A multicenter, matched case-control analysis comparing burden of illness among patients with tuberous sclerosis complex related epilepsy, generalized idiopathic epilepsy, and focal epilepsy in Germany.

BACKGROUND: Depending on the underlying etiology and epilepsy type, the burden of disease for patients with seizures can vary significantly. This analysis aimed to compare direct and indirect costs and quality of life (QoL) among adults with tuberous sclerosis complex (TSC) related with epilepsy, idiopathic generalized epilepsy (IGE), and focal epilepsy (FE) in Germany. METHODS: Questionnaire responses from 92 patients with TSC and epilepsy were matched by age and gender, with responses from 92 patients with IGE and 92 patients with FE collected in independent studies. Comparisons were made across the main QoL components, direct costs (patient visits, medication usage, medical equipment, diagnostic procedures, ancillary treatments, and transport costs), indirect costs (employment, reduced working hours, missed days), and care level costs. RESULTS: Across all three cohorts, mean total direct costs (TSC: €7602 [median €2620]; IGE: €1919 [median €446], P < 0.001; FE: €2598 [median €892], P < 0.001) and mean total indirect costs due to lost productivity over 3 months (TSC: €7185 [median €11,925]; IGE: €3599 [median €0], P < 0.001; FE: €5082 [median €2981], P = 0.03) were highest among patients with TSC. The proportion of patients with TSC who were unemployed (60%) was significantly larger than the proportions of patients with IGE (23%, P < 0.001) or FE (34%, P = P < 0.001) who were unemployed. Index scores for the EuroQuol Scale with 5 dimensions and 3 levels were significantly lower for patients with TSC (time-trade-off [TTO]: 0.705, visual analog scale [VAS]: 0.577) than for patients with IGE (TTO: 0.897, VAS: 0.813; P < 0.001) or FE (TTO: 0.879, VAS: 0.769; P < 0.001). Revised Epilepsy Stigma Scale scores were also significantly higher for patients with TSC (3.97) than for patients with IGE (1.48, P < 0.001) or FE (2.45, P < 0.001). Overall Quality of Life in Epilepsy Inventory-31 items scores was significantly lower among patients with TSC (57.7) and FE (57.6) than among patients with IGE (66.6, P = 0.004 in both comparisons). Significant differences between patients with TSC and IGE were also determined for Neurological Disorder Depression Inventory for Epilepsy (TSC: 13.1; IGE: 11.2, P = 0.009) and Liverpool Adverse Events Profile scores (TSC: 42.7; IGE: 37.5, P = 0.017) with higher score and worse results for TSC patients in both questionnaires. CONCLUSIONS: This study is the first to compare patients with TSC, IGE, and FE in Germany and underlines the excessive QoL burden and both direct and indirect cost burdens experienced by patients with TSC.

Late Onset of Primary Hemophagocytic Lymphohistiocytosis (HLH) with a Novel Constellation of Compound Heterozygosity Involving Two Missense Variants in the PRF1 Gene.

Hemophagocytic lymphohistiocytosis (HLH) is a rare but in most cases life-threatening immune-mediated disease of the hematopoietic system frequently associated with hematologic neoplasms. Here, we report on a case in which we detected a novel constellation of two missense variants affecting the PRF1 gene, leading to de novo primary HLH. Diagnostics included a comprehensive clinical work-up and standard methods of hematopathology as well as extended molecular genomics based on polymerase chain reaction (PCR) reactions and the calculation of three-dimensional molecule reconstructions of PRF1. Subsequently, a comprehensive review of the literature was performed, which showed that this compound heterozygosity has not been previously described. The patient was a 20-year-old female. Molecular diagnostics revealed two heterozygous missense variants in the PRF1 gene (A91V and R104C) on exon 2. Apart from the finding of two inconclusive genetic variants, all clinical criteria defined by the HLH study group of Histiocyte Society were met at initial presentation. The final diagnosis was made in cooperation with the Consortium of German HLH-reference centers. Here, chemotherapy did not lead to sufficient sustained disease control. Therefore, the decision for allogenic hematopoietic stem cell transplantation (alloHSCT) was made. Hitherto, the duration of response was 6 months. Due to severe and unmanageable hepatic graft-versus-host disease (GvHD), the patient died. We report on a novel constellation of a compound heterozygosity containing two missense variants on exon 2 of the PRF1 gene. To the authors' best knowledge, this is the first presentation of a primary HLH case harboring this genomic constellation with late-onset clinical manifestation.

Next-Generation Metabolic Glycosylation Reporters Enable Detection of Protein O-GlcNAcylation in Living Cells without S-Glyco Modification.

Protein O-GlcNAcylation is a ubiquitous posttranslational modification of cytosolic and nuclear proteins involved in numerous fundamental regulation processes. Investigation of O-GlcNAcylation by metabolic glycoengineering (MGE) has been carried out for two decades with peracetylated N-acetylglucosamine (GlcNAc) and N-acetylgalactosamine derivatives modified with varying reporter groups. Recently, it has been shown that these derivatives can result in non-specific protein labeling termed S-glyco modification. Here, we report norbornene-modified GlcNAc derivatives with a protected phosphate at the anomeric position and their application in MGE. These derivatives overcome two limitations of previously used O-GlcNAc reporters. They do not lead to detectable S-glyco modification, and they efficiently react in the inverse-electron-demand Diels-Alder (IEDDA) reaction, which can be carried out even within living cells. Using a derivative with an S-acetyl-2-thioethyl-protected phosphate, we demonstrate the protein-specific detection of O-GlcNAcylation of several proteins and the protein-specific imaging of O-GlcNAcylation inside living cells by Förster resonance energy transfer (FRET) visualized by confocal fluorescence lifetime imaging microscopy (FLIM).

Critical incidents, nocturnal supervision, and caregiver knowledge on SUDEP in patients with Dravet syndrome: A prospective multicenter study in Germany.

OBJECTIVE: The aim was to investigate the monitoring, interventions, and occurrence of critical, potentially life-threatening incidents in patients with Dravet syndrome (DS) and caregivers' knowledge about sudden unexpected death in epilepsy (SUDEP). METHODS: This multicenter, cross-sectional study of patients with DS and their caregivers in Germany consisted of a questionnaire and prospective diary querying the disease characteristics and demographic data of patients and caregivers. RESULTS: Our analysis included 108 questionnaires and 82 diaries. Patients with DS were 49.1% male (n = 53), with a mean age of 13.5 (SD ± 10.0 years) and primary caregivers were 92.6% (n = 100) female, with a mean age of 44.7 (SD ± 10.6 years). Monitoring devices were used regularly by 75.9% (n = 82) of caregivers, and most monitored daily/nightly. Frequently used devices were pulse oximeters (64.6%), baby monitors (64.6%), thermometers (24.1%), and Epi-Care (26.8%). Younger caregiver and patient age and history of status epilepticus were associated with increased use of monitoring, and 81% of monitor users reported having avoided a critical incident with nocturnal monitoring. The need for resuscitation due to cardiac or respiratory arrest was reported by 22 caregivers (20.4%), and most cases (72.7%) were associated with a seizure. Caregivers reported frequently performing interventions at night, including oropharyngeal suction, oxygenation, personal hygiene, and change of body position. Most caregivers were well informed about SUDEP (n = 102; 94%) and monitored for a lateral or supine body position; however, only 39.8% reported receiving resuscitation training, whereas 52.8% (n = 57) knew what to do in case the child's breathing or heart activity failed. SIGNIFICANCE: Critical incidents and the need for resuscitation are reported frequently by caregivers and may be related to high mortality and SUDEP rates in DS. Resuscitation training is welcomed by caregivers and should be continuously provided. Oxygen monitoring devices are frequently used and considered useful by caregivers.

Generalized onset seizures with focal evolution (GOFE) - a largely unknown ictal variation in genetic generalized epilepsies.

PURPOSE: At onset of generalized seizures, focal electroclinical features are commonly seen, while generalized onset seizures with focal evolution (GOFE) are largely unknown bearing the risk of misclassification. METHODS: In two German epilepsy-centers, patients with GOFE documented by video-EEG monitoring (VEM) between 2017 and 2022 were identified retrospectively. In addition to analysis of ictal electroclinical features, detailed epilepsy and family history, response to antiseizure medication (ASM), and findings from neuroimaging were considered. RESULTS: We identified five patients with GOFE, three females, age 14 to 22 years. All patients developed genetic generalized epilepsy in childhood or adolescence, each presenting with two or three generalized seizure types. In each of the five patients, one GOFE was recorded by VEM. At onset, EEG seizure patterns were characterized by generalized spike-wave discharges at 2.5 to 3.5/sec for 9 to 16 s followed by focal evolution of the discharges. Interictally, all patients presented with generalized spike-wave discharges without focal abnormalities. Semiology at onset was behavioral arrest in two patients and generalized increase in tone in one, while two onsets were clinically inapparent. Semiological signs during focal evolution were variable, comprising head and body version, figure 4 sign, unilateral arm clonic activity, and staring with oral automatisms. In one case, focality involved both hemispheres successively. CONCLUSION: Prominent focal semiological features in GOFE carry a high risk of misclassification as focal seizures and epilepsy and thus wrong choice of ASM. This calls for low-threshold VEM if any doubts of focal genesis of seizures exist.

In Situ Water Quality Monitoring Using an Optical Multiparameter Sensor Probe.

Optical methods such as ultraviolet/visible (UV/Vis) and fluorescence spectroscopy are well-established analytical techniques for in situ water quality monitoring. A broad range of bio-logical and chemical contaminants in different concentration ranges can be detected using these methods. The availability of results in real time allows a quick response to water quality changes. The measuring devices are configured as portable multi-parameter probes. However, their specification and data processing typically cannot be changed by users, or only with difficulties. Therefore, we developed a submersible sensor probe, which combines UV/Vis and fluorescence spectroscopy together with a flexible data processing platform. Due to its modular design in the hardware and software, the sensing system can be modified to the specific application. The dimension of the waterproof enclosure with a diameter of 100 mm permits also its application in groundwater monitoring wells. As a light source for fluorescence spectroscopy, we constructed an LED array that can be equipped with four different LEDs. A miniaturized deuterium-tungsten light source (200-1100 nm) was used for UV/Vis spectroscopy. A miniaturized spectrometer with a spectral range between 225 and 1000 nm permits the detection of complete spectra for both methods.

Vancomycin modestly attenuates symptom severity during onset of and recovery from exertional heat stroke in mice.

Increased intestinal permeability during exertion and subsequent leakage of bacteria into circulation is hypothesized to accelerate exertional heat stroke (EHS) onset and/or exacerbate EHS severity. To provide proof of concept for this theory, we targeted intestinal microbiota via antibiotic prophylaxis and determined whether vancomycin would delay EHS onset and/or mitigate EHS severity and mortality rates using a mouse model of EHS. Mice were 1) designated as EHS or Exercise Control (ExC) and 2) given 7 days of vancomycin (VEHS, VExC) or untreated water (EHS, ExC) before EHS/Exercise. Following EHS/ExC, mice were euthanized immediately (0 h) or returned to their home cage (25°C) and euthanized after 3 h or 24 h. VEHS mice exhibited reduced abundance and altered composition of fecal bacteria (with notable decreases in genera within orders Clostridiales and Bacteroidales); increased water consumption, lower core temperature (TC) before and during heating (TCMax), lower circulating markers of organ damage and inflammation at 24 h; and reduced hepatic activation of stress pathways at 0 and 3 h compared with EHS mice. Vancomycin-induced alterations to the intestinal microbiota likely influenced EHS outcomes, but it is unconfirmed whether this is due to attenuated bacterial leakage into circulation or other (in)direct effects on physiology and behavior (e.g., decreased TC, increased water consumption). To our knowledge, this is the first study quantitating antibiotic effects in conscious/unanesthetized, exertional HS animals.NEW & NOTEWORTHY Vancomycin prophylaxis lowered core temperature before and during EHS, mitigated EHS-associated rise of hepatic biomarkers and cytokines/chemokines in circulation (particularly at 24 h), and corresponded to inhibited phosphorylation of hepatic c-Jun NH2-terminal kinase on Threonine 183/Tyrosine 185 at 0 and 3 h in conscious, unanesthetized mice. However, vancomycin also induced cecal enlargement suggesting its off-target effects could limit its utility against EHS.

Tumor size, treatment patterns, and survival in neuro-oncology patients before and during the COVID-19 pandemic.

The COVID-19 pandemic has disrupted healthcare delivery worldwide, leading to significant delays in cancer diagnosis and treatment. This study aimed to investigate the impact of the pandemic on the diagnosis and treatment of malignant brain tumors, specifically glioblastoma (GBM) and cerebral metastasis (CM), in a specialized neuro-oncology center. We analyzed data from 236 patients diagnosed with previously unknown malignant brain tumors between January 2018 and December 2021. Patients were classified into two groups: pre-COVID (January 2018 to December 2019) and COVID (January 2020 to December 2021). Tumor volumes were compared between the two groups and factors affecting tumor volumes were studied. Of 236 patients diagnosed with previously unknown malignant brain tumors, 114 were in the pre-COVID group and 122 were in the COVID group. Median tumor volumes at first diagnosis were significantly larger in the COVID group compared to the pre-COVID group (21.7 vs 15.7 cm3; p < 0.05). The survival times for the overall cohort and the GBM and CM subgroups did not differ significantly between the pre-COVID and COVID periods. Delays in diagnosis and treatment during the COVID-19 pandemic led to larger tumor volumes at diagnosis for patients with malignant brain tumors. However, these larger tumors did not result in worse survival outcomes. This counterintuitive finding highlights the crucial role of specialized neuro-oncological centers in mitigating the potential negative impact of delayed treatment and emphasizes the need for continued access to specialized care during times of crisis.

Structural and Chemical Properties of NiOx Thin Films: Oxygen Vacancy Formation in O2 Atmosphere.

NiOx films on Si(111) were put in contact with oxygen at elevated temperatures. During heating and cooling in oxygen atmosphere Near Ambient Pressure (NAP)-XPS and -XAS and work function (WF) measurements reveal the creation and replenishing of oxygen vacancies in dependence of temperature. Oxygen vacancies manifest themselves as a distinct O1s feature at 528.9 eV on the low binding energy side of the main NiO peak as well as by a distinct deviation of the Ni2p3/2 spectral features from the typical NiO spectra. DFT calculations reveal that the presence of oxygen vacancies leads to a charge redistribution and altered bond lengths of the atoms surrounding the vacancies causing the observed spectral changes. Furthermore, we observed that a broadening of the lowest energy peak in the O K-edge spectra can be attributed to oxygen vacancies. In the presence of oxygen vacancies, the WF is lowered by 0.1 eV.

Structural and chemical properties of NiOx thin films: the role of oxygen vacancies in NiOOH formation in a H2O atmosphere.

NiOx films grown from 50 nm thick Ni on Si(111) were put in contact with oxygen and subsequently water vapor at elevated temperatures. Near ambient pressure (NAP)-XPS and -XAS reveal the formation of oxygen vacancies at elevated temperatures, followed by H2O dissociation and saturation of the oxygen vacancies with chemisorbing OH. Through repeated heating and cooling, OH-saturated oxygen vacancies act as precursors for the formation of thermally stable NiOOH on the sample surface. This is accompanied by a significant restructuring of the surface which increases the probability of NiOOH formation. Exposure of a thin NiOx film to H2O can lead to a partial reduction of NiOx to metallic Ni accompanied by a distinct shift of the NiOx spectra with respect to the Fermi edge. DFT calculations show that the formation of oxygen vacancies and subsequently Ni0 leads to a state within the band gap of NiO which pins the Fermi edge.

Micro-compartmentalized strand displacement reactions with a random pool background.

Toehold-mediated strand displacement (TMSD) is a widely used process in dynamic DNA nanotechnology, which has been applied for the actuation of molecular devices, in biosensor applications, and for DNA-based molecular computation. Similar processes also occur in a biological context, when RNA strands invade secondary structures or duplexes of other RNA or DNA molecules. Complex reaction environments-inside cells or synthetic cells-potentially contain a large number of competing nucleic acid molecules that transiently bind to the components of the strand displacement reaction of interest and thus slow down its kinetics. Here, we investigate the kinetics of TMSD reactions compartmentalized into water-in-oil emulsion droplets-in both the presence and absence of a random sequence background-using a droplet microfluidic 'stopped flow' set-up. The set-up enables one to determine the kinetics within thousands of droplets and easily vary experimental parameters such as the stoichiometry of the TMSD components. While the average kinetics in the droplets coincides precisely with the bulk behaviour, we observe considerable variability among the droplets. This variability is partially explained by the encapsulation procedure itself, but appears to be more pronounced in reactions involving a random pool background.

Amino acid solution mitigates hypothermia response and intestinal damage following exertional heat stroke in male mice.

Increased gut permeability is implicated in the initiation and extent of the cytokine inflammatory response associated with exertional heat stroke (EHS). The primary objective of this study was to determine if a five amino acid oral rehydration solution (5AAS), specifically designed for the protection of the gastrointestinal lining, would prolong time to EHS, maintain gut function and dampen the systemic inflammatory response (SIR) measured during EHS recovery. Male C57/BL6J mice instrumented with radiotelemetry were gavaged with 150 µL of 5AAS or H2 O, and ≈12 h later were either exposed to an EHS protocol where mice exercised in a 37.5°C environmental chamber to a self-limiting maximum core temperature (Tc,max) or performed the exercise control (EXC) protocol (25°C). 5AAS pretreatment attenuated hypothermia depth and length (p < 0.005), which are indicators of EHS severity during recovery, without any effect on physical performance or thermoregulatory responses in the heat as determined by percent body weight lost (≈9%), max speed (≈6 m/min), distance (≈700 m), time to Tc,max (≈160 min), thermal area (≈550°C∙min), and Tc,max (42.2°C). EHS groups treated with 5AAS showed a significant decrease in gut transepithelial conductance, decreased paracellular permeability, increased villus height, increased electrolyte absorption and changes in tight junction protein expression pattern suggestive of improved barrier integrity (p < 0.05). No differences were witnessed between EHS groups in acute phase response markers of liver, circulating SIR markers, or indicators of organ damage during recovery. These results suggest that a 5AAS improves Tc regulation during EHS recovery through maintaining mucosal function and integrity.

Membrane inlet-ion mobility spectrometry with automatic spectra evaluation as online monitoring tool for the process control of microalgae cultivation.

The cultivation of algae either in open raceway ponds or in closed bioreactors could allow the renewable production of biomass for food, pharmaceutical, cosmetic, or chemical industries. Optimal cultivation conditions are however required to ensure that the production of these compounds is both efficient and economical. Therefore, high-frequency analytical measurements are required to allow timely process control and to detect possible disturbances during algae growth. Such analytical methods are only available to a limited extent. Therefore, we introduced a method for monitoring algae release volatile organic compounds (VOCs) in the headspace above a bioreactor in real time. This method is based on ion mobility spectrometry (IMS) in combination with a membrane inlet (MI). The unique feature of IMS is that complete spectra are detected in real time instead of sum signals. These spectral patterns produced in the ion mobility spectrum were evaluated automatically via principal component analysis (PCA). The detected peak patterns are characteristic for the respective algae culture; allow the assignment of the individual growth phases and reflect the influence of experimental parameters. These results allow for the first time a continuous monitoring of the algae cultivation and thus an early detection of possible disturbances in the biotechnological process.

Sleep quality, anxiety, symptoms of depression, and caregiver burden among those caring for patients with Dravet syndrome: a prospective multicenter study in Germany.

BACKGROUND: This study measured sleep quality among caregivers of patients with Dravet syndrome (DS) and assessed the impacts of mental health problems and caregiver burden on sleep quality. METHODS: This multicenter, cross-sectional study of patients with DS and their caregivers throughout Germany consisted of a questionnaire and a prospective 4-week diary querying disease characteristics, demographic data, living conditions, nocturnal supervision, and caregivers' work situations. Sleep quality was assessed using the Pittsburgh Sleeping Quality Index (PSQI). The Hospital Anxiety and Depression Scale (HADS) and the Burden Scale for Family Caregivers (BSFC) were used to measure anxiety, symptoms of depression, and caregiver burden. RESULTS: Our analysis included 108 questionnaires and 82 four-week diaries. Patients with DS were 49.1% male (n = 53), with a mean age of 13.5 ± 10.0 years. Caregivers were 92.6% (n = 100) female, with a mean age of 44.7 ± 10.6 years. The overall mean PSQI score was 8.7 ± 3.5, with 76.9% of participants (n = 83) scoring 6 or higher, indicating abnormal sleep quality. The HADS for anxiety and depression had overall mean scores of 9.3 ± 4.3 and 7.9 ± 3.7, respectively; 61.8% and 50.9% of participants scored above the cutoff value of 8 for anxiety and depression, respectively. Statistical analyses revealed caregiver anxiety levels and patients' sleep disturbances as major factors influencing PSQI scores. The overall mean BSFC score of 41.7 ± 11.7 indicates a moderate burden, with 45.3% of caregivers scoring 42 or higher. CONCLUSIONS: Sleep quality is severely affected among caregivers of patients with DS, correlating with anxiety, comorbidities, and patients' sleep disturbances. A holistic therapeutic approach should be implemented for patients with DS and their caregivers, focusing on the sleep quality and mental health of caregivers. TRIAL REGISTRATION: German Clinical Trials Register (DRKS), DRKS00016967. Registered 27 May 2019, http://www.drks.de/DRKS00016967.

Multifocal and hormone-dependent epithelioid hemangioendothelioma with osteolysis of the second cervical vertebral body: report of an unprecedented surgical approach by using autologous bone graft.

We report the case of a 28-year-old female patient who complained of extreme neck pain when giving birth to a child. Magnetic resonance imaging (MRI) of the cervical spine demonstrated an osteolytic lesion at the second cervical vertebral body (C2). In this presentation, we highlight a transoral surgical approach in order to prevent instability of this osteolytic lesion. To the best of our knowledge, this is the first time that such a route of access has been described for this tumor entity. A histopathologic examination led to the diagnosis of epithelioid hemangioendothelioma. During a follow-up period of 33 months, the patient had no complaints.

Toehold-Mediated Strand Displacement in Random Sequence Pools.

Toehold-mediated strand displacement (TMSD) has been used extensively for molecular sensing and computing in DNA-based molecular circuits. As these circuits grow in complexity, sequence similarity between components can lead to cross-talk, causing leak, altered kinetics, or even circuit failure. For small non-biological circuits, such unwanted interactions can be designed against. In environments containing a huge number of sequences, taking all possible interactions into account becomes infeasible. Therefore, a general understanding of the impact of sequence backgrounds on TMSD reactions is of great interest. Here, we investigate the impact of random DNA sequences on TMSD circuits. We begin by studying individual interfering strands and use the obtained data to build machine learning models that estimate kinetics. We then investigate the influence of pools of random strands and find that the kinetics are determined by only a small subpopulation of strongly interacting strands. Consequently, their behavior can be mimicked by a small collection of such strands. The equilibration of the circuit with the background sequences strongly influences this behavior, leading to up to 1 order of magnitude difference in reaction speed. Finally, we compare two established and one novel technique that speed up TMSD reactions in random sequence pools: a three-letter alphabet, protection of toeholds by intramolecular secondary structure, or by an additional blocking strand. While all of these techniques were useful, only the latter can be used without sequence constraints. We expect that our insights will be useful for the construction of TMSD circuits that are robust to molecular noise.

Definition of the Neurotoxicity-Associated Metabolic Signature Triggered by Berberine and Other Respiratory Chain Inhibitors.

To characterize the hits from a phenotypic neurotoxicity screen, we obtained transcriptomics data for valinomycin, diethylstilbestrol, colchicine, rotenone, 1-methyl-4-phenylpyridinium (MPP), carbaryl and berberine (Ber). For all compounds, the concentration triggering neurite degeneration correlated with the onset of gene expression changes. The mechanistically diverse toxicants caused similar patterns of gene regulation: the responses were dominated by cell de-differentiation and a triggering of canonical stress response pathways driven by ATF4 and NRF2. To obtain more detailed and specific information on the modes-of-action, the effects on energy metabolism (respiration and glycolysis) were measured. Ber, rotenone and MPP inhibited the mitochondrial respiratory chain and they shared complex I as the target. This group of toxicants was further evaluated by metabolomics under experimental conditions that did not deplete ATP. Ber (204 changed metabolites) showed similar effects as MPP and rotenone. The overall metabolic situation was characterized by oxidative stress, an over-abundance of NADH (>1000% increase) and a re-routing of metabolism in order to dispose of the nitrogen resulting from increased amino acid turnover. This unique overall pattern led to the accumulation of metabolites known as biomarkers of neurodegeneration (saccharopine, aminoadipate and branched-chain ketoacids). These findings suggest that neurotoxicity of mitochondrial inhibitors may result from an ensemble of metabolic changes rather than from a simple ATP depletion. The combi-omics approach used here provided richer and more specific MoA data than the more common transcriptomics analysis alone. As Ber, a human drug and food supplement, mimicked closely the mode-of-action of known neurotoxicants, its potential hazard requires further investigation.

Identification of therapeutic targets in a murine model of severe exertional heat stroke.

Exertional heat stroke (EHS) is a potentially lethal condition resulting from high core body temperatures (TC) in combination with a systemic inflammatory response syndrome (SIRS) with varying degrees of severity across victims, and limited understanding of the underlying mechanism(s). We established a mouse model of severe EHS to identify mechanisms of hyperthermia/inflammation that may be responsible for organ damage. Mice were forced to run on a motorized wheel in a 37.5°C chamber until loss of consciousness and were either removed immediately (exertional heat injury or EHI; TCMax = 42.4 ± 0.2°C) or remained in the chamber an additional 20 min (EHS; TCMax = 42.5 ± 0.4°C). Exercise control mice (ExC) experienced identical procedures to EHS at 25°C. At 3 h post-EHS, there was evidence for an immune/inflammatory response as elevated blood chemokine [interferon γ-induced protein 10 (IP-10), keratinocytes-derived chemokine (KC), macrophage inflammatory proteins (MIP-1α), MIP-1ß, MIP-2] and cytokine [granulocyte colony-stimulating factor (G-CSF), interleukins (IL-10), IL-6] levels peaked and were highest in EHS mice compared with EHI and ExC mice. Immunoblotting of organs susceptible to EHS damage indicated that several kinases were sensitive to stress associated with heat/inflammation and exercise; specifically, phosphorylation of liver c-Jun NH2-terminal kinase (JNK) at threonine 183/tyrosine 185 immediately (0 h) postheating related to heat illness severity. We have established a mouse EHS model, and JNK [or its downstream target(s)] could underlie EHS symptomatology, allowing the identification of molecular pathways or countermeasure targets to mitigate heat illness severity, enable complete recovery, and decrease overall EHS-related fatalities.