Embracing the polypill as a cardiovascular therapeutic: is this the best strategy?

INTRODUCTION: Cardiovascular disease (CVD) is an important cause of mortality and morbidity worldwide. CVD morbidity and mortality are associated with significant financial costs related to hospitalization, medication, and lost productivity. The concept of the 'polypill' for the reduction of cardiovascular risk was proposed in 2000. A polypill is a fixed combination of drugs in a single tablet or capsule. The initial polypill consisted of three different classes of antihypertensive drugs (each at half dose), in addition to aspirin, a statin, and folic acid. The challenge today is to produce polypills containing drugs with established efficacy and complementary actions. Areas covered: The authors provide their expert perspectives on the polypill and consider the randomized clinical trials that have evaluated the safety, efficacy, adherence, and cost-effectiveness of polypills. Expert opinion: The polypill makes prescribing easier by reducing the need for complex treatment algorithms and dose titration. It also appears to be cost-effective. However, there are several issues that need to be addressed before the polypill can be used routinely. A single polypill formulation may not be suitable for all patients. It may be necessary to develop several types of polypill to meet the needs of different patient groups

Mice Lacking the Circadian Modulators SHARP1 and SHARP2 Display Altered Sleep and Mixed State Endophenotypes of Psychiatric Disorders

Increasing evidence suggests that clock genes may be implicated in a spectrum of psychiatric diseases, including sleep and mood related disorders as well as schizophrenia. The bHLH transcription factors SHARP1/DEC2/BHLHE41 and SHARP2/DEC1/ BHLHE40 are modulators of the circadian system and SHARP1/DEC2/BHLHE40 has been shown to regulate homeostatic sleep drive in humans. In this study, we characterized Sharp1 and Sharp2 double mutant mice (S1/2(-/-)) using online EEG recordings in living animals, behavioral assays and global gene expression profiling. EEG recordings revealed attenuated sleep/wake amplitudes and alterations of theta oscillations. Increased sleep in the dark phase is paralleled by reduced voluntary activity and cortical gene expression signatures reveal associations with psychiatric diseases. S1/2(-/-) mice display alterations in novelty induced activity, anxiety and curiosity. Moreover, mutant mice exhibit impaired working memory and deficits in prepulse inhibition resembling symptoms of psychiatric diseases. Network modeling indicates a connection between neural plasticity and clock genes, particularly for SHARP1 and PER1. Our findings support the hypothesis that abnormal sleep and certain (endo) phenotypes of psychiatric diseases may be caused by common mechanisms involving components of the molecular clock including SHARP1 and SHARP2

Dysregulated Expression of Neuregulin-1 by Cortical Pyramidal Neurons Disrupts Synaptic Plasticity

SummaryNeuregulin-1 (NRG1) gene variants are associated with increased genetic risk for schizophrenia. It is unclear whether risk haplotypes cause elevated or decreased expression of NRG1 in the brains of schizophrenia patients, given that both findings have been reported from autopsy studies. To study NRG1 functions in vivo, we generated mouse mutants with reduced and elevated NRG1 levels and analyzed the impact on cortical functions. Loss of NRG1 from cortical projection neurons resulted in increased inhibitory neurotransmission, reduced synaptic plasticity, and hypoactivity. Neuronal overexpression of cysteine-rich domain (CRD)-NRG1, the major brain isoform, caused unbalanced excitatory-inhibitory neurotransmission, reduced synaptic plasticity, abnormal spine growth, altered steady-state levels of synaptic plasticity-related proteins, and impaired sensorimotor gating. We conclude that an “optimal” level of NRG1 signaling balances excitatory and inhibitory neurotransmission in the cortex. Our data provide a potential pathomechanism for impaired synaptic plasticity and suggest that human NRG1 risk haplotypes exert a gain-of-function effect

A microfluidic device with fluorimetric detection for intracellular components analysis

An integrated microfluidic system that coupled lysis of two cell lines: L929 fibroblasts and A549 epithelial cells, with fluorescence-based enzyme assay was developed to determine β-glucocerebrosidase activity. The microdevice fabricated in poly(dimethylsiloxane) consists of three main parts: a chemical cell lysis zone based on the sheath flow geometry, a micromeander and an optical fibers detection zone. Unlike many methods described in literature that are designed to analyse intracellular components, the presented system enables to perform enzyme assays just after cell lysis process. It reduces the effect of proteases released in lysis process on determined enzymes. Glucocerebrosidase activity, the diagnostic marker for Gaucher’s disease, is the most commonly measured in leukocytes and fibroblasts using 4-methylumbelliferyl-β-D-glucopyranoside as synthetic β-glucoside. The enzyme cleavage releases the fluorescent product, i.e. 4-methylumbelliferone, and its fluorescence is measured as a function of time. The method of enzyme activity determination described in this paper was adapted for flow measurements in the microdevice. The curve of the enzymatic reaction advancement was prepared for three reaction times obtained from application of different flow rates of solutions introduced to the microsystem. Afterwards, determined β-glucocerebrosidase activity was recalculated with regard to 105 cells present in samples used for the tests. The obtained results were compared with a cuvette-based measurements. The lysosomal β-glucosidase activities determined in the microsystem were in good correlation with the values determined during macro-scale measurements

Zmodyfikowana struktura ze śledzeniem modelu

This paper presents a modified version of the control system with model following control (MFC). The auxiliary (corrective) controller has been designed for an input signal, which is the difference between the amplified state vectors of a model and process. The values of gain coefficients of the state variables of the model and process have been calculated according to the LQR (Linear Quadratic Regulator) procedure. It has been proved that a new controller improves the properties of the MFC system.Artykuł dotyczy dwu pętlowego układu regulacji ze śledzeniem modelu typu MFC (Model Following Control). Układ taki posiada dwa regulatory: główny oraz korekcyjny. W klasycznym rozwiązaniu sygnałem wejściowym regulatora pomocniczego jest różnica sygnałów wyjściowych z modelu i procesu. Pozwala to na generowanie korekcyjnego sygnału błędu w przypadku zaistnienia różnic między procesem i modelem. Takie rozwiązanie nie pozwala jednak w jawny sposób kontrolować zmiennych stanu procesu. Dlatego też w artykule przedstawiono zmodyfikowaną wersję układu regulacji MFC, z regulatorem pomocniczym (korekcyjnym), którego sygnałem wejściowym jest różnica odpowiednio wzmocnionych współrzędnych stanu modelu i procesu. Analizowany układ opisano w przestrzeni zmiennych stanu, a regulator korekcyjny został zaprojektowany jako regulator typu LQR (Linear Quadratic Regulator). W dalszej kolejności przeproawdzono analizę porównawczą własności nowego i klasycznego układu MFC (wartości własne, stopień oscylacyjności, stabilności oraz funkcję wrażliwości). Przedstawiono, że układ MFC może być wykorzystywany również jako tolerujący uszkodzenia (a nie tylko w przypadkach zmian dynamiki procesu), co umieszcza go w klasie układów regulacji odpornych na uszkodzenia. Zostało to zilustrowane przeprowadzonymi badaniami symulacyjnymi

Projektowanie odpornego, nieliniowego układu regulacji kąta kursu statku w strukturze MFC z linearyzacją typu wejście-wyjście

The paper presents a designing procedure of controllers in the structure of tracking model (Model Following Control, MFC) for nonlinear model of a ship as an object of the course angle control. In the article feedback linearization method for known nonlinearity in the input-output channel of plant has been used. Ideal linearization in the classical control system occurs only when the design nonlinearity of the model and the object are identical. Therefore, the article proposes the use of MFC structure, which is able to compensate for differences of non-linear characteristics of the process and model.Artykuł przedstawia procedurę projektowania regulatorów w strukturze ze śledzeniem modelu (Model Followig Control, MFC) dla nieliniowego modelu statku, jako obiektu regulacji kąta kursu. W artykule została wykorzystana metoda linearyzacji z ujemnym sprzężeniem zwrotnym dla znanej nieliniowości modelu obiektu w torze wejście-wyjście. Idealna linearyzacja w klasycznym układzie regulacji zachodzi jedynie wtedy, gdy projektowe nieliniowości modelu i obiektu są identyczne. Dlatego też w artykule zaproponowano zastosowanie układu MFC, który jest w stanie skompensować różnice nieliniowych charakterystyk procesu i jego modelu

The Choice of Model Dynamics in the Model

W strukturze nadążnego, odpornego układu regulacji (MFC) wykorzystywany jest model procesu regulowanego. Tematem artykułu są metody wyznaczania dynamiki tego modelu.A plant model is used in the structure of the robust, model following control system. The article deals with the determination of dynamics of this model