Hepadnaviruses, with the human hepatitis B virus as prototype, are small, enveloped hepatotropic DNA viruses which replicate by reverse transcription of an RNA intermediate. Replication is initiated ...by a unique protein-priming mechanism whereby a hydroxy amino acid side chain of the terminal protein (TP) domain of the viral polymerase (P) is extended into a short DNA oligonucleotide, which subsequently serves as primer for first-strand synthesis. A key component in the priming of reverse transcription is the viral RNA element epsilon, which contains the replication origin and serves as a template for DNA primer synthesis. Here, we show that recently discovered non-enveloped fish viruses, termed nackednaviruses C. Lauber
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22, 387-399 (2017), employ a fundamentally similar replication mechanism despite their huge phylogenetic distance and major differences in genome organization and viral lifestyle. In vitro cross-priming studies revealed that few strategic nucleotide substitutions in epsilon enable site-specific protein priming by heterologous P proteins, demonstrating that epsilon is functionally conserved since the two virus families diverged more than 400 Mya. In addition, other
elements crucial for the hepadnavirus-typical replication of pregenomic RNA into relaxed circular double-stranded DNA were identified at conserved positions in the nackednavirus genomes. Hence, the replication mode of both hepadnaviruses and nackednaviruses was already established in their Paleozoic common ancestor, making it a truly ancient and evolutionary robust principle of genome replication that is more widespread than previously thought.
Complete resection of contrast-enhancing tumor has been recognized as an important prognostic factor in patients with glioblastoma and is a primary goal of surgery. Various intraoperative ...technologies have recently been introduced to improve glioma surgery.
To evaluate the impact of using 5-aminolevulinic acid and intraoperative mapping and monitoring on the rate of complete resection of enhancing tumor (CRET), gross total resection (GTR), and new neurological deficits as part of an institutional protocol.
One hundred three consecutive patients underwent resection of glioblastoma from August 2008 to November 2010. Eligibility for CRET was based on the initial magnetic resonance imaging assessed by 2 reviewers. The primary end point was the number of patients with CRET and GTR. Secondary end points were volume of residual contrast-enhancing tissue and new postoperative neurological deficits.
Fifty-three patients were eligible for GTR/CRET (n = 43 newly diagnosed glioblastoma, n = 10 recurrent); 13 additional patients received surgery for GTR/CRET-ineligible glioblastoma. GTR was achieved in 96% of patients (n = 51, no residual enhancement >0.175 cm); CRET was achieved in 89% (n = 47, no residual enhancement). Postoperatively, 2 patients experienced worsening of preoperative hemianopia, 1 patient had a new mild hemiparesis, and another patient sustained sensory deficits.
Using 5-aminolevulinic acid imaging and intraoperative mapping/monitoring together leads to a high rate of CRET and an increased rate of GTR compared with the literature without increasing the rate of permanent morbidity. The combination of safety and resection-enhancing intraoperative technologies was likely to be the major drivers for this high rate of CRET/GTR.
Spontaneous intracranial hypotension (SIH) is an orthostatic headache syndrome with typical MRI findings among which engorgement of the venous sinuses, pachymeningeal enhancement, and effacement of ...the suprasellar cistern have the highest diagnostic sensitivity. SIH is in almost all cases caused by spinal CSF leaks. Spinal MRI scans showing so-called spinal longitudinal extradural fluid (SLEC) are suggestive of ventral dural tears (type 1 leak) which are located with prone dynamic (digital subtraction) myelography. As around half of the ventral dural tears are located in the upper thoracic spine, additional prone dynamic CT myelography is often needed. Leaking nerve root sleeves typically associated with meningeal diverticulae (type 2 leaks) and CSF-venous fistulas (type 3 leaks) are proven via lateral decubitus dynamic digital subtraction or CT myelography: type 2 leaks are SLEC-positive if the tear is proximal and SLEC-negative if it is distal, and type 3 leaks are always SLEC-negative. Although 30–70% of SIH patients show marked improvement following epidural blood patches applied via various techniques definite cure mostly requires surgical closure of ventral dural tears and surgical ligations of leaking nerve root sleeves associated with meningeal diverticulae or CSF-venous fistulas. For the latter, transvenous embolization with liquid embolic agents via the azygos vein system is a novel and valuable therapeutic alternative.
OBJECTIVEDelayed cerebral ischemia (DCI) is strongly associated with poor outcome after subarachnoid hemorrhage (SAH). Cerebral vasospasm is a major contributor to DCI and requires special attention. ...To evaluate the effect of vasospasm management on SAH outcome, we performed a pooled analysis of 2 observational SAH cohorts.
MATERIALSData from 2 institutional databases with consecutive patients with SAH treated between 2005 and 2012 were pooled. The effect of 2 institutional standards of conservative and endovascular vasospasm treatment (EVT) on the rates of DCI (new cerebral infarcts not visible on the post-treatment imaging) and unfavorable outcome (modified Rankin Scale score >2) at 6 months follow-up was analyzed.
RESULTSThe final analysis included 1,057 patients with SAH. There was no difference regarding demographic (age and sex), clinical (Hunt & Hess grades, acute hydrocephalus, treatment modality, and infections), and radiographic (Fisher grades and aneurysm location) characteristics of the populations. However, there was a significant difference in the rate (24.4% 121/495 vs 14.4% 81/562, p < 0.0001) and timing (first treatment on day 6 vs 8.9 after SAH, p < 0.0001) of EVT. The rates of DCI (20.8% vs 29%, p = 0.0001) and unfavorable outcome (44% vs 50.6%, p = 0.04) were lower in the cohort with more frequent and early EVT. Multivariate analysis confirmed independent effect of EVT standard on DCI risk and outcome.
CONCLUSIONSA preventive strategy utilizing frequent and early EVT seems to reduce the risk of DCI in patients with SAH and improve their functional outcome. We recommend prospective evaluation of the value of preventive EVT strategy on SAH.
CLASSIFICATION OF EVIDENCEThis study provides Class III evidence that for patients with SAH, a frequent and early EVT to treat vasospasm reduces the risk of DCI and improves functional outcome.
INTRODUCTION:
Spinal cerebrospinal fluid (CSF)-leaks cause spontaneous intracranial hypotension (SIH). In persisting symptoms despite treatment, surgical closure of spinal CSF-leaks is the treatment ...of choice.
METHODS:
Since April 2019 SIH patients were operated using the minimal invasive technique of tubular retractors. Leaks were sealed using an interlaminar dorsal access and if necessary a transdural route. Neuromonitoring was used for ventral leaks in the first 16 cases. The primary outcome was the benefit of surgery with respect to orthostatic symptoms; secondary outcome was the occurrence of complications.
RESULTS:
Between April 2019 and December 2020 we included 58 patients, mean age 46 years (IQR 36-55), 65% female, with the diagnosis of SIH. We treated 38 ventral leaks, 17 dorsal/lateral leaks, 2 CSF-venous fistulas. In all but two patients (96.6%) the leak could be approached, identified and closed via the tubular retractor. Leaks were visualized via a transdural approach, after cutting the dentate ligament and lateralization of the ventral dura. Microspurs were removed and leaks were closed by sandwich patch using a fibrin sealant patch (ventral leaks) or clipping of the respective nerve root (lateral leaks, CSF-venous fistula). At a median follow up of 21.5 months (IQR 16-28), eight patients were lost to follow up and 45 reported a benefit from surgery with respect to orthostatic symptoms. Mild permanent neurologic deficits occurred in 1.7%, the revision rate due to persisting or recurring leak was 3.4% and the overall revisioin rate was 10.3%.
CONCLUSIONS:
Minimally invasive surgery using tubular retractors of 18-20mm diameter can be safely and effectively performed for closure of spinal dural CSF-leaks in specialized centers.
Spontaneous intracranial hypotension (SIH) is characterized by loss of CSF volume. We hypothesize that in this situation of low volume, a larger CSF flow and spinal cord motion at the upper spine can ...be measured by noninvasive phase contrast MRI.
A prospective, age-, sex-, and body mass index (BMI)-matched controlled cohort study on patients with SIH presenting with spinal longitudinal extradural fluid collection (SLEC) was conducted from October 2021 to February 2022. Cardiac-gated 2D phase contrast MRI sequences were acquired at segment C2/C3, and C5/C6 for CSF flow, and spinal cord motion analysis. Data processing was fully automated. CSF flow and spinal cord motion were analyzed by peak-to-peak amplitude and total displacement per segment and heartbeat, respectively. Clinical data included age, height, BMI, duration of symptoms, Bern score according to Dobrocky et al., and type of the spinal CSF leak according to Schievink et al. Groups were compared via the Mann-Whitney
test; multiple linear regression analysis was performed to address possible relations.
Twenty patients with SIH and 40 healthy controls were analyzed; each group consisted of 70% women. Eleven patients with SIH presented with type 1 leak, 8 with type 2, and 1 was indeterminate. CSF flow per heartbeat was increased at C2/C3 (peak-to-peak amplitude 65.68 ± 18.3 vs 42.50 ± 9.8 mm/s, total displacement 14.32 ± 3.5 vs 9.75 ± 2.7 mm,
< 0.001, respectively). Craniocaudal spinal cord motion per heartbeat was larger at segment C2/C3 (peak-to-peak amplitude 7.30 ± 2.4 vs 5.82 ± 2.0 mm/s, total displacement 1.01 ± 0.4 vs 0.74 ± 0.4 mm,
= 0.006, respectively) and at segment C5/C6 (total displacement 1.41 ± 0.7 vs 0.97 ± 0.4 mm,
= 0.021).
SLEC-positive patients with SIH show higher CSF flow and higher spinal cord motion at the upper cervical spine. This increased craniocaudal motion of the spinal cord per heartbeat might produce increased mechanical strain on neural tissue and adherent structures, which may be a mechanism leading to cranial nerve dysfunction, neck pain, and stiffness in SIH. Noninvasive phase contrast MRI of CSF flow and spinal cord motion is a promising diagnostic tool in SIH.
German Clinical Trials Register, identification number: DRKS00017351.
This study provides Class III evidence that noninvasive phase contrast MRI of the upper spine identifies differences in CSF flow and spinal cord motion in patients with SIH compared with healthy controls.
Hepatitis B viruses (HBVs), which are enveloped viruses with reverse-transcribed DNA genomes, constitute the family Hepadnaviridae. An outstanding feature of HBVs is their streamlined genome ...organization with extensive gene overlap. Remarkably, the ∼1,100 bp open reading frame (ORF) encoding the envelope proteins is fully nested within the ORF of the viral replicase P. Here, we report the discovery of a diversified family of fish viruses, designated nackednaviruses, which lack the envelope protein gene, but otherwise exhibit key characteristics of HBVs including genome replication via protein-primed reverse-transcription and utilization of structurally related capsids. Phylogenetic reconstruction indicates that these two virus families separated more than 400 million years ago before the rise of tetrapods. We show that HBVs are of ancient origin, descending from non-enveloped progenitors in fishes. Their envelope protein gene emerged de novo, leading to a major transition in viral lifestyle, followed by co-evolution with their hosts over geologic eras.
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•Nackednaviruses are non-enveloped fish viruses related to hepadnaviruses•Both virus families separated from a common ancestor >400 million years ago•The envelope protein gene of hepadnaviruses emerged through two distinct processes•Hepadnaviruses mainly co-evolve with hosts while nackednaviruses jump between hosts
Hepatitis B viruses are enveloped viruses of global medical importance. Lauber et al. report the discovery of nackednaviruses, a non-enveloped sister family to hepatitis B viruses in fish. Both lineages separated >400 million years ago. The envelope gene of hepatitis B viruses emerged de novo, followed by virus-host co-evolution over geologic eras.
Mapping and monitoring are believed to provide an early warning sign to determine when to stop tumor removal to avoid mechanical damage to the corticospinal tract (CST). The objective of this study ...was to systematically compare subcortical monopolar stimulation thresholds (1-20 mA) with direct cortical stimulation (DCS)-motor evoked potential (MEP) monitoring signal abnormalities and to correlate both with new postoperative motor deficits. The authors sought to define a mapping threshold and DCS-MEP monitoring signal changes indicating a minimal safe distance from the CST.
A consecutive cohort of 100 patients underwent tumor surgery adjacent to the CST while simultaneous subcortical motor mapping and DCS-MEP monitoring was used. Evaluation was done regarding the lowest subcortical mapping threshold (monopolar stimulation, train of 5 stimuli, interstimulus interval 4.0 msec, pulse duration 500 μsec) and signal changes in DCS-MEPs (same parameters, 4 contact strip electrode). Motor function was assessed 1 day after surgery, at discharge, and at 3 months postoperatively.
The lowest individual motor thresholds (MTs) were as follows (MT in mA, number of patients): > 20 mA, n = 12; 11-20 mA, n = 13; 6-10 mA, n = 20; 4-5 mA, n = 30; and 1-3 mA, n = 25. Direct cortical stimulation showed stable signals in 70 patients, unspecific changes in 18, irreversible alterations in 8, and irreversible loss in 4 patients. At 3 months, 5 patients had a postoperative new or worsened motor deficit (lowest mapping MT 20 mA, 13 mA, 6 mA, 3 mA, and 1 mA). In all 5 patients DCS-MEP monitoring alterations were documented (2 sudden irreversible threshold increases and 3 sudden irreversible MEP losses). Of these 5 patients, 2 had vascular ischemic lesions (MT 20 mA, 13 mA) and 3 had mechanical CST damage (MT 1 mA, 3 mA, and 6 mA; in the latter 2 cases the resection continued after mapping and severe DCS-MEP alterations occurred thereafter). In 80% of patients with a mapping MT of 1-3 mA and in 75% of patients with a mapping MT of 1 mA, DCS-MEPs were stable or showed unspecific reversible changes, and none had a permanent motor worsening at 3 months. In contrast, 25% of patients with irreversible DCS-MEP changes and 75% of patients with irreversible DCS-MEP loss had permanent motor deficits.
Mapping should primarily guide tumor resection adjacent to the CST. DCS-MEP is a useful predictor of deficits, but its value as a warning sign is limited because signal alterations were reversible in only approximately 60% of the present cases and irreversibility is a post hoc definition. The true safe mapping MT is lower than previously thought. The authors postulate a mapping MT of 1 mA or less where irreversible DCS-MEP changes and motor deficits regularly occur. Therefore, they recommend stopping tumor resection at an MT of 2 mA at the latest. The limited spatial and temporal coverage of contemporary mapping may increase error and may contribute to false, higher MTs.
Despite recent advances in cancer immunotherapy, certain tumor types, such as Glioblastomas, are highly resistant due to their tumor microenvironment disabling the anti-tumor immune response. Here we ...show, by applying an in-silico multidimensional model integrating spatially resolved and single-cell gene expression data of 45,615 immune cells from 12 tumor samples, that a subset of Interleukin-10-releasing HMOX1
myeloid cells, spatially localizing to mesenchymal-like tumor regions, drive T-cell exhaustion and thus contribute to the immunosuppressive tumor microenvironment. These findings are validated using a human ex-vivo neocortical glioblastoma model inoculated with patient derived peripheral T-cells to simulate the immune compartment. This model recapitulates the dysfunctional transformation of tumor infiltrating T-cells. Inhibition of the JAK/STAT pathway rescues T-cell functionality both in our model and in-vivo, providing further evidence of IL-10 release being an important driving force of tumor immune escape. Our results thus show that integrative modelling of single cell and spatial transcriptomics data is a valuable tool to interrogate the tumor immune microenvironment and might contribute to the development of successful immunotherapies.
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