The full length of actin was amplified by RT-PCR in order to evaluate the synthesized cDNA by intact RNA. The presence of 138 bp bands confirmed the cDNA quality (figure 7). Figure 7 RT-PCR analysis of mRNA isolated from snap-frozen pancreatic tissues immersed in RNA-later for 24 h at -80ºC that were extracted with TriPure reagent. Lane M represents 50 bp DNA markers and lanes 1-5 show β-actin (138 bp) cDNAs amplified … Discussion Obtaining high-quality RNA is the first and most critical step in many molecular techniques such as reverse Inhibitors,research,lifescience,medical transcription real-time PCR (RT-qPCR), transcriptome

analysis that uses next-generation sequencing, array analysis, northern analysis, and cDNA library construction. Inhibitors,research,lifescience,medical RNA extraction is complicated because of the presence of ribonuclease enzymes in cells and tissues that can rapidly degrade RNA.14,17,18 RNases act without cofactors and are stable enzymes. The inactivation of RNases is difficult. Small amounts of RNase are sufficient to destroy RNA. In order to inactivate any RNases prior to surgery and in cases of removal of rat pancreatic tissue from the abdominal cavity, all surgical instruments should be cleaned with strong detergents, thoroughly rinsed, Inhibitors,research,lifescience,medical and placed in an oven for at

least 4 h at 240ºC. The place of surgery should be sterilized with NaOH and mild bleach to inactive the RNases.19 The pancreas has an extremely high level of RNase. RNA degradation occurs while the pancreas tissue is removed during dissection. In order

to increase efficiency dissection should be performed as quickly as possible.18,19 The pancreas is one of the important tissues that functions in the body’s homeostatic mechanisms. Therefore, improvement Inhibitors,research,lifescience,medical of RNA extraction procedures from the pancreas increases understanding of active pathways such as glucose regulation and redifferentiated β islets of the pancreas before and after treatment with different drugs. Knowledge of gene Inhibitors,research,lifescience,medical expression assays may potentially lead to the development of therapeutic drugs to restore β-cells and prevent apoptosis in diabetics.20 To identify novel metabolic genes and pathways that may play a role in the pathogenesis or treatment of diabetes, differential expression of metabolic genes is necessary. However, RNA extraction from to pancreatic tissue is difficult because of the abundance of RNase.21-23 Therefore we have attempted to design an efficient, simple optimized method to extract RNA from the pancreas based on our laboratory facilities. In order to enhance and correct this method, we assessed different common RNA extraction methods from pancreatic tissue with particular focus on the effect of frozen storage and RNase inhibition strategies, both of which affect RNA quality. The duration of surgery and amount of www.selleckchem.com/btk.html collected pancreatic tissue are the most crucial steps for obtaining intact RNA. Recent studies have shown a positive correlation between RNA degradation and the amount of pancreatic tissue.

11 In fact glucocorticoids, which are released from the adrenal gland into the bloodstream during stress, enter the brain through the blood-brain barrier and are distributed throughout different areas of the brain, including the prefrontal cortex, amygdala, and hippocampus.70 selleck glucocorticoids do interact with neurons and astrocytes in those specific areas and produce changes, both at the functional neurotransmitter Inhibitors,research,lifescience,medical and anatomic

levels.12,71,72 Of special relevance for aging of the brain are the effects mediated by glucocorticoids in the hippocampus,11,73 where they seem to be neurotoxic, affecting neuronal energy balance and the neuronal substrates for learning and memory.73 Moreover, the reduction in the number of neurons in this area of the brain produced by glucocorticoids has been correlated with a decline in cognitive functions.74 Interestingly, environmental enrichment is effective in attenuating the increases Inhibitors,research,lifescience,medical of glucocorticoids produced by acute stress in the prefrontal cortex of adult rats.1,11 Recent experimental findings are relevant

for further understand the chronic effects of stress and glucocorticoids, with particular implications for the aged Inhibitors,research,lifescience,medical brain. Up until recently the deleterious effects of glucocorticoids, particularly in the hippocampus, were mainly ascribed to the effects mediated by their elevated levels Inhibitors,research,lifescience,medical that result as a consequence of acute stress, rather than to chronic increases in the basal levels of these steroids. However, we and others have proposed that a permanent increase of the “basal” levels of glucocorticoids that results from a stressful lifestyle could also contribute to the neuronal damage that occurs in the these areas of the brain during aging.11,71 Conclusions Aging is a highly complex process influenced by a large number of factors that vary from individual to individual. It is clear that many factors, including controlling the amount of food we ingest as well as the components of our diet, the incorporation Inhibitors,research,lifescience,medical of aerobic physical activity

into our daily routine, and the attenuation of stress, are essential components for a successful aging of the brain. As reviewed here, aging of the brain Unoprostone is a process that is not only intrinsic to the neuronal mechanisms within the brain but also influenced by important hormones and neuromodulators that are released from peripheral organs and endocrine glands. Especially relevant in this context are the glucocorticoid hormones. During aging and with a chronic stressful lifestyle, corticosterone in rats or Cortisol in humans could potentially change the function of specific neuronal circuits in the brain. These effects could be modulated and attenuated in animals living in enriched environmental conditions, which emphasizes the importance of lifestyles in maintaining health during aging of the brain.

In general, the TCAs are distinguished by anticholinergic and antihlstamlc effects (Table V).36,41 Drug Interaction with TCAs and other medications affecting the hepatic enzyme (CYP 2D6) can lead to significantly altered TCA plasma levels. MAOIs are used sparingly, partly because of concern with hypertensive crises, as well

as their interaction with Inhibitors,research,lifescience,medical other prescribed medications and beer, red wine, and foodstuffs rich in the amino acid tyramine, such as aged cheese and liver. Clinical experiences in the last 15 years have shown that the SSRIs are relatively safe, but their adverse effect profile may not be the same across the entire class. While the efficacy and adverse effect profile should be considered in selecting among the SSRIs, in usual practice these drugs do not differ dramatically in efficacy from each other or from the older classes of antidepressants. Inhibitors,research,lifescience,medical The adverse effects that most frequently influence patients’ decisions to discontinue treatment are sexual dysfunction and weight gain. In inpatient Inhibitors,research,lifescience,medical settings, TCAs are still often used as first-line treatment. Not all SSRI (eg, citalopram and sertraline) have a high clinical trial degree of drug-drug interaction via the cytochrome P450 (CYP) system. While nausea, sedation, appetite change, and sexual dysfunction seem approximately similar for the SSRI class, claims Inhibitors,research,lifescience,medical for reduced adverse effects on sexual

functioning have been made for fluvoxamine (only approved by the FDA for obsessive-compulsive disorder),42

as have claims for reduced discontinuation effects for fluoxetine.43 Finally, the high degree of comorbidity of depression and cigarette consumption needs to be fully understood. Tobacco smoking can induce CYP enzyme changes affecting blood levels of various antidepressants, as well as complicate drug management when Inhibitors,research,lifescience,medical smoking cessation occurs.44 Table V Adverse effects of antidepressants.36-41 SSRl, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant; NSRI, noradrenaline and serotonin reuptake inhibitor; MAOI, those monoamine oxidase inhibitor; AMX, amoxapine; DOX, doxepine; IMI, imipramine; … Depression across the life span While some aspects of the symptom picture may change across the life span, the core features of depression are recognizable. In children and adolescents, depression is not always characterized by sadness, but instead by irritability, boredom, or an inability to experience pleasure. Depression is present in about 1% of children and 5% of adolescents at any given time.45 Before puberty, boys and girls are at equal risk for depression, whereas after the onset of puberty, the rate of depression is about twice as high in girls. While prepubertal depression is less prevalent than postpubertal depression, appropriate management at any age for major depression is recommended.

42 Therefore, two projects targeting quality assurance, either in inpatient, care or in outpatient care, have been performed within the GRNS. The first of these projects targeted the systematic development, implementation, and evaluation of specific measures of quality management in inpatient treatment of 597 schizophrenia Inhibitors,research,lifescience,medical patients at seven psychiatric hospitals, mostly district hospitals.43 Using an experimental control group design with preand

post-assessments, quality-orientated interventions according to the concept of Total Quality Management, (TQM) and with reference to the German treatment guidelines28 were compared in four experimental Inhibitors,research,lifescience,medical hospitals with documentation of structural

parameters (hospital and patient characteristics), of treatment, and of outcome in three control hospitals. Experimental hospitals received feedback by means of comparative benchmarking, and were guided in implementing Inhibitors,research,lifescience,medical quality circles for specific problem areas identified from the benchmarking process. Results indicated that, poorer average clinical outcome was associated with lower guideline conformity in a variety of treatment MDV3100 mw domains. After case-mix adjustment, benchmarking proved to be an opportunity to improve quality of treatment and promote

guideline conformity. The second project followed a similar approach for optimizing outpatient, Inhibitors,research,lifescience,medical treatment of schizophrenia. The main focus was to implement guidelines, but also other elements of internal (documentation Inhibitors,research,lifescience,medical system, monitoring) and external (benchmarking) quality management, in four hospital-associated networks of private psychiatric practices in three different, German cities (Düsseldorf, Freiburg, and Munich). One of the three experimental groups used a computer-based documentation system with implemented treatment, guidelines and decisionsupport, and received comparative benchmarking.44 This computerized documentation system draws the through attention of the physician to the treatment guidelines by means of a pop-up window showing the relevant guideline algorithm whenever the entered data indicate critical changes in the patient’s clinical status. Two further experimental groups used either the computer-based documentation system without, implemented guidelines and benchmarking, or papcr-and-pencil documentation with additional organization in quality circles. A control group used paper-and-pencil documentation without additional organization in quality circles.

Oct4 could be a useful tumour marker in an immunohistochemical panel designed to differentiate between ESCC and esophageal mucosa. Expression of Oct4 in AChR inhibition tumorospheres might indicate the presence of a population of ECSCs and its expression in xenograft tumours suggests that Oct4 is also associated with tumour metastasis. SOX2 gene is an amplification target of 3q26.3 in ESCC, and that SOX2 promotes ESCC cell proliferation in vitro (25). Inhibitors,research,lifescience,medical LY294002, an inhibitor of phosphatidylinositol 3-kinase, and rapamycin, an inhibitor of mTORC1, suppressed the ability of SOX2 to enhance proliferation

of ESCC cells in vitro. Effects of SOX2 knockdown, including reduced levels of phosphorylated AKT and decreased ESCC cell proliferation, were reversed with constitutive activation of

AKT with knockdown of phosphatase and tensin homolog. In mouse xenografts, SOX2 promoted in vivo tumor growth of ESCC, which was dependent on AKT/mTORC1 Inhibitors,research,lifescience,medical activation. LY294002 suppressed the ability of SOX2 to enhance tumor growth of ESCC by reducing cell proliferation, but not by enhancing apoptosis. These findings suggest that SOX2 promotes in vivo tumor growth of ESCC through activation of the AKT/mTORC1 signaling pathway, which enhances cell proliferation Inhibitors,research,lifescience,medical (67). Wang et al. (40) established that Sox2 expressions were significantly associated with higher histological grade (P<0.001 for both factors), indicating their correlation to dedifferentiation

in these tumours and a significant correlation between increasing levels of Sox2 immunostaining and decreasing survival for the patients (P<0.001) was observed. After being stratified Inhibitors,research,lifescience,medical by histological grade, Sox2 expressions were still significantly associated with unfavourable overall survival (P=0.008 and P=0.003, respectively). The role of OCT4 & Sox2 in esophageal carcinogenesis evidences further studies. Oestrogen receptor Oestrogens, the primary female Inhibitors,research,lifescience,medical sex hormones, are mechanistically linked to aspects of cancer risk and cancer development. A connection between oestrogen-activated signalling and carcinogenesis in many organs, including mammary glands (68), ovaries and colon (69) has been clearly defined, although it is unclear whether a similar connection exists for the esophagus, and esophageal adenocarcinoma Microbiology and Molecular Biology Reviews in particular. Furthermore, oestrogen is actively involved in the regulation of metabolism in adipose tissues (70), and it can be synthesized locally by activated aromatase in adipocytes in both men and women (71). Therefore it seems reasonable to consider that oestrogens might contribute towards the gender difference for esophageal adenocarcinoma. Involvement of oestrogen signalling in regulation of adipose tissue metabolism indicates a possible connection between the effects of oestrogen and male obesity-one of the main risk factors for esophageal adenocarcinoma.

How will the RDoC matrix actually function as a classification system for experimental purposes? For perspective, it may be pointed out that the current system imposes three constraints upon the independent variable (ie, group classification) in psychiatric studies: first, symptoms are the unit of analysis that must be utilized; second, find more particular constellations of symptoms

must be employed (ie, the DSM poly thetic Inhibitors,research,lifescience,medical criteria or their ICD equivalents); and third, the symptoms must be employed (with rare exceptions) simply to render a binary, diagnosis present/absent decision rather than being quantified in any way. RDoC is intended to free investigators from these constraints. An element from any unit of analysis may be the independent variable. In a study of working memory, performance on a working memory task could be the independent variable (possibly stratified by particular genetic polymorphisms), and activation of relevant working memory areas (as measured by fMRI) Inhibitors,research,lifescience,medical and real-world functional capacity might be dependent variables. As another example, patients presenting with internalizing (mood or anxiety) disorders might be classified along a dimension of their overall symptom reports of distress (but independent of DSM diagnosis), and fear circuit activation Inhibitors,research,lifescience,medical in some relevant task (eg, imagery, film clips) might be assessed in order to test the hypotheses

that increasing severity and/or chronicity of distress are associated with hyporeactivity in fear activation circuits. In each case, the independent variable cannot be assigned until after the experimental procedures are conducted; because the independent variable is dimensional, however, this does not necessarily pose problems in statistical Inhibitors,research,lifescience,medical power or matching subjects in groups. As these examples imply, the choice of which units of analysis to use as independent and dependent variables depends upon

the research question. Particularly in the early phases of studies using the RDoC approach, it may be heuristic for investigators to report the number of participants in study samples who meet diagnostic criteria for various DSM primary diagnoses in order to facilitate comparisons Inhibitors,research,lifescience,medical with traditional and RDoC classification. However, it should be noted that one major emphasis of Strategic Aim 1.4 is to delineate the entire range of a particular dimension, notably including Cediranib (AZD2171) patients who fall short of traditional diagnostic criteria or who may have an NOS (Not Otherwise Specified) diagnosis. Thus, including only those subjects who meet criteria for designated DSM/ICD disorders (even if more than one) is not a wholly satisfactory approach in the RDoC perspective. One of the inherent problems with the categorical approach is that, in spite of the acknowledged heterogeneity that is apparent in virtually all clinical diagnoses, the consequent analysis implicitly involves the notion of a unitary entity that has a “point” Expected Value and “normal” variance on any given measure.

The loss of regional interneuronal homeostasis must not necessarily affect huge brain areas; it might be only limited to certain small and circumscripted regions in the brain. As a consequence, clinicians should be able to choose the pharmacologically appropriate medication for the affected brain region.71 Concluding remarks Stem-cell maintenance and generation take place in a distinct microenvironment where appropriate external signals can best exert their regulatory function

Inhibitors,research,lifescience,medical on these cells. Signals provided by neural growth factors are responsible for neural stem-cell growth. Since components of regular stem-cell maintenance like BDNF are also implicated in mechanistic models characteristic of mood disorders, they thus offer new targets for pharmacologic intervention in neuropsychiatrie disease. More thorough knowledge about this complex connection mayhelp us render antidepressant treatment more efficient and reduce the undesirable side effects that impair patient compliance. Inhibitors,research,lifescience,medical So far there is no stem-cell-based approach really on the horizon for treating depression or any other psychosis. Selected abbreviations and acronyms 5-HT serotonin BDNF brain-derived neurotrophic factor CREB cAMP response element binding protein ES cells embryonic stem cells SCBI stem cell-based interventions
Pharmacological developments in the 20th

century have produced a wide range of drugs that have greatly improved the treatment of many Inhibitors,research,lifescience,medical serious diseases. In psychopharmacology, the discoveries of antipsychotic, Inhibitors,research,lifescience,medical tranquillizing, or antidepressant agents, such as selective serotonin reuptake inhibitors (SSRIs), were milestones in the treatment of mental illness. However, compared with the general pharmacological progress, the psychopharmacological development, whilst noteworthy, has been somewhat less spectacular. Despite

heavy investments Inhibitors,research,lifescience,medical in mental health-related research,1 there have been few important discoveries since the 1950s, when a number of psychopharmacological agents were discovered that are still in use. For example, clozapine was synthesized over 50 years ago but continues to be described as the “most effective antipsychotic drug” for the treatment of schizophrenia,2 and is recommended in the UK National Institute of Health and Clinical Excellence (NICE) 2009 update to its schizophrenia guidance.3 Traditionally, Carnitine dehydrogenase the drugs developed have been “one size fits all,” ie, standardized drugs targeting symptoms or syndromes that can be shared by various diseases, rather than being disease-specific, let alone patient-specific. Even though health care is by definition personalized in the sense that the patient’s needs broadly determine the nature of recommended treatment, eg, type and dosage of medication, traditional medication leaves little room for individual variations in 5-HT receptor agonist and antagonist review responses to treatment, notably through the randomized double -blind procedure used in clinical trials that is incompatible with individualized assessment.

It is not surprising that the law tries to titrate the use of mental illness and the potential impact of these illnesses.

The system is based on the premises that most people are competent and responsible for their behavior. The significance of personality disorders in the legal system remains highly dependent on how personality disorders are viewed within the mental health community. To the extent personality disorders fall short of being defined as severe and independent disorders clinically, they will have less significance in the law. If the law has to decide to draw a line somewhere, why not look to clinicians Inhibitors,research,lifescience,medical and see what illnesses Inhibitors,research,lifescience,medical they view as most important and where they focus most of their clinical and research attention? Perceptions (eg, if personality disorders are not defined as “major” or “severe” mental illnesses, then they must be “minor” or “mild” problems) may carry more weight in the courtroom than clinically intended. There are primarily two personality disorders of interest in forensics: ASPD and Borderline Personality Disorder (BPD). Inhibitors,research,lifescience,medical ASPD is of primary focus within the criminal forensic realm, whereas BPD is of considerable interest in the civil arena. ASPD tends to be excluded as a pertinent mental illness that qualifies as decreasing responsibility because it is a

disorder that is in general defined by “bad” or socially less tolerated or accepted behavior.30,32 BPD retains criminal legal interest when it crosses into symptoms of psychosis

and it is often identified as underlying, previously existing psychopathology in civil litigation. The combination Inhibitors,research,lifescience,medical of ASPD/BPD has been found to represent a criminogenic blend of traits that is overrepresented in high-secure forensic samples.33 Both psychiatry and the law define behavior as either within or outside of the norm, and define behavior as acceptable or not. The law KRX-0401 in vitro defines certain Inhibitors,research,lifescience,medical behaviors as crimes and certain actions as torts. Psychiatry defines certain behaviors and SB-3CT symptoms as abnormal or pathological, changeable or fixed, and treatable or not treatable. Both the law’s definition of mental illness and psychiatric definitions are often responsive to social pressures. Legal definitions of mental disorders are often quite vague across statutes and can at times be inconsistent with the psychiatric definitions.34 Usefulness in law does not necessarily mirror clinical conceptualizations or definitions.35 Statutory inclusion or exclusion of certain disorders can occur. The law has clarified (or claimed) its right to establish its own definitions of mental illness and by extension its own utility of the concept of personality disorder, as evidenced in the US Supreme Court decision for Kansas v. Hendricks36 and Kansas v. Crane.

2000b). Most of the toxic effects of NO appear to be a result of the reaction of NO with superoxide to form a very toxic compound peroxynitrite. Cytotoxicity of peroxynitrite is related to its roles in the initiation of lipid peroxidation, inactivation of a variety of enzymes, and depletion of GSH (Cuzzocrea et al. 2000b). Interventions to reduce the generation or the effects of peroxynitrite have showed beneficial effects in a model of cerebral ischemia as well as variety of models of inflammation and shock (Dawson and Dawson 1997). NAC’s antioxidant property of being a sulphydryl Inhibitors,research,lifescience,medical donor may contribute to the

regeneration of endothelium-derived relaxing factor and GSH (Aruoma et al. 1989). Positive changes in microcirculatory blood flow and tissue oxygenation after the start of NAC treatment were documented in animals

(Cuzzocrea et al. 2000b). In a Mongolian gerbil model, NAC treatment increased survival and reduced hyperactivity linked to neurodegeneration induced by cerebral ischemia and reperfusion. Histological observations Inhibitors,research,lifescience,medical of the pyramidal layer of cortex showed a reduction of neuronal loss in animals that received NAC. Generally, these Inhibitors,research,lifescience,medical results show that NAC http://www.selleckchem.com/products/BIBW2992.html improves brain injury induced by transient cerebral ischemia (Harrison et al. 1991). Similar results were obtained in a rat model of cerebral ischemia (Khan et al. 2004). However, no data are yet available on the use of NAC in

acute ischemic stroke patients. Subarachnoid hemorrhage The pathological production of free radicals and consequent lipid peroxidation are causally related to the development of cerebral vasospasm (Sen et al. 2006). Damage in the endothelium and apoptosis of endothelial Inhibitors,research,lifescience,medical cells are also contributing to cerebral vasospasm after subarachnoid hemorrhage (SAH) (Halliwell and Gutteridge 1986; Findlay et al. 1989), while protection of endothelium from apoptosis might attenuate vasospasm (Sen et al. 2006). Inhibitors,research,lifescience,medical Intraperitoneal administration of NAC was markedly effective against cerebral vasospasm development following SAH in rabbits. NAC can significantly reduce elevated lipid peroxidation and Cancer cell increase the level of tissue GSH and SOD enzymatic activities. Also, NAC treatment increased the luminal area and reduced wall thickness of the basilar artery. NAC markedly reduced apoptotic index and protected the endothelial integrity (Güney et al. 2010). Our group reported a 43-year-old woman with Hunt-Hess grade 3 SAH due to a ruptured right middle cerebral artery aneurysm that was coiled and she subsequently developed severe vasospasm. She was treated with oral NAC, 600 mg twice a day, with dramatic vasospasm resolution for 24 h, confirmed by Computed Tomography Angiography and Transcranial Doppler sonography (Friehs 2014). To our knowledge, this is the first report of NAC use and its possible effect on vasospasm in a patient with SAH.

A TTN mutation Gln4053ter found in a patient with DCM decreased the binding to α-actinin (12). We also reported that DCM-associated TCAP mutations Arg87Gln and Glu132Gln decreased binding to titin/connectin, MLP and calsarcin-1 (13). Likewise, DCM-associated CSRP3 mutations Trp4Arg and Lys69Arg decreased binding to T-cap/telethonin and α-actinin, respectively (21, 22). It should also be noted

here that a DCM-associated ACTN2 mutation Gln9Argreduced binding to MLP (22). These observations suggested that the impaired interaction among cytoskeletal Inhibitors,research,lifescience,medical Z-band components caused DCM; i.e., the decreased interaction might lead to loose sarcomere assembly and reduce the stretch response

of cardiomyocytes as shown in MLP-knock out mice with DCM phenotype (21). In this regard, it is of interest that stretch and passive tension of sarcomere can regulate Ca2+-sensitivity of cardiac muscle contraction (23), suggesting that the impaired interaction might alter the Ca2+-sensitivity Inhibitors,research,lifescience,medical of muscle contraction. The molecular mechanisms due to the genetic abnormalities of sarcomere components, especially the PR-171 clinical trial troponin complex, have been investigated. The troponin complex, composed of the Ca2+-binding subunit troponin C, inhibitory subunit troponin I and an elongated molecule Inhibitors,research,lifescience,medical troponin T, is an essential modulator of Ca2+-stimulated actomyosin interaction or ATPase activity in the striated muscle. It has been reported that a DCM-associated mutation in troponin T showed Ca2+-desensitization and decreased maximal force (24, Inhibitors,research,lifescience,medical 25). The decreased Ca2+-sensitivity of muscle contraction may well explain the systolic dysfunction, a common pathophysiological alteration in DCM. Another functional

study showed significant impairment of troponin complex assembly due to the mutant troponin I or C (26). On the other hand, a DCM-associated LDB3 mutation increased the binding ability to protein kinase C which plays a key role in the cell signaling pathway Inhibitors,research,lifescience,medical (27). In addition, we recently identified novel DCM-associated mutations in the genes for αB-crystallin (CRYAB) and four-and-a-half LIM domains 2 (FHL2, FHL2), which serve as a chaperon against stress and as a scaffold of signaling proteins localizing to the Unoprostone sites of energy consumption in the cardiac sarcomere, respectively. As for the functional alteration due to the mutations, the mutations of αB-crystallin and FHL2 impaired the binding ability to titin/connectin (28, 29). Although the molecular mechanisms of DCM due to these abnormalities remain to be elucidated, the cardiac dysfunction may be associated not only with the alteration of mechanical stretch response but also with the impairment/perturbation of the interaction between sarcomere/Z-band and signaling molecules.