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Nutrient and carbon dynamics within the river-estuary-coastal water systems are key processes in understanding the flux of matter from the terrestrial environment to the ocean. Here, we analysed those dynamics by following a sampling approach based on the travel time of water and an advanced calculation of nutrient fluxes in the tidal part. We started with a nearly Lagrangian sampling of the river (River Elbe, Germany; 580 km within 8 days). After a subsequent investigation of the estuary, we followed the plume of the river by raster sampling the German Bight (North Sea) using three ships simultaneously. In the river, we detected intensive longitudinal growth of phytoplankton connected with high oxygen saturation and pH values and an undersaturation of CO 2 , whereas concentrations of dissolved nutrients declined. In the estuary, the Elbe shifted from an autotrophic to a heterotrophic system: Phytoplankton died off upstream of the salinity gradient, causing minima in oxygen saturation and pH, supersaturation of CO 2 , and a release of nutrients. In the shelf region, phytoplankton and nutrient concentrations were low, oxygen was close to saturation, and pH was within a typical marine range. Over all sections, oxygen saturation was positively related to pH and negatively to pCO 2 . Corresponding to the significant particulated nutrient flux via phytoplankton, flux rates of dissolved nutrients from river into estuary were low and determined by depleted concentrations. In contrast, fluxes from the estuary to the coastal waters were higher and the pattern was determined by tidal current. Overall, the approach is appropriate to better understand land-ocean fluxes, particularly to illuminate the importance of these fluxes under different seasonal and hydrological conditions, including flood and drought events., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: During the coronavirus disease 2019 (COVID-19) pandemic a wide range of hygiene measures were implemented to contain the spread of infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Besides a mitigation of SARS-CoV‑2, a decline in the number of other respiratory tract infections could be observed. Interestingly, the numbers for some infections of the central nervous system (CNS) decreased as well., Objective: This review article shows the development of important CNS infections in Germany during the COVID-19 pandemic., Material and Method: This article is based on relevant literature on the epidemiology of CNS infections during the COVID-19 pandemic up to autumn 2022., Results: During the COVID-19 pandemic the frequency of bacterial meningitis caused by Streptococcus pneumoniae, Neisseria meningitidis and Haemophilus influenzae significantly declined. The frequency of viral meningitis, particularly those caused by Enterovirus, decreased as well. In contrast, the number of patients suffering from tick-borne encephalitis significantly increased within the first year of the pandemic., Discussion: During the pandemic there was a decrease in cases of bacterial and viral meningitis, most likely due to the general containment strategies and social contact restrictions. The increase of infections transmitted by ticks could be a consequence of changed leisure activities during the pandemic., (© 2022. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Introduction : Central nervous system (CNS) infections can be life-threatening and are often associated with disabling sequelae. One important factor in most CNS infections is a timely pathogen-specific treatment. The diagnostic methods available, however, do not always reach a satisfying sensitivity and specificity. In these cases, there is need for additional diagnostic biomarkers. Chemokines represent potential candidates as biomarkers, since they are an important pillar of the host immune response. The aim of this review is to discuss the diagnostic potential of cerebrospinal fluid (CSF) CXCL13 in patients with CNS infections. Areas covered : Data were obtained from a literature search in PubMed up to October 2019. This review focusses on articles on the potential of CXCL13 as a diagnostic tool. The majority of identified studies aimed to characterize its role in two diseases, namely Lyme neuroborreliosis and neurosyphilis. Expert opinion : CSF CXCL13 has a significant potential as a diagnostic and monitoring add-on marker in Lyme neuroborreliosis. Differences in study design, control groups and clinical parameters between studies, however, affect sensitivity, specificity and cutoff values, underlining the need of further studies to address these issues and pave the way for a generalized clinical practice.

Bacterial meningitis is a deadly disease most commonly caused by Streptococcus pneumoniae, leading to severe neurological sequelae including cerebral edema, seizures, stroke, and mortality when untreated. Meningitis is initiated by the transfer of S. pneumoniae from blood to the brain across the blood-cerebrospinal fluid barrier or the blood-brain barrier (BBB). The underlying mechanisms are still poorly understood. Current treatment strategies include adjuvant dexamethasone for inflammation and cerebral edema, followed by antibiotics. The success of dexamethasone is however inconclusive, necessitating new therapies for controlling edema, the primary reason for neurological complications. Since we have previously shown a general activation of hypoxia inducible factor (HIF-1α) in bacterial infections, we hypothesized that HIF-1α, via induction of vascular endothelial growth factor (VEGF) is involved in transmigration of pathogens across the BBB. In human, murine meningitis brain samples, HIF-1α activation was observed by immunohistochemistry. S. pneumoniae infection in brain endothelial cells (EC) resulted in in vitro upregulation of HIF-1α/VEGF (Western blotting/qRT-PCR) associated with increased paracellular permeability (fluorometry, impedance measurements). This was supported by bacterial localization at cell-cell junctions in vitro and in vivo in brain ECs from mouse and humans (confocal, super-resolution, electron microscopy, live-cell imaging). Hematogenously infected mice showed increased permeability, S. pneumoniae deposition in the brain, along with upregulation of genes in the HIF-1α/VEGF pathway (RNA sequencing of brain microvessels). Inhibition of HIF-1α with echinomycin, siRNA in bEnd5 cells or using primary brain ECs from HIF-1α knock-out mice revealed reduced endothelial permeability and transmigration of S. pneumoniae. Therapeutic rescue using the HIF-1α inhibitor echinomycin resulted in increased survival and improvement of BBB function in S. pneumoniae-infected mice. We thus demonstrate paracellular migration of bacteria across BBB and a critical role for HIF-1α/VEGF therein and hence propose targeting this pathway to prevent BBB dysfunction and ensuing brain damage in infections.

Parkinson's disease (PD) is a progressive neurodegenerative disease which is histologically characterized by loss of dopaminergic neurons in the substantia nigra and deposition of aggregated alpha-synuclein (aSyn) in the brain. The detection of aSyn in well accessible fluids has been one of the central approaches in the development of biomarkers for PD. Recently, real-time quaking-induced conversion (RT-QuIC) has been successfully adapted for use with aSyn seeds. Here, we systematically analysed parameters potentially impacting the reliability of this assay by using quantitative real-time quaking-induced conversion (qRT-QuIC) with in vitro-formed aSyn seeds. Seeds diluted in cerebrospinal fluid (CSF) accelerated the seeding reaction and slightly increased the sensitivity without affecting specificity. Repeated freeze-thaw cycles decreased the apparent lag times of seeds diluted in ddH 2 O but did not alter the seeding activity of seeds diluted in CSF. High levels of artificial contamination with blood resulted in prolonged apparent lag times, while sensitivity and specificity were unaffected. Altogether, qRT-QuIC with aSyn seems to be robust concerning sensitivity and specificity in our model system, but quantitative interpretation might be limited under certain conditions., (© 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)

Dendritic cells (DCs) and leukemia-derived DC (DC leu ) are potent stimulators of various immunoreactive cells and they play a pivotal role in the (re-) activation of the immune system. As a potential treatment tool for patients with acute myeloid leukemia, we developed and analyzed two new PGE 1 -containing protocols (Pici- PGE1 , Kit M) to generate DC/DC leu ex vivo from leukemic peripheral blood mononuclear cells (PBMCs) or directly from leukemic whole blood (WB) to simulate physiological conditions. Pici- PGE1 generated significantly higher amounts of DCs from leukemic and healthy PBMCs when compared to control and comparable amounts as the already established protocol Pici- PGE2 . The proportions of sufficient DC-generation were even higher after DC/DC leu -generation with Pici- PGE1 . With Kits, it was possible to generate DCs and DC leu directly from leukemic and healthy WB without induction of blast proliferation. The average amounts of generated DCs and DC leu -subgroups were comparable with all Kits. The PGE 1 containing Kit M generated significantly higher amounts of mature DCs when compared to the PGE 2 -containing Kit K and increased the anti-leukemic-activity. In summary PGE 1 -containing protocols were suitable for generating DC/DC leu from PBMCs as well as from WB, which reliably (re-) activated immunoreactive cells, improved the overall ex vivo anti-leukemic activity, and influenced cytokine-release-profiles.

A reduced concentration of Aβ 1-42 in CSF is one of the established biomarkers of Alzheimer's disease. Reduced CSF concentrations of Aβ 1-42 have also been shown in multiple sclerosis, viral encephalitis and bacterial meningitis. As neuroinflammation is one of the neuropathological hallmarks of Alzheimer's disease, an infectious origin of the disease has been proposed. According to this hypothesis, amyloid pathology is a consequence of a microbial infection and the resulting immune defense. Accordingly, changes in CSF levels of amyloid-β peptides should be similar in AD and inflammatory brain diseases. Aβ 1-42 and Aβ 1-40 levels were measured in cerebrospinal fluid by ELISA and Western blotting in 34 patients with bacterial meningitis ( n = 9), multiple sclerosis ( n = 5) or Alzheimer's disease ( n = 9) and in suitable controls ( n = 11). Reduced concentrations of Aβ 1-42 were detected in patients with bacterial meningitis, multiple sclerosis and Alzheimer's disease. However, due to a concurrent reduction in Aβ 1-40 in multiple sclerosis and meningitis patients, the ratio of Aβ 1-42 /Aβ 1-40 was reduced only in the CSF of Alzheimer's disease patients. Urea-SDS-PAGE followed by Western blotting revealed that all Aβ peptide variants are reduced in bacterial meningitis, whereas in Alzheimer's disease, only Aβ 1-42 is reduced. These results have two implications. First, they confirm the discriminatory diagnostic power of the Aβ 1-42 /Aβ 1-40 ratio. Second, the differential pattern of Aβ peptide reductions suggests that the amyloid pathology in meningitis and multiple sclerosis differs from that in AD and does not support the notion of AD as an infection-triggered immunopathology.

Background: B-cell survival is regulated through interactions of B-cell-activating factor and a proliferation-inducing ligand with their receptors transmembrane activator and CAML interactor (TACI) and B-cell maturation antigen (BCMA). We evaluated the diagnostic potential of soluble TACI (sTACI) and soluble BCMA (sBCMA) in CSF and serum as biomarkers in primary CNS lymphoma (PCNSL)., Methods: CSF (n = 176) and serum samples (n = 105) from patients with clinically or radiologically suspected PCNSL as well as from control patients were collected prospectively. Levels of sTACI and sBCMA were analyzed by enzyme-linked immunosorbent assay. Additionally, in patients with PCNSL, CSF was analyzed during disease course (time of diagnosis, n = 26; relapse, n = 10; remission, n = 14), and in 2 patients long-term longitudinal analysis was performed., Results: Soluble TACI and sBCMA are significantly increased in patients with PCNSL (sTACI, median: 445 pg/mL; sBCMA, median: 760 pg/mL) compared with control patients (sTACI, median: 0 pg/mL; sBCMA, median: 290 pg/mL). At a cutoff value of 68.4 pg/mL, sTACI shows high sensitivity (87.9%) and specificity (88.3%) for the diagnosis of active PCNSL. Soluble BCMA is less sensitive (72.7%) and specific (71.8%) (cutoff: 460 pg/mL). When both markers are combined, specificity increases, however, at the cost of a lower sensitivity. In serum, both sTACI and sBCMA are not increased in PCNSL patients. Both soluble receptors correlate with clinical course and therapy response., Conclusions: Our results suggest that sTACI and sBCMA in the CSF are promising new biomarkers for diagnosis and therapy monitoring in PCNSL. However, our findings need to be validated in an independent cohort., (© The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

To elucidate the role of bradykinin in the complex pathophysiology of bacterial meningitis we investigated the effect of the bradykinin B2 receptor antagonist Hoe140, icatibant (D-Arg[Hyp3-Thi5-D-Tic7-Oic8]-bradykinin), on pathophysiological alterations in experimental pneumococcal meningitis. Untreated rats injected intracisternally (i.c.) with heat-killed pneumococci developed an increase of regional cerebral blood flow (185.4 +/- 27.4%, baseline 100%, mean +/- S.D.), brain water content (79.16 +/- 0.23%), intracranial pressure (21.4 +/- 6.0 mm Hg), and white blood cell count in the cerebrospinal fluid (CSF) (4621 +/- 1894 cells/microliter) within 6 h after i.c. challenge. Treatment with Hoe140 (0.1 mg/kg i.v. at baseline and 0.05 mg/kg s.c. at 2 h after i.c. challenge) attenuated the increase of brain water content (78.53 +/- 0.28%; P < 0.05), intracranial pressure (7.5 +/- 2.2 mm Hg; P < 0.05), and regional cerebral blood flow (128.6 +/- 23.1%; P < 0.05), and reduced CSF pleocytosis (2690 +/- 1898 cells/microliter. N.S.). When treatment was started 4 h after i.c. challenge Hoe140 reduced intracranial pressure (P < 0.05), but was no more capable to significantly influence the other pathophysiological parameters. Treatment with lower (0.01 mg/kg i.v. at baseline, followed by 0.005 mg/kg s.c. at 2 h) and higher (2 mg/kg i.v., followed by 1 mg/kg s.c. at 2 h) concentrations of Hoe140 was ineffective. Likewise, i.c. injection of Hoe140, at different dosages (4 nmol, 40 nmol, 400 nmol) did not significantly alter the pathophysiological parameters in pneumococci-induced meningitis, but caused changes in mean arterial blood pressure at dosages greater than 4 nmol. We conclude that bradykinin is involved as an inflammatory mediator of microvascular changes, brain edema, and increased intracranial pressure during the early phase of experimental pneumococcal meningitis.

Recent studies using a rat model of pneumococcal meningitis have shown that nitric oxide synthase (NOS) inhibitors greatly attenuated microvascular changes and brain edema formation. The site of NO production during bacterial meningitis is unknown. In this study we tested whether primary astrocyte cultures from neonatal rat cortex can be induced to release NO upon stimulation with pneumococci. NO production was assessed by measuring nitrite in the cell culture supernatant using the Griess reaction. Stimulation with heat-killed unencapsulated pneumococci (HKP) increased nitrite concentrations in astrocyte culture supernatants in a dose-dependent fashion. Administration of N-nitro-L-arginine (L-NA), aminoguanidine, L-canavanine, cycloheximide, and dexamethasone prevented the increase in nitrite concentrations. Addition of L-arginine, but not of D-arginine, partially reversed the inhibitory effect of L-NA. Administration of SOD increased nitrite accumulation. Moreover, at 72 h after stimulation with heat-killed pneumococci (10(7) cfu/ml) astrocytes showed an inducible NOS-like immunoreactivity. Accumulation of nitrite was also observed when rat cerebellar neurons and microglia were stimulated with HKP, whereas there was only a slight increase of nitrite in media of rat C6 glioma cells, but no increase of nitrite when the human glioblastoma cell line LN-229 was stimulated with HKP. There was a stronger increase in nitrite levels when astrocytes from Lewis rats were used compared to that from Wistar rats. In conclusion, our study indicates that astrocytes, neurons and microglia are inducible for NO production upon stimulation with pneumococci.

Nitric oxide (NO) is a mediator of haemodynamic changes and cytotoxicity in in vivo models of inflammation such as endotoxaemic shock. The purpose of this study was to investigate whether NO may be involved in the increase of cerebral blood flow (CBF), intracranial pressure (ICP) and brain water content, known to occur in the early phase of pneumococcal meningitis. Rats injected intracisternally with live pneumococci were either untreated or received 5 mg kg-1 i.v. NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthase. Pretreatment with L-NAME prevented the increase in CBF, ICP and brain water content, as seen in untreated animals. CBF tended to return towards baseline when rats were treated with L-NAME 2 h after pneumococcal injection. Whereas none of the untreated and L-NAME-pretreated animals died during the 6 h observation period, 3 out of 9 rats treated with L-NAME and 7 out of 9 rats with simultaneous i.v. injection of L-NAME and L-arginine died. Our results provide preliminary evidence that NO may be involved as a mediator of CBF changes and oedema formation in the early phase of pneumococcal meningitis in the rat. NO inhibition, however, may have detrimental effects of still unidentified cause, as indicated by the increased mortality in treated animals. Further studies with analysis of the causes of mortality, structurally different NO synthase inhibitors and direct evaluation of NO synthase induction are needed to further support this hypothesis.

Previous studies have demonstrated that the radical scavenger superoxide dismutase completely blocked the increase of regional cerebral blood flow (rCBF), intracranial pressure (ICP), and brain water content during the early phase of experimental pneumococcal meningitis in the rat. To obtain information on the nature of the reactive oxygen species involved, the effect of catalase, a hydrogen peroxide scavenger, was tested. Rats injected intracisternally with live pneumococci were either untreated or received intravenous catalase. The increase of rCBF and brain water content in infected untreated rats was significantly attenuated by catalase 6 h after intracisternal challenge. ICP increased in both infected groups, with a trend toward lower ICP with catalase treatment. Cerebrospinal fluid white blood cell counts were not significantly different between infected groups. These results and previous experiments using superoxide dismutase suggest that the increase of rCBF, ICP, and brain water content is mainly caused by superoxide or superoxide reaction products.