Real-world data evaluating Guy's rapid diagnostic clinic as an alternate pathway for patients with FIT levels below 10.

OBJECTIVE: To analyse the effectiveness of rapid diagnostic clinics (RDCs) as an alternative pathway for patients with concerning symptoms and a faecal immunochemical test (FIT) result <10. Our primary endpoint was rate of colorectal cancer (CRC) detection. Second endpoints were rates of other cancers and gastrointestinal (GI) serious benign conditions. Finally, we analysed the specific pathway followed by FIT <10 patients with cancer at Guy's and St Thomas NHS Foundation Trust (GSTT) RDC. DESIGN: A retrospective and prospective cohort study. SETTING: GSTT RDC, one of England's largest single-centre RDCs. Sociodemographic and clinical characteristics of FIT <10 patients were analysed descriptively. PARTICIPANTS: Patients with an FIT result <10, seen at GSTT RDC between 1 January 2020 and 5 May 2023. RESULTS: A total of 1299 patients with an FIT<10 were seen at GSTT RDC between January 2020 and May 2023. Of these, 66% (n=861) reported weight loss, 62% (n=805) pain, 37% (n=481) fatigue, 34% (n=444) were anaemic and 23% (n=301) had nausea and vomiting. Among these patients, 7% (n=88) received a cancer diagnosis, 36% (n=462) were identified as having a serious benign condition. Within the patients with cancer, 9% (n=8) were diagnosed with CRC. Among patients with serious benign conditions, 7% (n=31) were referred to colorectal, hepatopancreatobiliary, or upper GI specialists. CONCLUSION: This study demonstrates the effectiveness of RDCs as an alternate pathway for FIT <10 patients with ongoing clinical concerns. These results contribute to enhancing patient care and optimising resource allocation within the healthcare system.

In Vitro Human Dermal Absorption Studies on Pesticides in Complex Mixtures: Investigation of Guidance Criteria and Possible Impact Parameters.

Pesticides must not pose unacceptable risks to human health, so risk assessments are conducted before products are authorised. Dermal exposure is often the main route of intake, so estimating realistic and trustworthy dermal absorption values is crucial for risk assessment. Although there are agreed test guidelines for in vitro dermal absorption studies, not every product is tested due to cost reasons. The present dataset consists of 945 individual in vitro experiments on the dermal absorption of human skin with 179 active substances of pesticides in 353 different mixtures, including concentrates and dilutions. The dataset was evaluated to identify the possible impacts of experimental conditions and physico-chemical properties on dermal absorption. The dataset was also analysed to assess the appropriateness of the pro rata correction for untested dilutions, and the set concentration cut-off to decide on the dilution status for choosing a default value on dermal absorption. The study found that the implementation of specific guidelines improved the harmonisation of study conduct, with support for approaches such as pro rata correction and default values. Further analysis of the specific co-formulants may identify influencing factors that may be more important than the experimental variables.

Guidance on the assessment of exposure of operators, workers, residents and bystanders in risk assessment of plant protection products.

This guidance is designed to assist risk assessors and applicants when quantifying potential non-dietary, systemic exposures as part of regulatory risk assessment for plant protection products (PPPs). It is based on the Scientific Opinion on 'Preparation of a Guidance Document on Pesticide Exposure Assessment for Workers, Operators, Residents and Bystanders' developed by the EFSA Panel on Plant Protection Products and their Residue (PPR) in 2010. Highlighting some inconsistencies between the approaches adopted by regulatory authorities, the PPR Panel proposed a number of changes to the practices in use (i.e. use of deterministic methods for individual PPPs; need to perform an acute risk assessment for PPPs that are acutely toxic; use of appropriate percentile for acute or longer term risk assessments). In the first version of the guidance, issued in 2014, several scenarios for outdoor uses were included, with an annexed calculator, as well as recommendations for further research. The guidance has been updated in 2021 with the inclusion of additional scenarios and revision of default values, on the basis of the evaluation of additional evidence. To support users in performing the assessment of exposure and risk, an online calculator, reflecting the guidance content, has been further developed.

Towards a tiered test strategy for plant protection products to address mixture toxicity by alternative approaches in human health assessment.

Plant protection products (PPPs) consist of pesticide active substances and co-formulants. Generally, active substance effects are assumed to dominate in PPP toxicity. Nevertheless, co-formulants may well affect the toxicity of PPPs via toxicodynamic and toxicokinetic interaction. To account for potential mixture effects and improve PPP data requirements for application in risk assessment, a tiered test strategy is proposed. The strategy is based on a comparison of PPP and active substance toxicity, which enables the prioritisation of PPPs for further testing, adaptation of the toxicological threshold value or removal of toxic co-formulants from the PPP. Moreover, it focuses on the integrative assessment of existing information and newly generated data using alternative test methods. The proposed strategy will improve PPP toxicological assessment by accounting for mixture toxicity, providing a set of regulatory options for risk assessment and the necessary data for hazard assessment. The predictivity of alternative methods for PPPs will improve by evaluation of their reliability and uncertainty. © 2020 The Authors. Pest Management Science published by JohnWiley & Sons Ltd on behalf of Society of Chemical Industry.

Vascular response to social cognitive performance measured by infrared thermography: A translational study from mouse to man.

To assess complex social recognition in mice, we previously developed the SocioBox paradigm. Unexpectedly, 4 weeks after performing in the SocioBox, mice displayed robust social avoidance during Y-maze sociability testing. This unique "sociophobia" acquisition could be documented in independent cohorts. We therefore employed infrared thermography as a non-invasive method of stress-monitoring during SocioBox testing (presentation of five other mice) versus empty box. A higher Centralization Index (body/tail temperature) in the SocioBox correlated negatively with social recognition memory and, after 4 weeks, with social preference in the Y-maze. Assuming that social stimuli might be associated with characteristic thermo-responses, we exposed healthy men (N = 103) with a comparably high intelligence level to a standardized test session including two cognitive tests with or without social component (face versus pattern recognition). In some analogy to the Centralization Index (within-subject measure) used in mice, the Reference Index (ratio nose/malar cheek temperature) was introduced to determine the autonomic facial response/flushing during social recognition testing. Whereas cognitive performance and salivary cortisol were comparable across human subjects and tests, the Face Recognition Test was associated with a characteristic Reference Index profile. Infrared thermography may have potential for discriminating disturbed social behaviors.

Comparative cytotoxicity of plant protection products and their active ingredients.

Toxicological testing of plant protection products (PPPs) is a legal requirement in the EU. The whole PPP formulation is tested for acute endpoints in vivo during approval procedure of PPPs. However, alternative methods such as the CLP calculation method (CM) are employed increasingly. In the first part of this study we analysed PPPs for the correlation of GHS classifications resulting mainly from in vivo LD50-values with classifications obtained from calculated LD50-values using the CM. Accordingly, the CM predicted 80% of the PPPs correctly. However 31% of classified products were not identified revealing a considerable inaccuracy of this method. Based on these results ten PPPs and corresponding ASs were further tested in a cytotoxicity assay employing 3T3 and hFF cells (one PPP and corresponding AS were tested in HepaRG cells). The study outcome revealed that the cytotoxicity data did not reliably reflect differences in toxicity between ASs and PPPs. Especially organic solvent based formulations demonstrated a higher cytotoxicity than water based formulations independently to their toxicity in vivo. Overall, the cytotoxicity test did not provide a more robust method than the CM. However, the database consisting of ten PPPs was small and therefore no robust conclusions can be drawn.

A comparative assessment of the CLP calculation method and in vivo testing for the classification of plant protection products.

In Europe, animal testing for the purpose of regulatory plant protection product (PPP) assessment should be undertaken only as a last resort. Nevertheless, there is a need to improve the acceptance of alternative methods, which has been slow due to a lack of data regarding the predictivity of in vivo effects. The CLP calculation method is an alternative method based on the concentration addition of all adverse substances in a mixture. It is often applied as a conservative approach for the estimation of toxicodynamic interactions. However, PPPs consist of pesticides and co-formulants, which in combination can also exhibit altered toxicokinetic properties. Our analysis revealed that oral and inhalation toxicity was underestimated for approximately 45% of the in vivo classified products by the CLP calculation method as compared to in vivo testing. With regard to skin and eye irritation, the CLP calculation method underestimated the irritating potential in 22% and 6% of PPPs, respectively. Based on specific concentration limits, skin sensitisation was underestimated in 34% of PPPs. Similar false negative rates have been reported for PPP in vitro testing. Hence, we suggest the development of an integrated assessment strategy, weighing all available information and considering relevant parameters influencing predictivity and uncertainty.

Riluzole: a potential therapeutic intervention in human brain tumor stem-like cells.

A small subpopulation of tumor stem-like cells has the capacity to initiate tumors and mediate radio- and chemoresistance in diverse cancers hence also in glioblastoma (GBM). It has been reported that this capacity of tumor initiation in the brain is mainly dependent on the body's nutrient supply. This population of so-called brain tumor initiating or brain tumor stem-like cells (BTSCs) is able to extract nutrients like glucose with a higher affinity. Riluzole, a drug approved for treating amyotrophic lateral sclerosis (ALS), was reported to possess anticancer properties, affecting the glutamate metabolism. We report that riluzole treatment inhibits the growth of brain tumor stem-like cells enriched cultures isolated from two human glioblastomas. The effects of riluzole on these cells were associated with an inhibition of a poor prognostic indicator: glucose transporter 3 (GLUT3). A decrease in GLUT3 is associated with a decrease in the p-Akt/HIF1α pathway. Further, downregulation of the DNA (Cytosine-5-)-methyltransferase 1 (DNMT1) gene that causes hypermethylation of various tumor-suppressor genes and leads to a poor prognosis in GBM, was detected. Two hallmarks of cancer cells-proliferation and cell death-were positively influenced by riluzole treatment. Finally, we observed that riluzole reduced the tumor growth in in vivo CAM assay, suggesting it could be a possible synergistic drug for the treatment of glioblastoma.

A First Standardized Swiss Electronic Maternity Record.

BACKGROUND: During the nine months of pregnancy, women have to regularly visit several physicians for continuous monitoring of the health and development of the fetus and mother. Comprehensive examination results of different types are generated in this process; documentation and data transmission standards are still unavailable or not in use. Relevant information is collected in a paper-based maternity record carried by the pregnant women. OBJECTIVES: To improve availability and transmission of data, we aim at developing a first prototype for an electronic maternity record for Switzerland. METHODS: By analyzing the documentation workflow during pregnancy, we determined a maternity record data set. Further, we collected requirements towards a digital maternity record. As data exchange format, the Swiss specific exchange format SMEEX (swiss medical data exchange) was exploited. Feedback from 27 potential users was collected to identify further improvements. RESULTS: The relevant data is extracted from the primary care information system as SMEEX file, stored in a database and made available in a web and a mobile application, developed as prototypes of an electronic maternity record. CONCLUSION: The user confirmed the usefulness of the system and provided multiple suggestions for an extension. An electronical maternity record as developed in this work could be in future linked to the electronic patient record.

µCT of ex-vivo stained mouse hearts and embryos enables a precise match between 3D virtual histology, classical histology and immunochemistry.

The small size of the adult and developing mouse heart poses a great challenge for imaging in preclinical research. The aim of the study was to establish a phosphotungstic acid (PTA) ex-vivo staining approach that efficiently enhances the x-ray attenuation of soft-tissue to allow high resolution 3D visualization of mouse hearts by synchrotron radiation based µCT (SRµCT) and classical µCT. We demonstrate that SRµCT of PTA stained mouse hearts ex-vivo allows imaging of the cardiac atrium, ventricles, myocardium especially its fibre structure and vessel walls in great detail and furthermore enables the depiction of growth and anatomical changes during distinct developmental stages of hearts in mouse embryos. Our x-ray based virtual histology approach is not limited to SRµCT as it does not require monochromatic and/or coherent x-ray sources and even more importantly can be combined with conventional histological procedures. Furthermore, it permits volumetric measurements as we show for the assessment of the plaque volumes in the aortic valve region of mice from an ApoE-/- mouse model. Subsequent, Masson-Goldner trichrome staining of paraffin sections of PTA stained samples revealed intact collagen and muscle fibres and positive staining of CD31 on endothelial cells by immunohistochemistry illustrates that our approach does not prevent immunochemistry analysis. The feasibility to scan hearts already embedded in paraffin ensured a 100% correlation between virtual cut sections of the CT data sets and histological heart sections of the same sample and may allow in future guiding the cutting process to specific regions of interest. In summary, since our CT based virtual histology approach is a powerful tool for the 3D depiction of morphological alterations in hearts and embryos in high resolution and can be combined with classical histological analysis it may be used in preclinical research to unravel structural alterations of various heart diseases.

SK3 Channel Overexpression in Mice Causes Hippocampal Shrinkage Associated with Cognitive Impairments.

The dysfunction of the small-conductance calcium-activated K+ channel SK3 has been described as one of the factors responsible for the progress of psychoneurological diseases, but the molecular basis of this is largely unknown. This report reveals through use of immunohistochemistry and computational tomography that long-term increased expression of the SK3 small-conductance calcium-activated potassium channel (SK3-T/T) in mice induces a notable bilateral reduction of the hippocampal area (more than 50 %). Histological analysis showed that SK3-T/T mice have cellular disarrangements and neuron discontinuities in the hippocampal formation CA1 and CA3 neuronal layer. SK3 overexpression resulted in cognitive loss as determined by the object recognition test. Electrophysiological examination of hippocampal slices revealed that SK3 channel overexpression induced deficiency of long-term potentiation in hippocampal microcircuits. In association with these results, there were changes at the mRNA levels of some genes involved in Alzheimer's disease and/or linked to schizophrenia, epilepsy, and autism. Taken together, these features suggest that augmenting the function of SK3 ion channel in mice may present a unique opportunity to investigate the neural basis of central nervous system dysfunctions associated with schizophrenia, Alzheimer's disease, or other neuropsychiatric/neurodegenerative disorders in this model system. As a more detailed understanding of the role of the SK3 channel in brain disorders is limited by the lack of specific SK3 antagonists and agonists, the results observed in this study are of significant interest; they suggest a new approach for the development of neuroprotective strategies in neuropsychiatric/neurodegenerative diseases with SK3 representing a potential drug target.

CX3CR1 Disruption Differentially Influences Dopaminergic Neuron Degeneration in Parkinsonian Mice Depending on the Neurotoxin and Route of Administration.

Parkinson's disease (PD) is characterized by progressive degeneration of dopaminergic neurons accompanied by an inflammatory reaction. The neuron-derived chemokine fractalkine (CX3CL1) is an exclusive ligand for the receptor CX3CR1 expressed on microglia. The CX3CL1/CX3CR1 signaling is important for sustaining microglial activity. Using a recently developed PD model, in which the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxin is delivered intranasally, we hypothesized that CX3CR1 could play a role in neurotoxicity and glial activation. For this, we used CX3CR1 knock-in mice and compared results with those obtained using the classical PD models through intraperitonal MPTP or intrastriatal 6-hydroxydopamine (6-OHDA). The striatum from all genotypes (CX3CR1(+/+), CX3CR1(+/GFP) and CX3CR1-deficient mice) showed a significant dopaminergic depletion after intranasal MPTP inoculation. In contrast to that, we could not see differences in the number of dopaminergic neurons in the substantia nigra of CX3CR1-deficient animals. Similarly, after 6-OHDA infusion, the CX3CR1 deletion decreased the amphetamine-induced turning behavior observed in CX3CR1(+/GFP) mice. After the 6-OHDA inoculation, a minor dopaminergic neuronal loss was observed in the substantia nigra from CX3CR1-deficient mice. Distinctly, a more extensive neuronal cell loss was observed in the substantia nigra after the intraperitoneal MPTP injection in CX3CR1 disrupted animals, corroborating previous results. Intranasal and intraperitoneal MPTP inoculation induced a similar microgliosis in CX3CR1-deficient mice but a dissimilar change in the astrocyte proliferation in the substantia nigra. Nigral astrocyte proliferation was observed only after intraperitoneal MPTP inoculation. In conclusion, intranasal MPTP and 6-OHDA lesion in CX3CR1-deficient mice yield no nigral dopaminergic neuron loss, linked to the absence of astroglial proliferation.

Analysis of the expression of Kv10.1 potassium channel in patients with brain metastases and glioblastoma multiforme: impact on survival.

BACKGROUND: Kv10.1, a voltage-gated potassium channel only detected in the healthy brain, was found to be aberrantly expressed in extracerebral cancers. Investigations of Kv10.1 in brain metastasis and glioblastoma multiforme (GBM) are lacking. METHODS: We analyzed the expression of Kv10.1 by immunohistochemistry in these brain tumors (75 metastasis from different primary tumors, 71 GBM patients) and the influence of a therapy with tricyclic antidepressants (which are Kv10.1 blockers) on survival. We also investigated Kv10.1 expression in the corresponding primary carcinomas of metastases patients. RESULTS: We observed positive Kv10.1 expression in 85.3 % of the brain metastases and in 77.5 % of GBMs. Patients with brain metastases, showing low Kv10.1 expression, had a significantly longer overall survival compared to those patients with high Kv10.1 expression. Metastases patients displaying low Kv10.1 expression and also receiving tricyclic antidepressants showed a significantly longer median overall survival as compared to untreated patients. CONCLUSIONS: Our data show that Kv10.1 is not only highly expressed in malignant tumors outside CNS, but also in the most frequent cerebral cancer entities, metastasis and GBM, which remain incurable in spite of aggressive multimodal therapies. Our results extend the correlation between dismal prognosis and Kv10.1 expression to patients with brain metastases or GBMs and, moreover, they strongly suggest a role of tricyclic antidepressants for personalized therapy of brain malignancies.

Potential bioavailability of lead, arsenic, and polycyclic aromatic hydrocarbons in compost-amended urban soils.

Urban soils may contain harmful concentrations of contaminants, such as lead (Pb), arsenic (As), and polycyclic aromatic hydrocarbons (PAHs), that can transfer from soil to humans via soil ingestion and consumption of food crops grown in such soils. The objective of this research was to assess the effectiveness of adding different compost types to reduce both direct (soil-human) and indirect (soil-plant-human) exposure of Pb, As, and PAHs to humans. A field experiment was conducted in 2011 and 2012 at an urban garden site with elevated concentrations of Pb (475 mg kg), As (95 mg kg), and PAHs (23-50 mg kg). Soil amendments were composted biosolids, noncomposted biosolids, mushroom compost, leaf compost, and a nonamended control. Collard greens, tomatoes, and carrots were then grown in the amended and nonamended soils and nonamended soils that received urea in 2011. At the beginning of the second season, N-P-K fertilizer was added to all plots. The potential for direct and indirect exposure was evaluated. Soil Pb bioaccessibility was 1 to 4.3%, and As bioaccessibility was 7.3 to 12.3%. Composted biosolids reduced the bioaccessibility of soil Pb by ∼17% compared with the control but temporarily increased the bioaccessibility of As by ∼ 69% compared with the control when soluble inorganic P concentration in soil was elevated by P fertilizer application in 2012. The bioaccessibility of soil Pb decreased by ∼38% in all treatments when soluble inorganic P concentration in soil was elevated by P fertilizer. Compost amendments reduced the concentrations of low molecular weight PAHs in soil. Regardless of the treatments, the concentrations of Pb, As, and PAHs measured in the vegetables were low or nondetectable, except for Pb in carrots. Consumption of vegetables grown at this site will cause insignificant transfer of Pb, As, and PAHs to humans.

Safety of gardening on lead- and arsenic-contaminated urban brownfields.

Elevated levels of lead (Pb) and arsenic (As) are not uncommon for urban soils. Test plots were established at urban gardens in Tacoma and Seattle, WA. The Tacoma site was contaminated with Pb (51-312 mg kg) and As (39-146 mg kg), and the Seattle site had high Pb soil concentrations ranging from 506 to 2022 mg kg and As concentrations of <20 mg kg. The efficacy of biosolids mix and compost amendment in reducing Pb and As concentrations in three vegetables (carrots, lettuce, and tomatoes) and the bioaccessibility of soil Pb and As were evaluated. Food-chain transfer of Pb and As were evaluated by measuring plant Pb and As concentrations after kitchen-style washing, a laboratory cleaning procedure, or peeling. The experimental design was a randomized complete block with a split-plot arrangement. Tacoma site treatments included a Class A biosolids mix (TAGRO) with dolomite, and soil at the Seattle site was amended with Cedar-Grove compost (CGC) plus dolomite. TAGRO amendment diluted soil Pb by 10 to 23% and As by 12 to 25% at the Tacoma site, and CGC + dolomite resulted in 20 to 50% dilution in soil Pb at the Seattle site. Both amendments reduced Pb concentrations in vegetables by 50 to 71%, and As reductions ranged from 46 to 80%. At the Tacoma site, Pb concentrations (dry weight basis) in carrots, lettuce, and tomatoes ranged from 8.89 to 25.0, from 0.37 to 3.83, and from 0.54 to 1.24 mg kg, respectively. Plant As concentrations were below 703 µg kg (dry weight) for the vegetables and followed the order lettuce > carrot > tomato. Food-chain transfer of Pb and As in vegetables grown in contaminated urban soils were reduced by laboratory cleaning.

Field evaluations on soil plant transfer of lead from an urban garden soil.

Lead (Pb) is one of the most common contaminants in urban soils. Gardening in contaminated soils can result in Pb transfer from soil to humans through vegetable consumption and unintentional direct soil ingestion. A field experiment was conducted in 2009 and 2010 in a community urban garden with a soil total Pb concentration of 60 to 300 mg kg. The objectives of this study were to evaluate soil-plant transfer of Pb, the effects of incorporation of a leaf compost as a means of reducing Pb concentrations in vegetables and the bioaccessibility of soil Pb, and the effects of vegetable cleaning techniques on the Pb concentrations in the edible portions of vegetables. The amount of compost added was 28 kg m. The tested plants were Swiss chard, tomato, sweet potato, and carrots. The vegetable cleaning techniques were kitchen cleaning, laboratory cleaning, and peeling. Compost addition diluted soil total Pb concentration by 29 to 52%. Lead concentrations of the edible portions of vegetables, except carrot, were below the maximum allowable limits of Pb established by the Food and Agriculture Organization and the World Health Organization. Swiss chard and tomatoes subjected to kitchen cleaning had higher Pb concentrations than laboratory-cleaned plants. Cleaning methods did not affect Pb concentrations in carrots. Bioaccessible Pb in the compost-added soils was 20 to 30% less than that of the no-compost soils; compost addition reduced the potential of transferring soil Pb to humans via vegetable consumption and direct soil ingestion. Thorough cleaning of vegetables further reduced the potential of transferring soil Pb to humans.

Doxycycline restrains glia and confers neuroprotection in a 6-OHDA Parkinson model.

Neuron-glia interactions play a key role in maintaining and regulating the central nervous system. Glial cells are implicated in the function of dopamine neurons and regulate their survival and resistance to injury. Parkinson's disease is characterized by the loss of dopamine neurons in the substantia nigra pars compacta, decreased striatal dopamine levels and consequent onset of extrapyramidal motor dysfunction. Parkinson's disease is a common chronic, neurodegenerative disorder with no effective protective treatment. In the 6-OHDA mouse model of Parkinson's disease, doxycycline administered at a dose that both induces/represses conditional transgene expression in the tetracycline system, mitigates the loss of dopaminergic neurons in the substantia nigra compacta and nerve terminals in the striatum. This protective effect was associated with: (1) a reduction of microglia in normal mice as a result of doxycycline administration per se; (2) a decrease in the astrocyte and microglia response to the neurotoxin 6-OHDA in the globus pallidus and substantia nigra compacta, and (3) the astrocyte reaction in the striatum. Our results suggest that doxycycline blocks 6-OHDA neurotoxicity in vivo by inhibiting microglial and astrocyte expression. This action of doxycycline in nigrostriatal dopaminergic neuron protection is consistent with a role of glial cells in Parkinson's disease neurodegeneration. The neuroprotective effect of doxycycline may be useful in preventing or slowing the progression of Parkinson's disease and other neurodegenerative diseases linked to glia function.

A CAG repeat polymorphism of KCNN3 predicts SK3 channel function and cognitive performance in schizophrenia.

KCNN3, encoding the small conductance calcium-activated potassium channel SK3, harbours a polymorphic CAG repeat in the amino-terminal coding region with yet unproven function. Hypothesizing that KCNN3 genotypes do not influence susceptibility to schizophrenia but modify its phenotype, we explored their contribution to specific schizophrenic symptoms. Using the Göttingen Research Association for Schizophrenia (GRAS) data collection of schizophrenic patients (n = 1074), we performed a phenotype-based genetic association study (PGAS) of KCNN3. We show that long CAG repeats in the schizophrenic sample are specifically associated with better performance in higher cognitive tasks, comprising the capacity to discriminate, select and execute (p < 0.0001). Long repeats reduce SK3 channel function, as we demonstrate by patch-clamping of transfected HEK293 cells. In contrast, modelling the opposite in mice, i.e. KCNN3 overexpression/channel hyperfunction, leads to selective deficits in higher brain functions comparable to those influenced by SK3 conductance in humans. To conclude, KCNN3 genotypes modify cognitive performance, shown here in a large sample of schizophrenic patients. Reduction of SK3 function may constitute a pharmacological target to improve cognition in schizophrenia and other conditions with cognitive impairment.

Host-guest inclusion compound from nitramine crystals exposed to condensed carbon dioxide.

HNIW or CL20 (2,4,6,8,10,12-hexanitro-2,4,6,8,10,12-hexaazaisowurtzitane) is a nitramine, which is considered as the highest energetic molecular compound known to date, therefore, attracting increasing interest in propulsion applications. Additionally, CL20 is an interesting system for fundamental studies, exhibiting several polymorphs, which can behave as host lattices for trapping guest molecules. Herein, a new CL20 structure that contains inserted CO(2) molecules is reported. A combination of Fourier transform infra red (FTIR) spectroscopy, scanning electron microscopy (SEM), single-crystal X-ray diffraction, and thermal analyses (thermogravimetric analysis coupled with mass spectrometry and differential scanning calorimetry) was used to characterize this new material.

Overexpression of Eag1 potassium channels in clinical tumours.

BACKGROUND: Certain types of potassium channels (known as Eag1, KCNH1, Kv10.1) are associated with the production of tumours in patients and in animals. We have now studied the expression pattern of the Eag1 channel in a large range of normal and tumour tissues from different collections utilising molecular biological and immunohistochemical techniques. RESULTS: The use of reverse transcription real-time PCR and specifically generated monoclonal anti-Eag1 antibodies showed that expression of the channel is normally limited to specific areas of the brain and to restricted cell populations throughout the body. Tumour samples, however, showed a significant overexpression of the channel with high frequency (up to 80% depending on the tissue source) regardless of the detection method (staining with either one of the antibodies, or detection of Eag1 RNA). CONCLUSION: Inhibition of Eag1 expression in tumour cell lines reduced cell proliferation. Eag1 may therefore represent a promising target for the tailored treatment of human tumours. Furthermore, as normal cells expressing Eag1 are either protected by the blood-brain barrier or represent the terminal stage of normal differentiation, Eag1 based therapies could produce only minor side effects.