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Titin is a giant protein that is in charge of the assembly and passive mechanical properties of the sarcomere. Cardiac titin contains a unique N2B region, which has been proposed to modulate elasticity of the titin filament and to be important for hypertrophy signaling and the ischemic stress response through its binding proteins FHL2 and ␣B-crystallin, respectively. To study the role of the titin N2B region in systole and diastole of the heart, we generated a knockout (KO) mouse deleting only the N2B exon 49 and leaving the remainder of the titin gene intact. The resulting mice survived to adulthood and were fertile. Although KO hearts were small, they produced normal ejection volumes because of an increased ejection fraction. FHL2 protein levels were significantly reduced in the KO mice, a finding consistent with the reduced size of KO hearts. Ultrastructural analysis revealed an increased extension of the remaining spring elements of titin (tandem Ig segments and the PEVK region), which, together with the reduced sarcomere length and increased passive tension derived from skinned cardiomyocyte experiments, translates to diastolic dysfunction as documented by echocardiography. We conclude from our work that the titin N2B region is dispensable for cardiac development and systolic properties but is important to integrate trophic and elastic functions of the heart. The N2B-KO mouse is the first titin-based model of diastolic dysfunction and, considering the high prevalence of diastolic heart failure, it could provide future mechanistic insights into the disease process.cardiac muscle ͉ hypertrophy ͉ mechanics ͉ cardiology ͉ disease T itin forms a continuous filament along the myofibril that determines the elastic properties of cardiac myocytes (for review, see ref. 1). The extensible region of titin is found in the I-band region of the sarcomere and comprises tandemly arranged Ig-like domains and the so-called PEVK region (2). In addition, cardiac titin contains a third extensible region, the N2B element (2), which is absent in skeletal muscle. The N2B region extends greatly toward the upper limit of the physiological sarcomere length of cardiac muscle (3, 4). It has been suggested that this extension reduces the steepness of the passive forcesarcomere length relation, decreasing the likelihood of the unfolding of Ig domains (3). Mutations in the N2B region can lead to dilated or hypertrophic cardiomyopathy, apparently through altered affinity to FHL2, a heart-specific member of the LIM domain gene family (5). To understand the role of the titin N2B region in cardiac function and disease, we have eliminated exon 49, which encodes the N2B region, and investigated its effect on the mechanical and trophical properties of the knockout (KO) heart.

OBJECTIVE: To evaluate and analyze the risk factors for burning mouth syndrome (BMS). METHODS: Eighty-seven consecutive patients with BMS and a randomly selected control group (n = 82) were comprehensively investigated with a self-designed questionnaire, Self-rating Anxiety Scale (SAS) and Self-rating Depression Scale (SDS). A complete blood count and serum sex hormone were also examined in patients with BMS and control subjects. All the data obtained were transferred to a data bank and analyzed statistically in SPSS 11.5 for windows. RESULTS: No statistical difference between the BMS group and the control group was found in blood analyses including white blood cell count, red blood cell count, hemoglobin and platelet count. Among the menopausal or postmenopausal women with BMS, the follicle stimulating hormone (FSH) level was significantly higher, but the estradiol level was significantly lower. The BMS group reported adverse life events more frequently than the control group. Patients with BMS significantly exhibited symptoms of somatization, and both the scores of anxiety, depression in patients with BMS were higher than those of the control group (P < 0.05). A regression equation which included six variables had been established by using logistic regression analysis, indicating that the habit of tongue thrusting, lip sucking, periodontitis, smoking, outcome of recent medication, depression were the principal risk factors, among which tongue thrusting was the most significant. CONCLUSION: Our study indicated that BMS may be of psychological origin, and the measures such as refraining from oral parafunctional activities, removing local irritating factors, stopping smoking, good mental health status could help in the prevention of BMS.

Rationale: The giant protein titin plays key roles in myofilament assembly and determines the passive mechanical properties of the sarcomere. The cardiac titin molecule has 2 mayor elastic elements, the N2B and the PEVK region. Both have been suggested to determine the elastic properties of the heart with loss of function data only available for the N2B region. Objective: The purpose of this study was to investigate the contribution of titin's proline-glutamate-valine-lysine (PEVK) region to biomechanics and growth of the heart. Methods and Results: We removed a portion of the PEVK segment (exons 219 to 225; 282 aa) that corresponds to the PEVK element of N2B titin, the main cardiac titin isoform. Adult homozygous PEVK knockout (KO) mice developed diastolic dysfunction, as determined by pressure-volume loops, echocardiography, isolated heart experiments, and muscle mechanics. Immunoelectron microscopy revealed increased strain of the N2B element, a spring region retained in the PEVK-KO. Interestingly, the PEVK-KO mice had hypertrophied hearts with an induction of the hypertrophy and fetal gene response that includes upregulation of FHL proteins. This contrasts the cardiac atrophy phenotype with decreased FHL2 levels that result from the deletion of the N2B element. Key Words: diastole Ⅲ connectin Ⅲ hypertrophy Ⅲ compliance Ⅲ FHL T itin is the largest protein in mammals and forms a continuous elastic filament along the myofibril (reviewed in 1 ). Because of its enormous size, titin is a prominent target for mutations that give rise to diseases such as familial dilated cardiomyopathy and muscular dystrophy. 2,3 Titin's extensible region resides in the I-band of the sarcomere and consists of immunoglobulin (Ig)-like domains arranged in tandem, the heart specific N2B element, and the prolineglutamate-valine-lysine (PEVK) element. 4 The PEVK element is thought to function as a largely unfolded polypeptide that extends at low force levels and that thereby provides an important source of elasticity at physiological sarcomere lengths. [5][6][7] Unlike the 1-exon heart specific N2B element, the titin gene contains 112 PEVK exons that are differentially expressed between muscle types. 8 Of these PEVK exons, 219 to 225 are expressed in the so-called N2B titin isoform, that constitutes the dominant cardiac isoform in the left ventricle of a wide range of species, including rodents and human. 9 Here we generated a mouse deficient in titin's exons 219 to 225 that results in a deletion of the c-terminal PEVK region (282 aa) and determined its role in cardiac function using echocardiography, in vivo pressure-volume loops, isolated heart physiology, muscle mechanics, immunoelectron microscopy, and expression analysis. We investigated the hypertrophy phenotype and studied members of the four-and-a-half LIM family involved in atrophy/hypertrophy signaling-FHL1 and FHL2. 10,11 Our results reveal the strong effect of the PEVK element on diastolic function but also that the role of the PEVK extends beyond that of a mechanical spr...