The endogenous neuropeptide calcitonin gene-related peptide after spontaneous subarachnoid hemorrhage–A potential psychoactive prognostic serum biomarker of pain-associated neuropsychological symptoms

Background: The pronociceptive neuromediator calcitonin gene-related peptide (CGRP) is associated with pain transmission and modulation. After spontaneous subarachnoid hemorrhage (sSAH), the vasodilatory CGRP is excessively released into cerebrospinal fluid (CSF) and serum and modulates psycho-behavioral function. In CSF, the hypersecretion of CGRP subacutely after good-grade sSAH was significantly correlated with an impaired health-related quality of life (hrQoL). Now, we prospectively analyzed the treatment-specific differences in the secretion of endogenous CGRP into serum after good-grade sSAH and its impact on hrQoL. Methods: Twenty-six consecutive patients (f:m = 13:8; mean age 50.6 years) with good-grade sSAH were enrolled (drop out n = 5): n = 9 underwent endovascular aneurysm occlusion, n = 6 microsurgery, and n = 6 patients with perimesencephalic SAH received standardized intensive medical care. Plasma was drawn daily from day 1 to 10, at 3 weeks, and at the 6-month follow-up (FU). CGRP levels were determined with competitive enzyme immunoassay in duplicate serum samples. All patients underwent neuropsychological self-report assessment after the onset of sSAH (t1: day 11–35) and at the FU (t2). Results: During the first 10 days, the mean CGRP levels in serum (0.470 ± 0.10 ng/ml) were significantly lower than the previously analyzed mean CGRP values in CSF (0.662 ± 0.173; p = 0.0001). The mean serum CGRP levels within the first 10 days did not differ significantly from the values at 3 weeks (p = 0.304). At 6 months, the mean serum CGRP value (0.429 ± 0.121 ng/ml) was significantly lower compared to 3 weeks (p = 0.010) and compared to the first 10 days (p = 0.026). Higher mean serum CGRP levels at 3 weeks (p = 0.001) and at 6 months (p = 0.005) correlated with a significantly poorer performance in the item pain, and, at 3 weeks, with a higher symptom burden regarding somatoform syndrome (p = 0.001) at t2. Conclusion: Our study reveals the first insight into the serum levels of endogenous CGRP in good-grade sSAH patients with regard to hrQoL. In serum, upregulated CGRP levels at 3 weeks and 6 months seem to be associated with a poorer mid-term hrQoL in terms of pain. In migraineurs, CGRP receptor antagonists have proven clinical efficacy. Our findings corroborate the potential capacity of CGRP in pain processing

The management of desmoid tumours: A joint global consensus-based guideline approach for adult and paediatric patients

Abstract Desmoid tumor (DT; other synonymously used terms: Desmoid-type fibromatosis, aggressive fibromatosis) is a rare and locally aggressive monoclonal, fibroblastic proliferation characterised by a variable and often unpredictable clinical course. Previously surgery was the standard primary treatment modality; however, in recent years a paradigm shift towards a more conservative management has been introduced and an effort to harmonise the strategy amongst clinicians has been made. We present herein an evidence-based, joint global consensus guideline approach to the management of this disease focussing on: molecular genetics, indications for an active treatment, and available systemic therapeutic options. This paper follows a one-day consensus meeting held in Milan, Italy, in June 2018 under the auspices of the European Reference Network for rare solid adult cancers, EURACAN, the European Organisation for Research and Treatment of Cancer (EORTC) Soft Tissue and Bone Sarcoma Group (STBSG) as well as Sarcoma Patients EuroNet (SPAEN) and The Desmoid tumour Research Foundation (DTRF). The meeting brought together over 50 adult and pediatric sarcoma experts from different disciplines, patients and patient advocates from Europe, North America and Japan

On the Security of the PKCS#1 v1.5 Signature Scheme

The RSA PKCS#1 v1.5 signature algorithm is the most widely used digital signature scheme in practice. Its two main strengths are its extreme simplicity, which makes it very easy to implement, and that verification of signatures is significantly faster than for DSA or ECDSA. Despite the huge practical importance of RSA PKCS#1 v1.5 signatures, providing formal evidence for their security based on plausible cryptographic hardness assumptions has turned out to be very difficult. Therefore the most recent version of PKCS#1 (RFC 8017) even recommends a replacement the more complex and less efficient scheme RSA-PSS, as it is provably secure and therefore considered more robust. The main obstacle is that RSA PKCS#1 v1.5 signatures use a deterministic padding scheme, which makes standard proof techniques not applicable. We introduce a new technique that enables the first security proof for RSA-PKCS#1 v1.5 signatures. We prove full existential unforgeability against adaptive chosen-message attacks (EUF-CMA) under the standard RSA assumption. Furthermore, we give a tight proof under the Phi-Hiding assumption. These proofs are in the random oracle model and the parameters deviate slightly from the standard use, because we require a larger output length of the hash function. However, we also show how RSA-PKCS#1 v1.5 signatures can be instantiated in practice such that our security proofs apply. In order to draw a more complete picture of the precise security of RSA PKCS#1 v1.5 signatures, we also give security proofs in the standard model, but with respect to weaker attacker models (key-only attacks) and based on known complexity assumptions. The main conclusion of our work is that from a provable security perspective RSA PKCS#1 v1.5 can be safely used, if the output length of the hash function is chosen appropriately

Sarcoma classification by DNA methylation profiling

Sarcomas are malignant soft tissue and bone tumours affecting adults, adolescents and children. They represent a morphologically heterogeneous class of tumours and some entities lack defining histopathological features. Therefore, the diagnosis of sarcomas is burdened with a high inter-observer variability and misclassification rate. Here, we demonstrate classification of soft tissue and bone tumours using a machine learning classifier algorithm based on array-generated DNA methylation data. This sarcoma classifier is trained using a dataset of 1077 methylation profiles from comprehensively pre-characterized cases comprising 62 tumour methylation classes constituting a broad range of soft tissue and bone sarcoma subtypes across the entire age spectrum. The performance is validated in a cohort of 428 sarcomatous tumours, of which 322 cases were classified by the sarcoma classifier. Our results demonstrate the potential of the DNA methylation-based sarcoma classification for research and future diagnostic applications

Species data of littoral macroinvertebrate communities of alpine lakes along an elevational gradient (Hohe Tauern National Park, Austria) in July/August 2018

Alpine lakes support unique communities which may respond with great sensitivity to climate change. To understand the drivers of benthic macroinvertebrate community structure, samples were collected in the littoral of 28 lakes within Hohe Tauern National Park, Austria. Sampling took place from early July to early August 2018 between altitudes of 2,000 and 2,700 m a.s.l. The extent of habitat types in the lake littoral was estimated. Habitat types were classified into sediment (maximum grain size of 2 mm), small rocks (up to 20 cm x 15 cm x 5 cm), and large boulders/sheer rock faces. The extent of rocky habitats was calculated as the sum of areas covered by small rocks and boulders/sheer rock faces. A total area of 1 m² was sampled in each lake, using a hand net with a sharp frame (25 cm in width) and 500 µm mesh-size. Mixed samples were taken, covering each habitat type proportional to its extent in the lake (100% corresponding to 1 m²). For habitats covering up to 10% of the lake, a standardized area of 0.1 m² was sampled. In sediment, the uppermost 5 cm of the ground were scooped into the net by sweeping it swiftly through the sediment. When sampling large boulders or rock faces, a metal spatula was used to scrape macroinvertebrates off the surface and collect them in the net. Macroinvertebrates were brushed off small rocks using a toothbrush over water-filled trays. The dimensions of those small rocks were measured, and total surface area was calculated, assuming a suitable geometric form (ellipsoid or cuboid). Samples were presorted in the field and preserved in 4% formalin. After 3-4 weeks, all samples were rinsed in tap water and transferred to 70% ethanol for further storage. Identification was performed using a stereomicroscope (OLYMPUS SZX16, 11.2x-184x) to the lowest taxon possible

Functional outcome after surgical treatment of spinal meningioma

Objective: Space-occupying spinal meningiomas (SM), commonly diagnosed due to gradual neurological deterioration, are treated surgically by decompression and tumor resection. In this series of patients with surgically treated SM, we determined individual predictors of functional outcome in the context of intraoperative neuromonitoring (IOM). Methods: This retrospective study included 45 patients (39 women, 6 men; mean age 63 years). We reviewed pre- and postoperative charts, surgical reports, radiographic data for demographics, use of IOM, duration of symptoms, histopathology, co-morbidities, radiographic extension, surgical strategy, neurological performance (Japanese Orthopedic Association Score [JOA score]. Median follow-up was 34 months (12-190 months). Results: Most frequent surgical approaches were laminectomy (71.1%, n = 32) and hemi-laminectomy (28.9%, n = 13). Predominant SM site was the thoracic spine (55.6%, n = 25). Most common symptoms were sensory deficits (77.8%, n = 35), gait disorders (55.6%, n = 25), motor deficits (42.2%, n = 19), and radiating pain (37.8%, n = 17). Simpson grade 1 resection was achieved in 6 patients, most common type of resection was Simpson grade 2 in 36 patients. During follow-up, 80.0% of patients had fully recovered sensory deficits (p < 0.001), 76.0% of patients with preoperative gait disorders had been asymptomatic (p < 0.001), and motor deficits in 12/19 (63.1%). Pain had decreased significantly from admission to follow-up (p = 0.001). IOM was used in 20 (44.4%) patients. Postoperatively, 6 (13.3%) patients had developed a new neurological deficit, 4 of them operated without IOM. Conclusion: Resection of SM with IOM showed good recovery, excellent functional results with low surgical morbidity. (C) 2020 Elsevier Ltd. All rights reserved

Littoral macroinvertebrate communities and environmental parameters of alpine lakes along an elevational gradient (Hohe Tauern National Park, Austria) in July/August 2018

Alpine lakes support unique communities which may respond with great sensitivity to climate change. To understand the drivers of benthic macroinvertebrate community structure, samples were collected in the littoral of 28 lakes within Hohe Tauern National Park, Austria. Sampling took place from early July to early August 2018 between altitudes of 2,000 and 2,700 m a.s.l. The extent of habitat types in the lake littoral was estimated. Habitat types were classified into sediment (maximum grain size of 2 mm), small rocks (up to 20 cm x 15 cm x 5 cm), and large boulders/sheer rock faces. The extent of rocky habitats was calculated as the sum of areas covered by small rocks and boulders/sheer rock faces. A total area of 1 m² was sampled in each lake, using a hand net with a sharp frame (25 cm in width) and 500 µm mesh-size. Mixed samples were taken, covering each habitat type proportional to its extent in the lake (100% corresponding to 1 m²). For habitats covering up to 10% of the lake, a standardized area of 0.1 m² was sampled. In sediment, the uppermost 5 cm of the ground were scooped into the net by sweeping it swiftly through the sediment. When sampling large boulders or rock faces, a metal spatula was used to scrape macroinvertebrates off the surface and collect them in the net. Macroinvertebrates were brushed off small rocks using a toothbrush over water-filled trays. The dimensions of those small rocks were measured, and total surface area was calculated, assuming a suitable geometric form (ellipsoid or cuboid). Samples were presorted in the field and preserved in 4% formalin. After 3-4 weeks, all samples were rinsed in tap water and transferred to 70% ethanol for further storage. Identification was performed using a stereomicroscope (OLYMPUS SZX16, 11.2x-184x) to the lowest taxon possible. Lake size was determined by aerial photograph in Google Earth Pro. To do so, the outlines of the lakes were traced, and the area of the polygon then calculated. Physical and chemical water parameters were measured with a multi-parameter sonde (EXO2 YSI) (for lakes 1-18 from a boat, otherwise from a rock or by wading into the lake): water temperature (°C), dissolved oxygen (% saturation), conductivity (µS/m), pH, nitrate (mg/l), turbidity (FNU), blue-green algae phycocyanin (µg/l) and chlorophyll-a (µg/l). Maximum depth (m) was measured with a sonar by rowing up to 10 transects across lakes. Maximum depth was not measured for lakes 19-28. Two data loggers had been planted per lake in lakes 1-18 in the previous year and were recovered in 2018. Data loggers measured water temperature at about half a meter depth in six-hour intervals over an entire year. Ice-free days were deduced from available logger data, assuming an ice-cover at water temperatures below 2 °C (daily maximum temperature). Additionally, zoo- and phytoplankton samples were taken from the first 18 lakes. Zooplankton was sampled with vertical tows from the hypolimnion to the surface in deeper lakes, and with oblique tows in shallow lakes using a 29 cm diameter net with a 30 µm mesh size. Samples were then fixed in sucrose-formalin and counted under an Olympus SZX16 stereomicroscope equipped with a 0.7 – 11.5 zoom objective. Phytoplankton samples from lakes 1-18 were taken with a 1.2 L water sampler from the middle of the epilimnion, and when one was present, also from the deep chlorophyll maximum. Samples were fixed with Lugol's iodine and counted in sampling chambers with a Nikon TE2000 inverted microscope using a 20x objective

Effect of surgical decompression of spinal metastases in acute treatment – Predictors of neurological outcome

Objective: Space-occupying spinal metastases (SM), commonly diagnosed because of acute neurological deterioration, consequently lead to immediate decompression with tumor removal or debulking. In this study, we analyzed a series of patients with surgically treated spinal metastases and explicitly sought to determine individual predictors of functional outcome. Patients and methods: 94 patients (26 women, 68 men; mean age 64.0 years) with spinal metastases, who had been surgically treated at our department, were included retrospectively. We reviewed the pre- and postoperative charts, surgical reports, radiographic data for demographics, duration of symptoms, histopathology, stage of systemic disease, co-morbidities, radiographic extension, surgical strategy, neurological performance (Frankel Grade Classification), and the Karnofsky Performance Index (KPI). Results: Emergency surgery within <24 h after discharge had been conducted in 33% of patients. Prostate carcinoma (29.5%) and breast carcinoma (11.6%) were the most common histopathologies. Median KPI was 60% at admission that had significantly improved at discharge (KPI 70%; p = 0.01). The rate of complications without revision was 4.3%, the revision rate 4.2%. From admission to discharge, pain had been significantly reduced (p = 0.019) and motor deficits significantly improved (p = 0.003). KPI had been significantly improved during in-hospital treatment (median 60 vs 70, p = 0.010). In the multivariable analysis, predictors of poor outcome (KPI < 70) were male sex, multiple metastases, and pre-existing bowel and bladder dysfunction. Median follow up was 2 months. Discussion: In our series, surgery for spinal metastases (laminectomy, tumor removal, and mass reduction) significantly reduced pain as well as sensory and motor deficits. We identified male sex, multiple metastases, and pre-existing bowel and bladder dysfunction as predictors of negative outcome. (C) 2018 Elsevier Ltd. All rights reserved

Degenerative symptomatic spinal synovial cysts: Clinical presentation and functional outcome

Spinal synovial cysts (SSC) are a rare but important differential diagnosis for degenerative or space-occupying spinal lesions. There is controversy about the most beneficial treatment, which can be conservative or surgical. We provide a review of our surgical data for purposes of quality assessment and improvement. 5313 patients with surgically treated degenerative spinal diseases were analyzed retrospectively. The incidence of SSC was 1.14%. 61 patients (31 women, 30 men; mean age 65.3 years) with SSC were included in this study. The charts, surgical reports, and radiographic data were reviewed for demographics, duration of symptoms, size of SSC, anatomical site, surgical approach, Visual Analog Scale (VAS), and neurological performance including the Japanese Orthopedic Association Score (JOA score) and the Frankel score. Laminotomy was the most common surgical approach in 93.4% of the patients followed by hemilaminectomy in 6.6%. The predominant site of SSC was the lumbar spine in 86.9%. 95.1% had experienced local and radicular pain as the predominant symptom and 47.5% preoperative sensory and motor deficits. At discharge, the JOA score was significantly increased compared to admission (median value of 17). At follow-up, 94.4% had normal neurological function and 5.6% showed grade 1 neurological deficits. Leg pain had decreased in 94.4% and back pain in 70.6%. At long-term follow-up, all patients presented neurologically stable. The median value for pain classified with the VAS had decreased from 6 at admission to I at long-term follow-up. During long-term follow-up, 6 patients (9.8%) had developed spinal instability requiring stabilization, 5 patients had received facet joint infiltration due to symptomatic facet joint syndrome. The epidemiological and clinical patterns of symptomatic SSC are similar to those of other degenerative spinal diseases. Thus, SSC should always be considered as a rare but important differential diagnosis. Surgical outcome was excellent with immediate symptom relief and recovery, which further improved over time. Our data support the benefit of surgical treatment and may be useful in recommending neurosurgical therapy to patients with SSC. (C) 2018 Elsevier Ltd. All rights reserved

Neurological outcome after resection of spinal schwannoma

Introduction: Spinal schwannoma (SS) is the most frequently diagnosed benign spinal tumor, constituting approximately 25 % of all intradural tumors. Aim of our study was to identify factors that potentially affect immediate postoperative neurological outcome, and the rate of functional recovery within 12 months. Methods: Screening of our institutional database yielded 90 consecutive patients (mean age 57.1 years, 39 women [43.3 %]) with newly diagnosed SS between March 1997 and October 2018. We pre- and postoperatively reviewed patient charts, surgical reports, radiographic data, use of IOM, duration of symptoms, histopathology, co-morbidities, radiographic extension, surgical strategy, neurological performance (Japanese Orthopedic Association Score [JOA score] and Frankel Grade Classification). Results: Mean duration of preoperative symptoms was 3.6 +/- 1.6 months. Most common symptoms were local pain (n = 77, 85.6 %). Macroscopic complete resection was achieved in 84 patients (93.3 %). During follow-up, complete recovery from local pain was documented for 41 patients (59.7 %), from radiating pain for 41 (69.5 %; p < 0.001). Postoperatively, 25 (27.7 %) patients developed a new neurological deficit (motor deficits n = 3 and sensory deficits n = 23; one patient developed both); after 12 months, however, motor deficits had abated in all patients, and 16 (69.5 %) patients had completely recovered from sensory deficits. Use of intraoperative monitoring (IOM) was a significant predictor for good functional outcome (p < 0.001). Conclusion: Resection of SS accompanied by IOM whenever feasible should be advocated. We achieved a high number of complete resections with a low rate of morbidity. New postoperative motor or sensory deficits had a very high rate of complete recovery within 12 months