropriate tests were in the lower normal range for all patients for fluid and crystallized intelligence, selective attention, visual-spatial processing (VSP) and verbal short-term memory (median=93-103), but distinctly below for processing speed (PS), and psychomotor speed abilities (PMS) (median=65-84). Higher doses of craniospinal irradiation (>23.4Gy/23.4Gy) resulted in lower scores for most domains for MB-patients compared to LGG-patients (e.g., PS-estimate: >23.4Gy:-27.71, p=0.026/23.4Gy:-9.93, p=0.286). EP-patients (surgery+54Gy local radiation) scored better than LGG-patients except for PS (estimate:-15.65, p=0.111). Impairments were accentuated with higher degrees of hydrocephalus (estimate:-7.64, p=0.103) in patients with incomplete resection (estimate:12.23, p=0.006) for PMS both hands. CONCLUSION: Following age-adapted comprehensive treatment, survivors of a cerebellar tumor show significant impairments of PMS abilities in our trials. Our data suggest that slow growing LGG impair neurocognitive development more than local radiotherapy for ependymoma, while craniospinal irradiation compromises VSP and PS in MB. Initial symptomatic intracranial pressure remains a strong predictor for general neuropsychological impairment

Quality of life in men with Klinefelter syndrome: a multicentre study

Background: Klinefelter syndrome (KS) is associated with an increased risk of lower socioeconomic status and a higher risk for morbidity and mortal ity, which may have a significant impact on quality of life (QOL). The objective of this study is to investigate QOL in a large European cohort of men with KS. Design: Cross-sectional multicentre study. Methods: Two-hundred-eighteen men with KS were recruited from 14 clinic al study centres in 6 European countries which participated in the Europ ean dsd-LIFE study. Male normative data from a healthy and a psychiatric reference population were used for comparison. The validated World Health Organization (WHO) Q OL (WHOQOL)-BREF questionnaire was used to investigate five main domains of quali ty of life (WHOQOL): global, physical, psychological, environment, and social. Results: The QOL physical domain score was lower for men with KS compar ed to the healthy reference population (KS: 66.9; s.d. 19.4, n = 193; healthy reference population: 76.5; s.d. 16.2, n = 1324, P < 0.001) but higher compared to the psychiatric reference population (54.6; s.d. 20.6; n = 77, P < 0.001). The WHOQOL-psychological domain score was lower for men with KS compared to the healthy reference pop ulation (KS: 63.6; s.d. 17.8, n = 193; healthy reference population: 67.8; s.d. 15.6, n = 1324, P < 0.05) but higher compared to the psychiatric reference population (45.9; s.d. 26.0), n = 77, P < 0.001). The social domain score on the WHOQOL questionnaire was found t o be lower in men with Klinefelter syndrome (KS) compared to the healthy referenc e population (KS: 60.0; s.d. 21.6, n = 193; healthy reference population: 68.2; s.d. 13.8, n = 1324, P < 0.001). However, this score was similar to that of the psychiatric refe rence population (61.0; s.d. 17.0, n = 77, P = 0.5). The WHO environment domain score of men with KS (70.0; s.d. 15.0, n = 193) was similar to the healthy reference population (70.5; s.d. 20.7, n = 1324) but higher compared to the psychiatric reference population (61 .9; s.d. 20.8, n = 77, P = 0.002). Experienced discrimination, less social activities, and the presence of chronic health problems were associated with significantly decreased QOL in men with KS. Conclusion: Overall QOL in European men with KS is significantly worse comp ared to a healthy European reference population. Especially, the presen ce of discrimination, less social activities, and chronic health problems is associat ed with lower physical, psychological, and social QOL. Further studies are necessary to investigate if a multidisciplinary approach may help to provide adequate counsel ling and psychosocial support to improve QOL

Primary intradural extramedullary spinal melanoma in the lower thoracic spine

Up to date, only four cases of primary intradural extramedullary spinal cord melanoma (PIEM) have been reported. No previous reports have described a case of PIEM located in the lower thoracic spine with long-termfollow-up. Purpose. Demonstrating an unusual, extremely rare case of melanoma manifestation. Study Design. Case report. Methods. We report a case of a 57-year-old female suffering from increasing lower extremity pain, left-sided paresis, and paraesthesia due to spinal cord compression caused by PIEM in the lower thoracic spine. Results. Extensive investigation excluded other possible primary melanoma sites and metastases. For spinal cord decompression, the tumor at level T12 was resected, yet incompletely. Adjuvant radiotherapy was administered two weeks after surgery. The patient was recurrence-free at 104 weeks after radiotherapy but presents with unchanged neurological symptoms. Conclusion. Primary intradural extramedullary melanoma (PIEM) is extremely rare and its clinical course is unpredictable

Concerted Actions of a Thermo-labile Regulator and a Unique Intergenic RNA Thermosensor Control Yersinia Virulence

Expression of all Yersinia pathogenicity factors encoded on the virulence plasmid, including the yop effector and the ysc type III secretion genes, is controlled by the transcriptional activator LcrF in response to temperature. Here, we show that a protein-and RNA-dependent hierarchy of thermosensors induce LcrF synthesis at body temperature. Thermally regulated transcription of lcrF is modest and mediated by the thermo-sensitive modulator YmoA, which represses transcription from a single promoter located far upstream of the yscW-lcrF operon at moderate temperatures. The transcriptional response is complemented by a second layer of temperature-control induced by a unique cis-acting RNA element located within the intergenic region of the yscW-lcrF transcript. Structure probing demonstrated that this region forms a secondary structure composed of two stemloops at 25 degrees C. The second hairpin sequesters the lcrF ribosomal binding site by a stretch of four uracils. Opening of this structure was favored at 37 degrees C and permitted ribosome binding at host body temperature. Our study further provides experimental evidence for the biological relevance of an RNA thermometer in an animal model. Following oral infections in mice, we found that two different Y. pseudotuberculosis patient isolates expressing a stabilized thermometer variant were strongly reduced in their ability to disseminate into the Peyer's patches, liver and spleen and have fully lost their lethality. Intriguingly, Yersinia strains with a destabilized version of the thermosensor were attenuated or exhibited a similar, but not a higher mortality. This illustrates that the RNA thermometer is the decisive control element providing just the appropriate amounts of LcrF protein for optimal infection efficiency

Decompensated right heart failure, intensive care and perioperative management in patients with pulmonary hypertension: Updated recommendations from the Cologne Consensus Conference 2018

In June 2016, members of the German Society of Cardiology (DGK), the German Society of Respiratory Medicine (DGP) and the German Society of Pediatric Cardiology (DGPK) met for a Consensus Conference in Cologne, Germany. Aim of this Conference was to compile consensus based practice recommendations based on the 2015 European Pulmonary Hypertension guidelines, aiming at their practical implementation, considering country-specific issues, and including new evidence, where available. This article summarizes the results and updated recommendations 2018 of the working group on decompensated right heart failure (RHF), intensive care and perioperative management in patients with pulmonary hypertension. The RHF section comprises definition and pathophysiology, diagnosis and monitoring, identification of triggering factors and supportive therapy of RHF, volume management as well as PAH targeting therapy, therapy with inotropic, inodilator and vasopressor drugs, extracorporeal support and transplantation. The second part of this article summarizes preoperative management, perioperative monitoring and choice of anesthesia

Enzymatic probing of the <i>yscW-lcrF</i> intergenic region variants.

<p>(<b>A</b>) Enzymatic hydrolysis of the <i>yscW-lcrF</i> wildtype sequence with endonucleases T1 (0.001 U/µl) and V (0.0002 U/µl) performed on the 5′-end labelled intergenic region between the <i>yscW</i> and <i>lcrF</i> gene on the pYV at 25°C and 37°C. The G nucleotides in single stranded regions are indicated. (<b>B</b>) Magnification of the enzymatic probing pattern of the fourU/Shine-Dalgarno region. (<b>C</b>) Enzymatic probing of the <i>yscW-lcrF</i> of the repressed UU-28/-27CC variant, and (<b>D</b>) enzymatic probing of the <i>yscW-lcrF</i> of the derepressed GUU-30/-28AAA variant. The RNA fragments were separated on 8% polyacrylamide gels. Lane L: alkaline ladder; lane C: controls without RNase. The Shine-Dalgarno sequence and the nucleotide exchanges are indicated.</p

Predicted secondary structure of the <i>lcrF</i> RNA thermometer.

<p>(<b>A</b>) The Mfold program <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1002518#ppat.1002518-Zuker2" target="_blank">[81]</a> was used for the prediction of the secondary structure of the <i>yscW-lcrF</i> 124 nt intergenic region. The most probable prediction with the lowest free energy is shown. The blue dots represent base pairing. The start of the protein synthesis at the AUG start codon (START) and the ribosome binding site (RBS) paired with the fourU motif are labelled. Deletion of the hairpin I and II are indicated. Nucleotide exchanges leading to increased complementarity are marked in red, mutations impairing base pair formation are given in green. Numbers indicate the nucleotides relative to the <i>lcrF</i> start codon. (<b>B</b>) Strains YPIII harboring the P<i>_BAD</i>::<i>lcrF</i>′ (−124)-‘<i>lacZ</i>, including the different hairpin deletions or nucleotide exchanges were grown overnight in LB medium at 25°C or 37°C supplemented with 0.05% arabinose. β-Galactosidase activity from overnight cultures was determined and is given in µmol min⁻¹ mg⁻¹ for comparison. The data represent the average ± SD from at least three different experiments each done in duplicate. Data were analyzed by the Student's t test. Stars indicate the results that differed significantly from those of the wildtype at the same temperature with * (P<0.05), ** (P<0.01), and *** (P<0.001). (<b>C</b>) <i>Y. pseudotuberculosis</i> strains harboring the deletion and nucleotide substitution illustrated in (<b>A</b>) in the pYV were grown at 25°C and 37°C. Whole cell extracts of equal amounts of the bacteria were prepared, separated on a 15% SDS polyacrylamide gel, transferred onto a Immobilon membrane and intracellular LcrF was visualized by Western blotting. A higher molecular weight protein (c) that reacted with the polyclonal antiserum was used as loading control.</p

<i>lcrF</i> thermosensor-dependent expression of the <i>yadA</i> and <i>yopE</i> genes.

<p>(<b>A</b>) Strains YPIII (wildtype), YP66 (Δ<i>lcrF</i>) and the repressed and derepressed <i>yscW-lcrF</i> variants YP90 (UU-28/-27CC) and YP95 (GUU-30/-28AAA) harboring the <i>yadA-lacZ</i> fusion plasmid pSF1 were grown in LB medium at 25°C or 37°C. β-Galactosidase activity from overnight cultures was determined and is given in µmol min⁻¹ mg⁻¹ for comparison. The data represent the average ± SD from at least three different experiments each done in duplicate. Data were analyzed by the Student's t test. Stars indicate the results that differed significantly from those of the wildtype at the same temperature with ** (P<0.01), and *** (P<0.001). Whole-cell extracts from overnight cultures of <i>Y. pseudotuberculosis</i> YPIII (wildtype) and the repressed and derepressed <i>yscW-lcrF</i> variants YP90 (UU-28/-27CC) and YP95 (GUU-30/-28AAA) grown at 25°C or 37°C were prepared, and analysed by Western blotting with a polyclonal antibody directed against LcrF and YadA. A higher molecular weight protein (c) was used as control the protein content of the cell extracts. (<b>B</b>) Strains YPIII (wildtype) and the repressed and derepressed <i>yscW-lcrF</i> variants YP90 (UU-28/-27CC) and YP95 (GUU-30/-28AAA) harboring the <i>yopE-luxCDABE</i> plasmid pWO34 were grown in LB medium at 25°C and 37°C. Bioluminescence emitted by the cultures was monitored and is given as relative luminescence units (RLU) and represents the mean of three independent experiments done in triplicate. Data were analyzed by the Student's t test. Stars indicate the results that differed significantly from those of the wildtype at the same temperature with ** (P<0.01), and *** (P<0.001). The panel below shows TCA-precipitated supernatants of YPIII (wildtype), the repressed and derepressed <i>yscW-lcrF</i> variants YP90 (UU-28/-27CC) and YP95 (GUU-30/-28AAA) grown at 25°C and 37°C in the presence (+) or absence (−) of Ca²⁺. The secreted Yop proteins are indicated.</p