Rapid switching from levetiracetam to brivaracetam in pharmaco-resistant epilepsy in people with and without intellectual disabilities: a naturalistic case control study.

BACKGROUND: Approximately one quarter of people with an intellectual disability (PwID) have epilepsy of whom nearly three-quarters are pharmaco-resistant. There are higher reported neuropsychiatric side-effects to anti-seizure medication (ASM) in this group. Levetiracetam (LEV) is a first-line ASM with a stronger association with neuropsychiatric symptoms for PwID than other ASMs. Brivaracetam (BRV) is a newer ASM. Recent studies suggest a beneficial effect of swapping people who experience neuropsychiatric events with LEV to BRV. However, there is limited evidence of this for PwID. This evaluation analyses real world outcomes of LEV to BRV swap for PwID compared to those without ID. METHODS: We performed a multicentre, retrospective review of clinical records. Demographic, clinical characteristics and reported adverse events of patients switched from LEV to BRV (2016-2020) were recorded at 3 months pre and 6- and 12-month post-BRV initiation. Outcomes were compared between PwID and those without and summarised using cross-tabulations and logistic regression models. A Bonferroni correction was applied. RESULTS: Of 77 participants, 46 had ID and 52% had a past psychiatric illness. 71% participants switched overnight from LEV to BRV. Seizure reduction of > 50% was seen in 40% patients. Psychiatric illness history was predictive of having neuropsychiatric side-effects with LEV but not BRV (p = 0.001). There was no significant difference for any primary outcomes between PwID versus without ID. CONCLUSIONS: Switching from LEV to BRV appears as well tolerated and efficacious in PwID as those without ID with over 90% still on BRV after 12 months.

Isolation and characterisation of 14 novel microsatellite markers through Next Generation Sequencing for the commercial Atlantic seabob shrimp Xiphopenaeus kroyeri.

Assessing population genetic structure is a crucial step to support fisheries and conservation management. DNA microsatellite molecular markers are a widely used tool in population genotyping. In the present study, we characterised and developed 14 novel polymorphic microsatellite markers for a decapod crustacean, the Atlantic seabob shrimp Xiphopenaeus kroyeri (Heller, 1862), through rapid and cost-effective Illumina shotgun sequencing and a Galaxy-based bioinformatic pipeline. We genotyped 60 individuals from 2 populations with the newly developed microsatellites, resulting in the detection of 3 to 29 alleles per locus. Four loci deviated from Hardy-Weinberg equilibrium. Cross-amplification in a cryptic congeneric species was successful for eight loci (57%). The microsatellite loci developed in this study will be highly relevant for genetic and evolutionary studies of X. kroyeri, and for the stock management of this commercially exploited species.

One ring to bind them - Cohesin's interaction with chromatin fibers.

In the nuclei of eukaryotic cells, the genetic information is organized at several levels. First, the DNA is wound around the histone proteins, to form a structure termed as chromatin fiber. This fiber is then arranged into chromatin loops that can cluster together and form higher order structures. This packaging of chromatin provides on one side compaction but also functional compartmentalization. The cohesin complex is a multifunctional ring-shaped multiprotein complex that organizes the chromatin fiber to establish functional domains important for transcriptional regulation, help with DNA damage repair, and ascertain stable inheritance of the genome during cell division. Our current model for cohesin function suggests that cohesin tethers chromatin strands by topologically entrapping them within its ring. To achieve this, cohesin's association with chromatin needs to be very precisely regulated in timing and position on the chromatin strand. Here we will review the current insight in when and where cohesin associates with chromatin and which factors regulate this. Further, we will discuss the latest insights into where and how the cohesin ring opens to embrace chromatin and also the current knowledge about the 'exit gates' when cohesin is released from chromatin.

Earth observations and integrative models in support of food and water security.

Global food production depends upon many factors that Earth observing satellites routinely measure about water, energy, weather, and ecosystems. Increasingly sophisticated, publicly-available satellite data products can improve efficiencies in resource management and provide earlier indication of environmental disruption. Satellite remote sensing provides a consistent, long-term record that can be used effectively to detect large-scale features over time, such as a developing drought. Accuracy and capabilities have increased along with the range of Earth observations and derived products that can support food security decisions with actionable information. This paper highlights major capabilities facilitated by satellite observations and physical models that have been developed and validated using remotely-sensed observations. Although we primarily focus on variables relevant to agriculture, we also include a brief description of the growing use of Earth observations in support of aquaculture and fisheries.

Advances in the Remote Sensing of Terrestrial Evaporation.

Characterizing the terrestrial carbon, water and energy cycles depends strongly on a capacity to accurately reproduce the spatial and temporal dynamics of land surface evaporation. For this, and many other reasons, monitoring terrestrial evaporation across multiple space and time scales has been an area of focused research for many decades. Much of this activity has been supported by developments in satellite remote sensing, which have been leveraged to deliver new process insights, model development and methodological improvements. In this Special Issue, published contributions explored a range of research topics directed towards the enhanced estimation of terrestrial evaporation. Here we summarize these cutting-edge efforts and provide an overview of some of the state-of-the-art approaches for retrieving this key variable. Some perspectives on outstanding challenges, issues, and opportunities are also presented.

Role of Chemosensory TRP Channels in Lung Cancer.

Transient receptor potential (TRP) channels represent a large family of cation channels and many members of the TRP family have been shown to act as polymodal receptor molecules for irritative or potentially harmful substances. These chemosensory TRP channels have been extensively characterized in primary sensory and neuronal cells. However, in recent years the functional expression of these proteins in non-neuronal cells, e.g., in the epithelial lining of the respiratory tract has been confirmed. Notably, these proteins have also been described in a number of cancer types. As sensor molecules for noxious compounds, chemosensory TRP channels are involved in cell defense mechanisms and influence cell survival following exposure to toxic substances via the modulation of apoptotic signaling. Of note, a number of cytostatic drugs or drug metabolites can activate these TRP channels, which could affect the therapeutic efficacy of these cytostatics. Moreover, toxic inhalational substances with potential involvement in lung carcinogenesis are well established TRP activators. In this review, we present a synopsis of data on the expression of chemosensory TRP channels in lung cancer cells and describe TRP agonists and TRP-dependent signaling pathways with potential relevance to tumor biology. Furthermore, we discuss a possible role of TRP channels in the non-genomic, tumor-promoting effects of inhalational carcinogens such as cigarette smoke.

Global Investigation of Soil Moisture and Latent Heat Flux Coupling Strength.

As a key variable in the climate system, soil moisture (SM) plays a central role in the earth's terrestrial water, energy, and biogeochemical cycles through its coupling with surface latent heat flux (LH). Despite the need to accurately represent SM/LH coupling in earth system models, we currently lack quantitative, observation-based, and unbiased estimates of its strength. Here, we utilize the triple collocation (TC) approach introduced in Crow et al. (2015) to SM and LH products obtained from multiple satellite remote sensing platforms and land surface models (LSMs) to obtain unbiased global maps of SM/LH coupling strength. Results demonstrate that, relative to coupling strength estimates acquired directly from remote sensing-based datasets, the application of TC generally enhances estimates of warm-season SM/LH coupling, especially in the western United States, the Sahel, Central Asia, and Australia. However, relative to triple collocation estimates, LSMs (still) over-predict SM/LH coupling strength along transitional climate regimes between wet and dry climates, such as the central Great Plains of North America, India, and coastal Australia. Specific climate zones with biased relations in LSMs are identified to geographically focus the re-examination of LSM parameterizations. TC-based coupling strength estimates are robust to our choice of LSM contributing SM and LH products to the TC analysis. Given their robustness, TC-based coupling strength estimates can serve as an objective benchmark for investigating model predicted SM/LH coupling.

Assessment of the impact of spatial heterogeneity on microwave satellite soil moisture periodic error.

An accurate temporal and spatial characterization of errors is required for the efficient processing, evaluation, and assimilation of remotely-sensed surface soil moisture retrievals. However, empirical evidence exists that passive microwave soil moisture retrievals are prone to periodic artifacts which may complicate their application in data assimilation systems (which commonly treat observational errors as being temporally white). In this paper, the link between such temporally-periodic errors and spatial land surface heterogeneity is examined. Both the synthetic experiment and site-specified cases reveal that, when combined with strong spatial heterogeneity, temporal periodicity in satellite sampling patterns (associated with exact repeat intervals of the polar-orbiting satellites) can lead to spurious high frequency spectral peaks in soil moisture retrievals. In addition, the global distribution of the most prominent and consistent 8-day spectral peak in the Advanced Microwave Scanning Radiometer - Earth Observing System soil moisture retrievals is revealed via a peak detection method. Three spatial heterogeneity indicators - based on microwave brightness temperature, land cover types, and long-term averaged vegetation index - are proposed to characterize the degree to which the variability of land surface is capable of inducing periodic error into satellite-based soil moisture retrievals. Regions demonstrating 8-day periodic errors are generally consistent with those exhibiting relatively higher heterogeneity indicators. This implies a causal relationship between spatial land surface heterogeneity and temporal periodic error in remotely-sensed surface soil moisture retrievals.

Hyperconnectivity in juvenile myoclonic epilepsy: a network analysis.

OBJECTIVE: Juvenile myoclonic epilepsy (JME) is a common idiopathic (genetic) generalized epilepsy (IGE) syndrome characterized by impairments in executive and cognitive control, affecting independent living and psychosocial functioning. There is a growing consensus that JME is associated with abnormal function of diffuse brain networks, typically affecting frontal and fronto-thalamic areas. METHODS: Using diffusion MRI and a graph theoretical analysis, we examined bivariate (network-based statistic) and multivariate (global and local) properties of structural brain networks in patients with JME (N = 34) and matched controls. Neuropsychological assessment was performed in a subgroup of 14 patients. RESULTS: Neuropsychometry revealed impaired visual memory and naming in JME patients despite a normal full scale IQ (mean = 98.6). Both JME patients and controls exhibited a small world topology in their white matter networks, with no significant differences in the global multivariate network properties between the groups. The network-based statistic approach identified one subnetwork of hyperconnectivity in the JME group, involving primary motor, parietal and subcortical regions. Finally, there was a significant positive correlation in structural connectivity with cognitive task performance. CONCLUSIONS: Our findings suggest that structural changes in JME patients are distributed at a network level, beyond the frontal lobes. The identified subnetwork includes key structures in spike wave generation, along with primary motor areas, which may contribute to myoclonic jerks. We conclude that analyzing the affected subnetworks may provide new insights into understanding seizure generation, as well as the cognitive deficits observed in JME patients.

Ethnicity can predict GLRA1 genotypes in hyperekplexia.

OBJECTIVES: Hyperekplexia is predominantly caused by mutations in the α-1 subunit of the inhibitory glycine receptor (GLRA1). Three quarters of cases show autosomal-recessive inheritance. METHODS: We carefully ascertained reports of ethnicity from our hyperekplexia research cohort. These were compared with all published cases of hyperekplexia with an identified genetic cause. Ethnicities were subgrouped as Caucasian, Asian, Arabic, Turkish, Jewish or Afro-American. RESULTS: We report the ethnicity of 90 cases: 56 cases from our service augmented by 34 cases from the literature. Homozygous deletions of exons 1 to 7 are predominantly seen in people with Turkish backgrounds (n=16/17, p<0.001). In contrast, the dominant point mutation R271 is seen in people of Asian, Caucasian and African-American heritage (n=19) but not in people with Arab or Turkish ethnicities (p<0.001). CONCLUSIONS: Self-declared ethnicity can predict gene-screening outcomes. Cultural practices influence the inheritance patterns and a Caucasian founder is postulated for R271 mutations.

TSH induces metallothionein 1 in thyrocytes via Gq/11- and PKC-dependent signaling.

Metallothioneins (MTs) are cytoprotective proteins acting as scavengers of toxic metal ions or reactive oxygen species. MTs are upregulated in follicular thyroid carcinoma and are regarded as a marker of thyroid stress in Graves' disease. However, the mechanism of MT regulation in thyrocytes is still elusive. In other cellular systems, cAMP-, calcium-, or protein kinase C (PKC)-dependent signaling cascades have been shown to induce MT expression. Of note, all of these three pathways are activated following the stimulation of the TSH receptor (TSHR). Thus, we hypothesized that TSH represents a key regulator of MT expression in thyrocytes. In fact, TSHR stimulation induced expression of MT isoform 1X (MT1X) in human follicular carcinoma cells. In these cells, Induction of MT1X expression critically relied on intact Gq/11 signaling of the TSHR and was blocked by chelation of intracellular calcium and inhibition of PKC. TSHR-independent stimulation of cAMP formation by treating cells with forskolin also led to an upregulation of MT1X, which was completely dependent on PKA. However, inhibition of PKA did not affect the regulation of MT1X by TSH. As in follicular thyroid carcinoma cells, TSH also induced MT1 protein in primary human thyrocytes, which was PKC dependent as well. In summary, these findings indicate that TSH stimulation induces MT1X expression via Gq/11 and PKC, whereas cAMP-PKA signaling does not play a predominant role. To date, little has been known regarding cAMP-independent effects of TSHR signaling. Our findings extend the knowledge about the PKC-mediated functions of the TSHR.

Clostridial abdominal gas gangrene masquerading as a bowel perforation in an advanced-stage ovarian cancer patient.

The coexistence of clostridial gas gangrene and a gynecologic malignancy is extremely rare, with very few cases involving ovarian cancer. A patient originally presented to our gynecologic oncology service with stage IV ovarian cancer; she underwent a diagnostic laparoscopy and neoadjuvant chemotherapy. On postoperative day 6, the patient developed severe abdominal pain, nausea, and emesis, suggestive of a bowel perforation. Further evaluation confirmed that her symptoms were attributed to Clostridium perfringens-related gas gangrene. Despite immediate surgical intervention, the patient succumbed to her disease. Clostridial gas gangrene is associated with an extremely high mortality rate. Therefore, accurate detection and prompt management are indispensable to ensuring a favorable patient outcome.

Stimulation of the chemosensory TRPA1 cation channel by volatile toxic substances promotes cell survival of small cell lung cancer cells.

TRPA1, a member of the transient receptor potential (TRP) family of cation channels, has mainly been characterized as a chemosensory protein in neuronal cells. TRPA1 is activated by toxic or irritating volatile agents like allyl isothiocyanate (AITC), tear gas, formalin, or cigarette smoke. To date, little is known about a function of TRPA1 in non-neuronal cells in the respiratory system and even less regarding a possible role in cancer biology. Here, we show that TRPA1 is expressed in a panel of human small cell lung cancer (SCLC) cell lines. Of note, TRPA1 mRNA was also significantly higher expressed in tumor samples of SCLC patients as compared to non-SCLC tumor samples or non-malignant lung tissue. Stimulation of SCLC cells with AITC led to a rise of the intracellular calcium concentration. This calcium response was inhibited by TRPA1 antagonists. Furthermore, AITC or formalin stimulated ERK1/2 in TRPA1-expressing HEK293 cells and in SCLC cells via a Src- and calcium-dependent mechanism. More importantly, TRPA1 activation in SCLC cells prevented apoptosis induced by serum starvation and thus promoted cell survival, an effect which could be blocked by inhibition of TRPA1 or ERK1/2. Vice versa, down-regulation of TRPA1 severely impaired anchorage-independent growth of SCLC cells. Since TRPA1 appears to play a pivotal role for cell survival in SCLC cells we propose that this channel could represent a promising target for therapeutic interventions. Furthermore, our data suggest that exogenous, inhalable activators of TRPA1 could be able to exert tumor promoting effects in SCLC cells.

Melanocortin-induced PKA activation inhibits AMPK activity via ERK-1/2 and LKB-1 in hypothalamic GT1-7 cells.

α-Melanocyte-stimulating hormone (α-MSH)-induced activation of the melanocortin-4 receptor in hypothalamic neurons increases energy expenditure and inhibits food intake. Active hypothalamic AMP-activated protein kinase (AMPK) has recently been reported to enhance food intake, and in vivo experiments suggested that intrahypothalamic injection of melanocortins decreased food intake due to the inhibition of AMPK activity. However, it is not clear whether α-MSH affects AMPK via direct intracellular signaling cascades or if the release of paracrine factors is involved. Here, we used a murine, hypothalamic cell line (GT1-7 cells) and monitored AMPK phosphorylation at Thr(172), which has been suggested to increase AMPK activity. We found that α-MSH dephosphorylated AMPK at Thr(172) and consequently decreased phosphorylation of the established AMPK substrate acetyl-coenzyme A-carboxylase at Ser(79). Inhibitory effects of α-MSH on AMPK were blocked by specific inhibitors of protein kinase A (PKA) or ERK-1/2, pointing to an important role of both kinases in this process. Because α-MSH-induced activation of ERK-1/2 was blunted by PKA inhibitors, we propose that ERK-1/2 serves as a link between PKA and AMPK in GT1-7 cells. Furthermore, down-regulation of liver kinase B-1, but not inhibition of calcium-calmodulin-dependent kinase kinase-ß or TGFß-activated kinase-1 decreased basal phosphorylation of AMPK and its dephosphorylation induced by α-MSH. Thus, we propose that α-MSH inhibits AMPK activity via a linear pathway, including PKA, ERK-1/2, and liver kinase B-1 in GT1-7 cells. Given the importance of the melanocortin system in the formation of adipositas, detailed knowledge about this pathway might help to develop drugs targeting obesity.

'Reverse' scarf osteotomy for bunionette correction: Initial results of a new surgical technique.

BACKGROUND: The bunionette or tailor's bunion is a lateral prominence of the fifth metatarsal head. It is usually characterised by a wide intermetatarsal angle (IMA) between the 4th and 5th metatarsals, varus of the metatarsophalangeal (MTP) joint, pain and callus formation. Various distal, shaft and basal osteotomies have been described in the literature. We have described a reverse scarf osteotomy for bunionette correction. PATIENTS AND METHODS: We have used a 'reverse' scarf osteotomy in 12 cases (10F: 2M) with a mean follow-up of 12 months (range 5-22 months) with radiographs and clinical scoring. RESULTS: Post operatively, mean IMA improved from 13.1° to 7.27° (range 2.0-11.5°); mean 5th MTP angle improved from 19.9° to 6.36° (range 2.8-9.0°) and postoperative mean AOFAS improved from 54.25 to 89.58 (range 70-100). CONCLUSION: 'Reverse' scarf osteotomy in the correction of bunionette deformity offers promising results in the short term.

Genetic epilepsy with febrile seizures plus: definite and borderline phenotypes.

Generalised epilepsy with febrile seizures plus (GEFS+) is the most studied familial epilepsy syndrome. However, characteristics of UK families have not previously been reported. Among the first 80 families recruited to our families study, four broad subphenotypes were identified: families with classical GEFS+; families with borderline GEFS+; families with unclassified epilepsy; and families with an alternative syndromal diagnosis. Borderline GEFS+ families shared many characteristics of classical GEFS+ families-such as prominent febrile seizures plus and early onset febrile seizures-but included more adults with focal epilepsies (rather than the idiopathic generalised epilepsies predominating in GEFS+) and double the prevalence of migraine. Thus the authors believe that a novel and robust familial epilepsy phenotype has been identified. Subcategorising families with epilepsy is helpful in targeting both clinical and research resources. Most families with GEFS+ have no identified causal mutation, and so predicting genetic homogeneity by identifying endophenotypes becomes more important.