Decreased cardiac excitability secondary to reduction of sodium current may be a significant contributor to reduced contractility in a rat model of sepsis

Pembelajaran pada hakekatnya adalah proses interaksi antara peserta didik dengan lingkungannya. Pembelajaran merupakan aktualisasi kurikulum yang menuntut keaktifan guru dalam menciptakan dan menumbuhkan kegiatan peserta didik sesuai dengan rencana yang telah diprogramkan. Dalam pembelajaran matematika sering kita temui adanya siswa yang kesulitan dalam menerima materi yang diajarkan, untuk mengantisipasi hal itu pembelajaran matematika hendaknya dimulai dengan pengenalan masalah yang sesuai dengan situasi (contextual problem). Salah satu pendekatan yang sesuai untuk menunjang guru sebagai guru profesional adalah pendekatan PMRI, sehingga siswa bisa mengkonstruksi pengetahuannya sendiri. Rumusan masalah yang diteliti dalam penelitian ini adalah bagaimana mengembangkan bahan ajar yang valid dan praktis yang dikembangkan dengan pendekatan PMRI, dan bagaimana efek potensial bahan ajar yang dikembangkan dengan pendekatan PMRI terhadap hasil belajar siswa. Penelitian ini merupakan penelitian pengembangan (development research) yang bertujuan untuk menghasilkan bahan ajar yang valid, praktis dan efektif untuk pembelajaran matematika di kelas VII SMP Negeri 4 Pangkal Pinang. Subjek penelitian ini adalah siswa kelas VII.D sebanyak 36 siswa. Dengan kesimpulan bahwa bahan ajar yang dikembangkan dalam penelitian ini dikategorikan valid, praktis dan memiliki potential effect terhadap hasil belajar siswa di kelas VII.D SMP Negeri 4 Pangkal Pinang. Kata kunci : himpunan, pendekatan PMRI DOI: http://dx.doi.org/10.22342/jpm.8.1.1859.43-5

Homeostatic Synaptic Plasticity of Miniature Excitatory Postsynaptic Currents in Mouse Cortical Cultures Requires Neuronal Rab3A

Following prolonged activity blockade, amplitudes of miniature excitatory postsynaptic currents (mEPSCs) increase, a form of homeostatic plasticity termed “synaptic scaling.” We previously showed that a presynaptic protein, the small GTPase Rab3A, is required for full expression of the increase in miniature endplate current amplitudes following prolonged blockade of action potential activity at the mouse neuromuscular junction in vivo (Wang et al., 2011), but it is unknown whether this form of Rab3A-dependent homeostatic plasticity shares any characteristics with central synapses. We show here that synaptic scaling of mEPSCs is impaired in mouse cortical neuron cultures prepared from Rab3A-/- and Rab3A Earlybird mutant mice. To determine if Rab3A is involved in the well-established homeostatic increase in postsynaptic AMPA-type receptors (AMPARs), we performed a series of experiments in which electrophysiological recordings of mEPSCs and confocal imaging of synaptic AMPAR immunofluorescence were assessed within the same cultures. We found that Rab3A is required for the increase in synaptic AMPARs following prolonged activity blockade, but the comparison of mEPSC amplitude and synaptic AMPARs in the same cultures revealed that mEPSC amplitude cannot solely be determined by postsynaptic AMPAR levels. Finally, we demonstrate that Rab3A is acting in neurons because selective loss of Rab3A in astrocytes did not disrupt homeostatic plasticity, whereas selective loss in neurons strongly reduced the homeostatic increase in mEPSC amplitudes. Taken together with the results at the neuromuscular junction, we propose that Rab3A is a presynaptic homeostatic regulator that controls quantal size on both sides of the synapse

The Mechanism Underlying Transient Weakness in Myotonia Congenita

In addition to the hallmark muscle stiffness, patients with recessive myotonia congenita (Becker disease) experience debilitating bouts of transient weakness that remain poorly understood despite years of study. We performed intracellular recordings from muscle of both genetic and pharmacologic mouse models of Becker disease to identify the mechanism underlying transient weakness. Our recordings reveal transient depolarizations (plateau potentials) of the membrane potential to -25 to -35 mV in the genetic and pharmacologic models of Becker disease. Both Na + and Ca 2+ currents contribute to plateau potentials. Na + persistent inward current (NaPIC) through Na V 1.4 channels is the key trigger of plateau potentials and current through Ca V 1.1 Ca 2+ channels contributes to the duration of the plateau. Inhibiting NaPIC with ranolazine prevents the development of plateau potentials and eliminates transient weakness in vivo. These data suggest that targeting NaPIC may be an effective treatment to prevent transient weakness in myotonia congenita

Effects of prostratin on Cyclin T1/P-TEFb function and the gene expression profile in primary resting CD4(+ )T cells

BACKGROUND: The latent reservoir of human immunodeficiency virus type 1 (HIV-1) in resting CD4(+ )T cells is a major obstacle to the clearance of infection by highly active antiretroviral therapy (HAART). Recent studies have focused on searches for adjuvant therapies to activate this reservoir under conditions of HAART. Prostratin, a non tumor-promoting phorbol ester, is a candidate for such a strategy. Prostratin has been shown to reactivate latent HIV-1 and Tat-mediated transactivation may play an important role in this process. We examined resting CD4(+ )T cells from healthy donors to determine if prostratin induces Cyclin T1/P-TEFb, a cellular kinase composed of Cyclin T1 and Cyclin-dependent kinase-9 (CDK9) that mediates Tat function. We also examined effects of prostratin on Cyclin T2a, an alternative regulatory subunit for CDK9, and 7SK snRNA and the HEXIM1 protein, two factors that associate with P-TEFb and repress its kinase activity. RESULTS: Prostratin up-regulated Cyclin T1 protein expression, modestly induced CDK9 protein expression, and did not affect Cyclin T2a protein expression. Although the kinase activity of CDK9 in vitro was up-regulated by prostratin, we observed a large increase in the association of 7SK snRNA and the HEXIM1 protein with CDK9. Using HIV-1 reporter viruses with and without a functional Tat protein, we found that prostratin stimulation of HIV-1 gene expression appears to require a functional Tat protein. Microarray analyses were performed and several genes related to HIV biology, including APOBEC3B, DEFA1, and S100 calcium-binding protein genes, were found to be regulated by prostratin. CONCLUSION: Prostratin induces Cyclin T1 expression and P-TEFb function and this is likely to be involved in prostratin reactivation of latent HIV-1 proviruses. The large increase in association of 7SK and HEXIM1 with P-TEFb following prostratin treatment may reflect a requirement in CD4(+ )T cells for a precise balance between active and catalytically inactive P-TEFb. Additionally, genes regulated by prostratin were identified that have the potential to regulate HIV-1 replication both positively and negatively

Frequent Long-Range Epigenetic Silencing of Protocadherin Gene Clusters on Chromosome 5q31 in Wilms' Tumor

Wilms' tumour (WT) is a pediatric tumor of the kidney that arises via failure of the fetal developmental program. The absence of identifiable mutations in the majority of WTs suggests the frequent involvement of epigenetic aberrations in WT. We therefore conducted a genome-wide analysis of promoter hypermethylation in WTs and identified hypermethylation at chromosome 5q31 spanning 800 kilobases (kb) and more than 50 genes. The methylated genes all belong to α-, β-, and γ-protocadherin (PCDH) gene clusters (Human Genome Organization nomenclature PCDHA@, PCDHB@, and PCDHG@, respectively). This demonstrates that long-range epigenetic silencing (LRES) occurs in developmental tumors as well as in adult tumors. Bisulfite polymerase chain reaction analysis showed that PCDH hypermethylation is a frequent event found in all Wilms' tumor subtypes. Hypermethylation is concordant with reduced PCDH expression in tumors. WT precursor lesions showed no PCDH hypermethylation, suggesting that de novo PCDH hypermethylation occurs during malignant progression. Discrete boundaries of the PCDH domain are delimited by abrupt changes in histone modifications; unmethylated genes flanking the LRES are associated with permissive marks which are absent from methylated genes within the domain. Silenced genes are marked with non-permissive histone 3 lysine 9 dimethylation. Expression analysis of embryonic murine kidney and differentiating rat metanephric mesenchymal cells demonstrates that Pcdh expression is developmentally regulated and that Pcdhg@ genes are expressed in blastemal cells. Importantly, we show that PCDHs negatively regulate canonical Wnt signalling, as short-interfering RNA–induced reduction of PCDHG@ encoded proteins leads to elevated β-catenin protein, increased β-catenin/T-cell factor (TCF) reporter activity, and induction of Wnt target genes. Conversely, over-expression of PCDHs suppresses β-catenin/TCF-reporter activity and also inhibits colony formation and growth of cancer cells in soft agar. Thus PCDHs are candidate tumor suppressors that modulate regulatory pathways critical in development and disease, such as canonical Wnt signaling

Randomised controlled trial of the short-term effects of OROS-methylphenidate on ADHD symptoms and behavioural outcomes in young male prisoners with attention-deficit/hyperactivity disorder (CIAO-II)

Background Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent disorder, seen in 20–30% of young adult prisoners. Pharmacoepidemiological studies, a small randomised controlled trial and open trial data of methylphenidate suggest clinically significant reductions in ADHD symptoms, emotional dysregulation, disruptive behaviour and increased engagement with educational activities. Yet, routine treatment of ADHD in offenders is not yet established clinical practice. There is continued uncertainty about the clinical response to methylphenidate (MPH), a first-line treatment for ADHD, in offenders, who often present with an array of complex mental health problems that may be better explained by states of inattentive, overactive, restless and impulsive behaviours. To address this problem, we will conduct an efficacy trial to establish the short-term effects of osmotic-controlled release oral delivery system (OROS)-methylphenidate (Concerta XL), an extended release formulation of MPH, on ADHD symptoms, emotional dysregulation and behaviour. Methods This study is a parallel-arm, randomised, placebo-controlled trial of OROS-MPH on ADHD symptoms, behaviour and functional outcomes in young male prisoners aged 16–25, meeting Diagnostic and Statistical Manual of Mental Disorders, fifth edition criteria for ADHD. Participants are randomised to 8 weeks of treatment with OROS-MPH or placebo, titrated over 5 weeks to balance ADHD symptom improvement against side effects. Two hundred participants will be recruited with a 1:1 ratio of drug to placebo. The primary outcome is change in level of ADHD symptoms after 8 weeks of trial medication. Discussion Potential benefits include improvement in ADHD symptoms, emotional dysregulation, attitudes towards violence and critical incidents and increased engagement with educational and rehabilitation programmes. Demonstrating the efficacy and safety of MPH on ADHD symptoms and associated impairments may provide the data needed to develop effective healthcare pathways for a significant group of young offenders. Establishing efficacy of MPH in this population will provide the foundation needed to establish long-term effectiveness studies with the potential for demonstrating significant reductions in criminal behaviour and improved health-economic outcomes

European consensus statement on diagnosis and treatment of adult ADHD: The European Network Adult ADHD.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is among the most common psychiatric disorders of childhood that persists into adulthood in the majority of cases. The evidence on persistence poses several difficulties for adult psychiatry considering the lack of expertise for diagnostic assessment, limited treatment options and patient facilities across Europe. METHODS: The European Network Adult ADHD, founded in 2003, aims to increase awareness of this disorder and improve knowledge and patient care for adults with ADHD across Europe. This Consensus Statement is one of the actions taken by the European Network Adult ADHD in order to support the clinician with research evidence and clinical experience from 18 European countries in which ADHD in adults is recognised and treated. RESULTS: Besides information on the genetics and neurobiology of ADHD, three major questions are addressed in this statement: (1) What is the clinical picture of ADHD in adults? (2) How can ADHD in adults be properly diagnosed? (3) How should ADHD in adults be effectively treated? CONCLUSIONS: ADHD often presents as an impairing lifelong condition in adults, yet it is currently underdiagnosed and treated in many European countries, leading to ineffective treatment and higher costs of illness. Expertise in diagnostic assessment and treatment of ADHD in adults must increase in psychiatry. Instruments for screening and diagnosis of ADHD in adults are available and appropriate treatments exist, although more research is needed in this age group

Rab3A as a Modulator of Homeostatic Synaptic Plasticity

The nervous system is faced with perturbations in activity levels throughout development and in disease or injury states. Neurons need to adapt to these changes in activity, but also need to maintain circuit firing within a normal range to stabilize the network from becoming too excited or too depressed. Homeostatic synaptic plasticity, the compensatory increase or decrease in synaptic strength as a result of excessive circuit inhibition or excitation, is a mechanism that the nervous system utilizes to keep network activity at normal levels. Despite intense effort, little is known about the mechanisms underlying homeostatic synaptic plasticity. Numerous studies have implicated postsynaptic modulation of AMPA receptors, but disagreement exists as to which receptor subtype, GluR1 or GluR2, predominates. Here, we demonstrate the completely novel finding that a presynaptic protein, Rab3A, a small GTPase that binds synaptic vesicles by switching between its active GTP-bound form and its inactive GDP-bound form, is essential for the regulation of homeostatic synaptic plasticity in dissociated mouse cortical neuron cultures. Using a combination of electrophysiology, pharmacology, and immunohistochemistry, we show that multiple mechanisms exist to increase synaptic strength in response to chronic activity deprivation, including but not limited to modulation of GluR1 and GluR2-containing AMPA receptors. Despite the variability and complexity of underlying mechanisms mediating the change in synaptic strength, we consistently found that modulation of synaptic strength in response to chronic network activity deprivation was completely lost in the absence of neuronal Rab3A, and that loss of Rab3A prevented the homeostatic increase in GluR2 levels but not GluR1. We conclude that there exist a biphasic mechanism for homeostatic synaptic plasticity, as suggested for LTP, where the induction (Phase 1) of the homeostatic increase in synaptic strength is first due to increasing GluR1-containing AMPA receptors, which is then followed by a Rab3A-dependent switch to GluR2-containing AMPA receptors to maintain the increase in synaptic strength (Phase 2)

Decreased Cardiac Excitability Secondary to Reduction of Sodium Current May Be a Significant Contributor to Reduced Contractility in a Rat Model of Sepsis

Introduction: Multisystem organ failure remains a poorly understood complication of sepsis. During sepsis, reduced excitability contributes to organ failure of skeletal muscle, nerves and the spinal cord. The goal of this study was to determine whether reduced excitability might also contribute to cardiac failure during sepsis.Methods: Wistar rats were made septic by cecal ligation and puncture. One day later, action potentials were recorded from beating left ventricular papillary muscle ex vivo by impaling myocytes with sharp microelectrodes.Results: In cardiac papillary muscle from septic rats, action potential amplitude and rate of rise were reduced, while threshold was elevated. These changes in action potential properties suggest sepsis selectively reduces sodium current. To determine the effects of selective reduction in sodium current, we applied tetrodotoxin to papillary muscle from healthy rats and found reduction in action potential amplitude and rate of rise, as well as elevation of threshold. The changes were similar to those triggered by sepsis. Blocking calcium current using nifedipine did not mimic action potential changes induced by sepsis. Contractility of healthy papillary muscle was reduced to 40% of normal following partial block of sodium current by tetrodotoxin, close to the low contractility of septic papillary muscle, which was 30% of normal.Conclusions: Our data suggest cardiac excitability is reduced during sepsis in rats. The reduction in excitability appears to be primarily due to reduction of sodium current. The reduction in sodium current may be sufficient to explain most of the reduction in cardiac contractility during sepsis

Diverging from the Norm: Reevaluating What Miniature Excitatory Postsynaptic Currents Tell Us about Homeostatic Synaptic Plasticity

The idea that the nervous system maintains a set point of network activity and homeostatically returns to that set point in the face of dramatic disruption—during development, after injury, in pathologic states, and during sleep/wake cycles—is rapidly becoming accepted as a key plasticity behavior, placing it alongside long-term potentiation and depression. The dramatic growth in studies of homeostatic synaptic plasticity of miniature excitatory synaptic currents (mEPSCs) is attributable, in part, to the simple yet elegant mechanism of uniform multiplicative scaling proposed by Turrigiano and colleagues: that neurons sense their own activity and globally multiply the strength of every synapse by a single factor to return activity to the set point without altering established differences in synaptic weights. We have recently shown that for mEPSCs recorded from control and activity-blocked cultures of mouse cortical neurons, the synaptic scaling factor is not uniform but is close to 1 for the smallest mEPSC amplitudes and progressively increases as mEPSC amplitudes increase, which we term divergent scaling. Using insights gained from simulating uniform multiplicative scaling, we review evidence from published studies and conclude that divergent synaptic scaling is the norm rather than the exception. This conclusion has implications for hypotheses about the molecular mechanisms underlying synaptic scaling