Subunit-Specific Developmental Roles of PI3K in SF1-Expressing Cells.

Backgruound: Phosphatidylinositol 3-kinase (PI3K) regulates cellular development and energy homeostasis. However, the roles of its subunits in organ development remain largely unknown.

Methods: We explored the roles of PI3K catalytic subunits in steroidogenic factor 1 (SF1)-expressing cells through knockout (KO) of the p110α and p110β subunits.

A clinically compatible in vitro drug-screening platform identifies therapeutic vulnerabilities in primary cultures of brain metastases.

Purpose: Brain metastases represent the most common intracranial tumors in adults and are associated with a poor prognosis. We used a personalized in vitro drug screening approach to characterize individual therapeutic vulnerabilities in brain metastases.

Methods: Short-term cultures of cancer cells isolated from brain metastasis patients were molecularly characterized using next-generation sequencing and functionally evaluated using high-throughput in vitro drug screening to characterize pharmacological treatment sensitivities.

A multiscale computational model of angiogenesis after traumatic brain injury, investigating the role location plays in volumetric recovery.

Vascular endothelial growth factor (VEGF) is a key protein involved in the process of angiogenesis. VEGF is of particular interest after a traumatic brain injury (TBI), as it re-establishes the cerebral vascular network in effort to allow for proper cerebral blood flow and thereby oxygenation of damaged brain tissue. For this reason, angiogenesis is critical in the progression and recovery of TBI patients in the days and weeks post injury.

Vietnamese version of the coronary artery disease education questionnaire-Short version: Translation, adaptation and validation.

What Is Known And Objective: Coronary artery disease (CAD) is the leading cause of mortality worldwide. Patient education is an essential part of cardiac patients' care targeting self-management behaviour to reduce risk factors and subsequent events. There has been no Vietnamese questionnaire to assess patient's knowledge about CAD; therefore, the purpose of this study was to translate, cross-culturally adapt and validate the Coronary Artery Disease Education Questionnaire-Short Version (CADE-Q SV) for use in Vietnam.

Testosterone replacement therapy reduces biochemical recurrence after radical prostatectomy.

Objective: To evaluate risk of prostate cancer biochemical recurrence (BCR) after radical prostatectomy (RP) in men receiving vs not receiving testosterone replacement therapy (TRT).

Patients And Methods: A total of 850 patients underwent RP by a single surgeon. All patients had preoperative testosterone and sex hormone-binding globulin levels determined; free testosterone was calculated prospectively.

Insulin Regulates Adrenal Steroidogenesis by Stabilizing SF-1 Activity.

Development of metabolic syndrome is associated with hyperactivity of the HPA axis characterized by elevated levels of circulating adrenal hormones including cortisol and aldosterone. However, the molecular mechanism leading to the dysregulation of the HPA axis is not well elucidated. In this study, we found that insulin regulates adrenal steroidogenesis by increasing the expression and activity of steroidogenic factor 1 (SF-1) both in vitro and in vivo and this insulin effect was partly through inhibition of FoxO1.

4-hydroxy-3-methoxycinnamic acid regulates orexigenic peptides and hepatic glucose homeostasis through phosphorylation of FoxO1.

4-hydroxy-3-methoxycinnamic acid (ferulic acid, FA) is known to have numerous beneficial health effects, including anti-obesity and anti-hyperglycemic properties. However, the molecular networks that modulate the beneficial FA-induced metabolic effects have not been well elucidated. In this study, we explored the molecular mechanisms mediating the beneficial metabolic effects of FA.

Hypothalamic AMPK as a Regulator of Energy Homeostasis.

Activated in energy depletion conditions, AMP-activated protein kinase (AMPK) acts as a cellular energy sensor and regulator in both central nervous system and peripheral organs. Hypothalamic AMPK restores energy balance by promoting feeding behavior to increase energy intake, increasing glucose production, and reducing thermogenesis to decrease energy output. Besides energy state, many hormones have been shown to act in concert with AMPK to mediate their anorexigenic and orexigenic central effects as well as thermogenic influences.

Evidence for Resident Memory T Cells in Rasmussen Encephalitis.

Rasmussen encephalitis (RE) is a rare pediatric neuroinflammatory disease of unknown etiology characterized by intractable seizures, and progressive atrophy usually confined to one cerebral hemisphere. Surgical removal or disconnection of the affected cerebral hemisphere is currently the only intervention that effectively stops the seizures. Histopathological evaluation of resected brain tissue has shown that activated brain resident macrophages (microglia) and infiltrating T cells are involved in the inflammatory reaction.

Enhanced GABAergic Inputs Contribute to Functional Alterations of Cholinergic Interneurons in the R6/2 Mouse Model of Huntington's Disease.

In Huntington's disease (HD), a hereditary neurodegenerative disorder, striatal medium-sized spiny neurons undergo degenerative changes. In contrast, large cholinergic interneurons (LCIs) are relatively spared. However, their ability to release acetylcholine (ACh) is impaired.

Evidence for the involvement of gamma delta T cells in the immune response in Rasmussen encephalitis.

Background: Rasmussen encephalitis (RE) is a rare neuroinflammatory disease characterized by intractable seizures and progressive atrophy on one side of the cerebrum. Perivascular cuffing and clusters of T cells in the affected cortical hemisphere are indicative of an active cellular immune response.

Methods: Peripheral blood mononuclear cells (PBMCs) and brain-infiltrating lymphocytes (BILs) were isolated from 20 RE surgery specimens by standard methods, and CD3(+) T cell populations were analyzed by flow cytometry.

In Rasmussen encephalitis, hemichannels associated with microglial activation are linked to cortical pyramidal neuron coupling: a possible mechanism for cellular hyperexcitability.

Aims: Rasmussen encephalitis (RE) is a rare but devastating condition, mainly in children, characterized by sustained brain inflammation, atrophy of one cerebral hemisphere, epilepsy, and progressive cognitive deterioration. The etiology of RE-induced seizures associated with the inflammatory process remains unknown.

Methods: Cortical tissue samples from children undergoing surgical resections for the treatment of RE (n = 16) and non-RE (n = 12) were compared using electrophysiological, morphological, and immunohistochemical techniques to examine neuronal properties and the relationship with microglial activation using the specific microglia/macrophage calcium-binding protein, IBA1 in conjunction with connexins and pannexin expression.

Comparison of Glucose Measures in Patients Receiving Concomitant Paroxetine and Pravastatin to Other SSRI/Statin Combinations.

Background: An analysis of the US Food and Drug Administration's Adverse Event Reporting System database found evidence suggesting that the combination of the cholesterol-lowering drug pravastatin and the antidepressant paroxetine, produced a significant increase in average blood glucose measures.

Objective: Our intent was to investigate the reproducibility of these findings by conducting a similar analysis of administrative and prescription claims data from patients receiving primary care at the Palo Alto Medical Foundation.

Method: We conducted an observational, retrospective review of 2149 adult patient records to compare mean measures of blood glucose between groups receiving concomitant paroxetine and pravastatin with the pooled means of those receiving 19 different combinations of a statin and a selective serotonin reuptake inhibitor (SSRI) antidepressant.

Differential expression of interferon-γ and chemokine genes distinguishes Rasmussen encephalitis from cortical dysplasia and provides evidence for an early Th1 immune response.

Background: Rasmussen encephalitis (RE) is a rare complex inflammatory disease, primarily seen in young children, that is characterized by severe partial seizures and brain atrophy. Surgery is currently the only effective treatment option. To identify genes specifically associated with the immunopathology in RE, RNA transcripts of genes involved in inflammation and autoimmunity were measured in brain tissue from RE surgeries and compared with those in surgical specimens of cortical dysplasia (CD), a major cause of intractable pediatric epilepsy.

Effects of the Pimelic Diphenylamide Histone Deacetylase Inhibitor HDACi 4b on the R6/2 and N171-82Q Mouse Models of Huntington's Disease.

This report represents a detailed description of experiments designed to replicate and extend the findings of a published study on the effects of treating the R6/2 Huntington's disease (HD) mouse model with ~300 CAG repeats using the pimelic diphenylamide histone deacetylase (HDAC) inhibitor, HDACi 4b (Thomas et al., 2008). In addition to testing the R6/2 mice, similar experiments examined the effects of the drug on a second transgenic HD mouse model, the N171-82Q mice.

Synaptoneurosome micromethod for fractionation of mouse and human brain, and primary neuronal cultures.

Brain and primary neuron fractions enriched in synaptic terminals are important tools for neuroscientists in biochemical, neuroanatomical and physiological studies. We describe an annotated updated micro-method for preparing synaptoneurosomes (SNs) enriched in presynaptic and postsynaptic elements. An easy to follow, step-by-step, protocol is provided for making SNs from small amounts of mammalian brain tissue.

De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway cause hemimegalencephaly.

De novo somatic mutations in focal areas are well documented in diseases such as neoplasia but are rarely reported in malformation of the developing brain. Hemimegalencephaly (HME) is characterized by overgrowth of either one of the two cerebral hemispheres. The molecular etiology of HME remains a mystery.

Enhanced GABAergic network and receptor function in pediatric cortical dysplasia Type IIB compared with Tuberous Sclerosis Complex.

Tuberous Sclerosis Complex (TSC) and cortical dysplasia Type IIB (CDIIB) share histopathologic features that suggest similar epileptogenic mechanisms. This study compared the morphological and electrophysiological properties of cortical cells in tissue from pediatric TSC (n=20) and CDIIB (n=20) patients using whole-cell patch clamp recordings and biocytin staining. Cell types were normal-appearing and dysmorphic-cytomegalic pyramidal neurons, interneurons, and giant/balloon cells, including intermediate neuronal-glial cells.

Differential electrophysiological changes in striatal output neurons in Huntington's disease.

There is considerable evidence that alterations in striatal medium-sized spiny neurons (MSSNs) giving rise to the direct (D1 receptor-expressing) and indirect (D2 receptor-expressing) pathways differentially contribute to the phenotype of Huntington's disease (HD). To determine how each subpopulation of MSSN is functionally affected, we examined spontaneous excitatory postsynaptic currents (sEPSCs) and dopamine (DA) modulation in two HD mouse models, the YAC128 and the BACHD (a bacterial-artificial chromosome). These mice also expressed enhanced green fluorescent protein (EGFP) under the control of the promoter for either DA D1 or D2 receptors to identify neurons.

Interneurons, GABAA currents, and subunit composition of the GABAA receptor in type I and type II cortical dysplasia.

Interneurons, gamma-aminobutyric acid (GABA)(A) receptor density, and subunit composition determine inhibitory function in pyramidal neurons and control excitability in cortex. Abnormalities in GABAergic cells or GABA(A) receptors could contribute to seizures in malformations of cortical development. Herein we review data obtained in resected cortex from pediatric epilepsy surgery patients with type I and type II cortical dysplasia (CD) and non-CD pathologies.

Pyramidal cell responses to gamma-aminobutyric acid differ in type I and type II cortical dysplasia.

Abnormalities in the gamma-aminobutyric acid (GABA)-ergic system could be responsible for seizures in cortical dysplasia (CD). We examined responses of pyramidal neurons to exogenous application of GABA, as well as alterations of GABAergic interneuron number and size in pediatric epilepsy surgery patients with non-CD, type I CD, and type II CD pathologies. We used the dissociated cell preparation for electrophysiology along with immunohistochemistry to identify number and size of GABAergic cells.

The possible role of proton-coupled electron transfer (PCET) in water oxidation by photosystem II.

All higher life forms use oxygen and respiration as their primary energy source. The oxygen comes from water by solar-energy conversion in photosynthetic membranes. In green plants, light absorption in photosystem II (PSII) drives electron-transfer activation of the oxygen-evolving complex (OEC).

Cervical cancer prevention for all the world's women: genuine promise resides in skilled quality management rather than novel screening approaches.

The debate over the best route for cervical cancer prevention in developing countries may be considered part of a larger debate over whether the global health community has become enamored with the promise of new approaches at the expense of delivering available preventives today. Pap screening, which is feasible anywhere cervical screening is appropriate, is the only intervention currently available for the prevention of cervical cancer in developing countries, and the Pap test will be an essential component of future novel preventive approaches. Cervical cancer vaccination, the long-term effectiveness of which is uncertain, will not eliminate screening requirements and is currently not affordable in developing countries.