Pharmacotherapy in patients with epilepsy and psychosis.

The recognition and treatment of psychosis in persons with epilepsy (PWE) is recommended with the apparent dilemma between treating psychosis and opening the possibility of exacerbating seizures. The pooled prevalence estimate of psychosis in PWE is 5.6%. It has been proposed that a 'two hit' model, requiring both aberrant limbic activity and impaired frontal control, may account for the wide range of clinical phenotypes. The role of antiepileptic drugs in psychosis in PWE remains unclear. Alternating psychosis, the clinical phenomenon of a reciprocal relationship between psychosis and seizures, is unlikely to be an exclusively antiepileptic drug-specific phenomenon but rather, linked to the neurobiological mechanisms underlying seizure control. Reevaluation of antiepileptic treatment, including the agent/s being used and degree of epileptic seizure control is recommended. The authors found very few controlled studies to inform evidence-based treatment of psychosis in PWE. However, antipsychotics and benzodiazepines are recommended as the symptomatic clinical treatments of choice for postictal and brief interictal psychoses. The general principle of early symptomatic treatment of psychotic symptoms applies in epilepsy-related psychoses, as for primary psychotic disorders. In the authors' experience, low doses of antipsychotic medications do not significantly increase clinical risk of seizures in PWE being concurrently treated with an efficacious antiepileptic regimen

Predominant sarcomatoid carcinoma of the lung concurrent with jejunal metastasis and leukocytosis

Sarcomatoid carcinoma is an extremely rare biphasic tumor characterized by a combination of malignant epithelial and mesenchymal cells. Limited data on sarcomatoid carcinoma showed that most cases occurred with advanced local disease and metastasis, and paraneoplastic syndromes were rare. We present the case of a 63-year-old man with lung sarcomatoid carcinoma associated with jejunum metastasis and leukocytosis, and its clinical, macroscopic, and histopathological features. This case emphasizes the importance of recognizing paraneoplastic syndromes and metastasis of sarcomatoid carcinoma at diagnosis

Identification of the Transgenic Integration Site in Immunodeficient tgε26 Human CD3ε Transgenic Mice

A strain of human CD3ε transgenic mice, tgε26, exhibits severe immunodeficiency associated with early arrest of T cell development. Complete loss of T cells is observed in homozygous tgε26 mice, but not in heterozygotes, suggesting that genomic disruption due to transgenic integration may contribute to the arrest of T cell development. Here we report the identification of the transgenic integration site in tgε26 mice. We found that multiple copies of the human CD3ε transgene are inserted between the Sstr5 and Metrn loci on chromosome 17, and that this is accompanied by duplication of the neighboring genomic region spanning 323 kb. However, none of the genes in this region were abrogated. These results suggest that the severe immunodeficiency seen in tgε26 mice is not due to gene disruption resulting from transgenic integration

Uncovering Blind Spots in Urban Carbon Management: The Role of Consumption-Based Carbon Accounting in Bristol, UK

The rapid urbanisation of the twentieth century, along with the spread of high-consumption urban lifestyles, has led to cities becoming the dominant drivers of global anthropogenic greenhouse gas emissions. Reducing these impacts is crucial, but production-based frameworks of carbon measurement and mitigation—which encompass only a limited part of cities’ carbon footprints—are much more developed and widely applied than consumption-based approaches that consider the embedded carbon effectively imported into a city. Frequently, therefore, cities are left blind to the importance of their wider consumption-related climate impacts, while at the same time left lacking effective tools to reduce them. To explore the relevance of these issues, we implement methodologies for assessing production- and consumption-based emissions at the city-level and estimate the associated emissions trajectories for Bristol, a major UK city, from 2000 to 2035. We develop mitigation scenarios targeted at reducing the former, considering potential energy, carbon and financial savings in each case. We then compare these mitigation potentials with local government ambitions and Bristol’s consumption-based emissions trajectory. Our results suggest that the city’s consumption-based emissions are three times the production-based emissions, largely due to the impacts of imported food and drink. We find that low-carbon investments of circa £3 billion could reduce production-based emissions by 25% in 2035. However, we also find that this represents <10% of Bristol’s forecast consumption-based emissions for 2035 and is approximately equal to the mitigation achievable by eliminating the city’s current levels of food waste. Such observations suggest that incorporating consumption-based emission statistics into cities’ accounting and decision-making processes could uncover largely unrecognised opportunities for mitigation that are likely to be essential for achieving deep decarbonisation

Novel computed tomographic chest metrics to detect pulmonary hypertension

<p>Abstract</p> <p>Background</p> <p>Early diagnosis of pulmonary hypertension (PH) can potentially improve survival and quality of life. Detecting PH using echocardiography is often insensitive in subjects with lung fibrosis or hyperinflation. Right heart catheterization (RHC) for the diagnosis of PH adds risk and expense due to its invasive nature. Pre-defined measurements utilizing computed tomography (CT) of the chest may be an alternative non-invasive method of detecting PH.</p> <p>Methods</p> <p>This study retrospectively reviewed 101 acutely hospitalized inpatients with heterogeneous diagnoses, who consecutively underwent CT chest and RHC during the same admission. Two separate teams, each consisting of a radiologist and pulmonologist, blinded to clinical and RHC data, individually reviewed the chest CT's.</p> <p>Results</p> <p>Multiple regression analyses controlling for age, sex, ascending aortic diameter, body surface area, thoracic diameter and pulmonary wedge pressure showed that a main pulmonary artery (PA) diameter ≥29 mm (odds ratio (OR) = 4.8), right descending PA diameter ≥19 mm (OR = 7.0), true right descending PA diameter ≥ 16 mm (OR = 4.1), true left descending PA diameter ≥ 21 mm (OR = 15.5), right ventricular (RV) free wall ≥ 6 mm (OR = 30.5), RV wall/left ventricular (LV) wall ratio ≥0.32 (OR = 8.8), RV/LV lumen ratio ≥1.28 (OR = 28.8), main PA/ascending aorta ratio ≥0.84 (OR = 6.0) and main PA/descending aorta ratio ≥ 1.29 (OR = 5.7) were significant predictors of PH in this population of hospitalized patients.</p> <p>Conclusion</p> <p>This combination of easily measured CT-based metrics may, upon confirmatory studies, aid in the non-invasive detection of PH and hence in the determination of RHC candidacy in acutely hospitalized patients.</p

Laminin γ1 chain peptide, C-16 (KAFDITYVRLKF), promotes migration, MMP-9 secretion, and pulmonary metastasis of B16–F10 mouse melanoma cells

Laminin-1, a heterotrimer of α1, β1, and γ1 chains specific to basement membrane, promotes cell adhesion and migration, proteinase secretion and metastases of tumour cells. Several active sites on the α1 chain have been found to promote B16–F10 melanoma lung colonisation and here we have determined whether additional tumour promoting sites exist on the β1 and γ1 chains. Recently, we have identified novel cell adhesive peptides derived from laminin β1 and γ1 chains by systematic screening of synthetic peptides. Nine β1 peptides and seven γ1 peptides active for cell adhesion were tested for their effects on experimental pulmonary metastases of B16–F10 mouse melanoma cells in vivo. The most active adhesive peptide derived from the γ1 chain globular domain, C-16 (KAFDITYVRLKF), significantly enhanced pulmonary metastases of B16–F10 cells, whereas no other peptides showed enhancement. C-16 also stimulated migration of B16–F10 cells in the Boyden chamber assay in vitro. Furthermore, C-16 significantly induced the production of MMP-9 from B16–F10 cells. These results suggest that this specific laminin γ1 chain peptide has a metastasis-promoting activity and might be a new molecular target of anti-cancer treatment

Cellular injury and neuroinflammation in children with chronic intractable epilepsy

<p>Abstract</p> <p>Objective</p> <p>To elucidate the presence and potential involvement of brain inflammation and cell death in neurological morbidity and intractable seizures in childhood epilepsy, we quantified cell death, astrocyte proliferation, microglial activation and cytokine release in brain tissue from patients who underwent epilepsy surgery.</p> <p>Methods</p> <p>Cortical tissue was collected from thirteen patients with intractable epilepsy due to focal cortical dysplasia (6), encephalomalacia (5), Rasmussen's encephalitis (1) or mesial temporal lobe epilepsy (1). Sections were processed for immunohistochemistry using markers for neuron, astrocyte, microglia or cellular injury. Cytokine assay was performed on frozen cortices. Controls were autopsy brains from eight patients without history of neurological diseases.</p> <p>Results</p> <p>Marked activation of microglia and astrocytes and diffuse cell death were observed in epileptogenic tissue. Numerous fibrillary astrocytes and their processes covered the entire cortex and converged on to blood vessels, neurons and microglia. An overwhelming number of neurons and astrocytes showed DNA fragmentation and its magnitude significantly correlated with seizure frequency. Majority of our patients with abundant cell death in the cortex have mental retardation. IL-1beta, IL-8, IL-12p70 and MIP-1beta were significantly increased in the epileptogenic cortex; IL-6 and MCP-1 were significantly higher in patients with family history of epilepsy.</p> <p>Conclusions</p> <p>Our results suggest that active neuroinflammation and marked cellular injury occur in pediatric epilepsy and may play a common pathogenic role or consequences in childhood epilepsy of diverse etiologies. Our findings support the concept that immunomodulation targeting activated microglia and astrocytes may be a novel therapeutic strategy to reduce neurological morbidity and prevent intractable epilepsy.</p

Combinatorial Activation and Repression by Seven Transcription Factors Specify Drosophila Odorant Receptor Expression

A systematic analysis reveals a regulatory network controlling selective odorant receptor expression and neuronal diversity in Drosophila

Dysfunctional GABAergic inhibition in the prefrontal cortex leading to "psychotic" hyperactivation

<p>Abstract</p> <p>Background</p> <p>The GABAergic system in the brain seems to be dysfunctional in various psychiatric disorders. Many studies have suggested so far that, in schizophrenia patients, GABAergic inhibition is selectively but consistently reduced in the prefrontal cortex (PFC).</p> <p>Results</p> <p>This study used a computational model of the PFC to investigate the dynamics of the PFC circuit with and without chandelier cells and other GABAergic interneurons. The inhibition by GABAergic interneurons other than chandelier cells effectively regulated the PFC activity with rather low or modest levels of dopaminergic neurotransmission. This activity of the PFC is associated with normal cognitive functions and has an inverted-U shaped profile of dopaminergic modulation. In contrast, the chandelier cell-type inhibition affected only the PFC circuit dynamics in hyperdopaminergic conditions. Reduction of chandelier cell-type inhibition resulted in bistable dynamics of the PFC circuit, in which the upper stable state is associated with a hyperactive mode. When both types of inhibition were reduced, this hyperactive mode and the conventional inverted-U mode merged.</p> <p>Conclusion</p> <p>The results of our simulation suggest that, in schizophrenia, a reduction of GABAergic inhibition increases vulnerability to psychosis by (i) producing the hyperactive mode of the PFC with hyperdopaminergic neurotransmission by dysfunctional chandelier cells and (ii) increasing the probability of the transition to the hyperactive mode from the conventional inverted-U mode by dysfunctional GABAergic interneurons.</p