The structural and functional integrities of porcine myocardium are mostly preserved by cryopreservation.

Structural and functional studies of heart muscle are important to gain insights into the physiological bases of cardiac muscle contraction and the pathological bases of heart disease. While fresh muscle tissue works best for these kinds of studies, this is not always practical to obtain, especially for heart tissue from large animal models and humans. Conversely, tissue banks of frozen human hearts are available and could be a tremendous resource for translational research. It is not well understood, however, how liquid nitrogen freezing and cryostorage may impact the structural integrity of myocardium from large mammals. In this study, we directly compared the structural and functional integrity of never-frozen to previously frozen porcine myocardium to investigate the consequences of freezing and cryostorage. X-ray diffraction measurements from hydrated tissue under near-physiological conditions and electron microscope images from chemically fixed porcine myocardium showed that prior freezing has only minor effects on structural integrity of the muscle. Furthermore, mechanical studies similarly showed no significant differences in contractile capabilities of porcine myocardium with and without freezing and cryostorage. These results demonstrate that liquid nitrogen preservation is a practical approach for structural and functional studies of myocardium.

Open Foveal Repair of the Triangular Fibrocartilage Complex Tears Associated with Symptomatic Ulnar Styloid Non-union.

Background: Symptomatic ulnar styloid non-union can be treated by excision of the ulnar styloid fragment. For combined triangular fibrocartilage complex (TFCC) tears, several repair techniques such as arthroscopic repair, open repair to the fracture site or reconstruction using a tendon graft have been introduced. This study reports the technique and outcomes of open foveal repair of the TFCC with excision of the ulnar styloid fragment in patients with symptomatic ulnar styloid non-union and distal radioulnar joint (DRUJ) instability. Methods: Consecutive patients with symptomatic ulnar styloid non-union with TFCC tears and DRUJ instability who underwent excision of the ulnar styloid fragment and open foveal repair of the TFCC were retrospectively reviewed. After excising the ulnar styloid fragment, a capsular window was created between the triquetrum and TFCC, followed by attaching the TFCC to the fovea using three sutures through a bone tunnel from the ulnar cortex to the fovea. Additional ulnar shortening osteotomies were performed in patients with positive ulnar variance and ulnar impaction test. The outcomes were evaluated in terms of DRUJ stability and the Quick Disabilities of the Arm, Shoulder and Hand (DASH) scores. Results: In total, 21 patients with a mean age of 40 were enrolled in the study. All patients demonstrated DRUJ stability at a mean follow-up duration of 14 months. The mean Quick DASH score significantly improved from 18.9 ± 11.7 to 2.5 ± 4.1 (p < 0.05). Eleven patients underwent combined ulnar shortening osteotomies, and no difference in the Quick DASH score was found between patients who underwent ulnar shortening osteotomy and those who did not. Conclusions: This study demonstrates that open foveal repair of the TFCC with ulnar styloid fragment excision is an effective strategy to surgically treat patients with symptomatic ulnar styloid non-union with TFCC tear and DRUJ instability. Level of Evidence: Level III (Therapeutic).

Myofibril orientation as a metric for characterizing heart disease.

Myocyte disarray is a hallmark of many cardiac disorders. However, the relationship between alterations in the orientation of individual myofibrils and myofilaments to disease progression has been largely underexplored. This oversight has predominantly been because of a paucity of methods for objective and quantitative analysis. Here, we introduce a novel, less-biased approach to quantify myofibrillar and myofilament orientation in cardiac muscle under near-physiological conditions and demonstrate its superiority as compared with conventional histological assessments. Using small-angle x-ray diffraction, we first investigated changes in myofibrillar orientation at increasing sarcomere lengths in permeabilized, relaxed, wild-type mouse myocardium from the left ventricle by assessing the angular spread of the 1,0 equatorial reflection (angle σ). At a sarcomere length of 1.9 µm, the angle σ was 0.23 ± 0.01 rad, decreased to 0.19 ± 0.01 rad at a sarcomere length of 2.1 µm, and further decreased to 0.15 ± 0.01 rad at a sarcomere length of 2.3 µm (p < 0.0001). Angle σ was significantly larger in R403Q, a MYH7 hypertrophic cardiomyopathy model, porcine myocardium (0.24 ± 0.01 rad) compared with wild-type myocardium (0.14 ± 0.005 rad; p < 0.0001), as well as in human heart failure tissue (0.19 ± 0.006 rad) when compared with nonfailing samples (0.17 ± 0.007 rad; p = 0.01). These data indicate that diseased myocardium suffers from greater myofibrillar disorientation compared with healthy controls. Finally, we showed that conventional, histology-based analysis of disarray can be subject to user bias and/or sampling error and lead to false positives. Our method for directly assessing myofibrillar orientation avoids the artifacts introduced by conventional histological approaches that assess myocyte orientation and only indirectly evaluate myofibrillar orientation, and provides a precise and objective metric for phenotypically characterizing myocardium. The ability to obtain excellent x-ray diffraction patterns from frozen human myocardium provides a new tool for investigating structural anomalies associated with cardiac diseases.

Radiocapitellar incongruity of the radial head in magnetic resonance imaging correlates with pathologic changes of the lateral elbow stabilizers in lateral epicondylitis.

OBJECTIVE: Post-traumatic posterolateral rotatory instability (PLRI) can be shown as radiocapitellar incongruity or posterior translation (PT) of the radial head in magnetic resonance imaging (MRI). We aimed to evaluate whether PT correlated with pathologic changes of lateral elbow stabilizers in patients with lateral epicondylitis. MATERIALS AND METHODS: In MRIs of 160 patients with lateral epicondylitis, we measured PT of the radial head in the sagittal images. We qualitatively graded five lesions of the lateral elbow structures that included common extensor tendon (CET) lesion (grade 1-3), lateral collateral ligament complex (LCLC) insufficiency (grade 0-2), and absence or presence of bone marrow signal change, osteochondral lesion, and calcification. We analyzed whether the PT correlated with pathologic changes of the lateral elbow stabilizers and evaluated the diagnostic value of the PT for severe lesions. RESULTS: The average PT was 1.9 mm. The PT correlated with both the CET lesion (p < 0.001) and LCLC insufficiency (p < 0.001). The optimal cutoff values of the PT for grade 3 CET lesion and grade 2 LCLC lesion were 2.6 and 2.8 mm, respectively. When potential PLRI was defined as the PT of > 3.4mm as suggested for post-traumatic PLRI, 21 patients had potential PLRI. The positive predictive values of the PT > 3.4mm were 76% for grade 3 CET lesions and 67% for grade 2 LCLC insufficiency. CONCLUSION: This study demonstrates that PT of the radial head correlates with pathological changes of the lateral elbow stabilizers. As radiocapitellar incongruity is easy to measure quantitatively, it can be used for screening potential PLRI in patients with lateral epicondylitis.

Screening major depressive disorder using vocal acoustic features in the elderly by sex.

BACKGROUND: Vocal acoustic features are potential biomarkers of elderly depression. Previous automated diagnostic tests for depression have employed unstandardized speech samples, and few studies have considered differences in voice reactivity. We aimed to develop a voice-based screening test for depression measuring vocal acoustic features of elderly Koreans while they read a series of mood-inducing sentences (MIS). METHODS: In this case-control study, we recruited 61 individuals with major depressive disorder and 143 healthy controls (mean age [SD]: 72 [6]; female, 70%) from the community-dwelling elderly population. Participants were asked to read MIS and their variation pattern of acoustic features represented by the correlation distance between two MIS were analyzed as input features using the univariate feature selection technique and subsequently classified by AdaBoost. RESULTS: Acoustic features showing significant discriminatory performances were spectral and energy-related features for males (sensitivity 0.95, specificity 0.88, and accuracy 0.86) and prosody-related features for females (sensitivity 0.73, specificity 0.86, and accuracy 0.77). The correlation distance between negative and positive MIS was significantly shorter in the depressed group than in the healthy control (F = 18.574, P < 0.001). LIMITATIONS: Small sample size and relatively homogenous clinical profile of depression could limit the generalizability. CONCLUSIONS: While reading MIS, spectral and energy-related acoustic features for males and prosody-related features for females are good discriminators for major depressive disorder. These features may be used as biomarkers of depression in the elderly.

Fast skeletal myosin-binding protein-C regulates fast skeletal muscle contraction.

Fast skeletal myosin-binding protein-C (fMyBP-C) is one of three MyBP-C paralogs and is predominantly expressed in fast skeletal muscle. Mutations in the gene that encodes fMyBP-C, MYBPC2, are associated with distal arthrogryposis, while loss of fMyBP-C protein is associated with diseased muscle. However, the functional and structural roles of fMyBP-C in skeletal muscle remain unclear. To address this gap, we generated a homozygous fMyBP-C knockout mouse (C2-/-) and characterized it both in vivo and in vitro compared to wild-type mice. Ablation of fMyBP-C was benign in terms of muscle weight, fiber type, cross-sectional area, and sarcomere ultrastructure. However, grip strength and plantar flexor muscle strength were significantly decreased in C2-/- mice. Peak isometric tetanic force and isotonic speed of contraction were significantly reduced in isolated extensor digitorum longus (EDL) from C2-/- mice. Small-angle X-ray diffraction of C2-/- EDL muscle showed significantly increased equatorial intensity ratio during contraction, indicating a greater shift of myosin heads toward actin, while MLL4 layer line intensity was decreased at rest, indicating less ordered myosin heads. Interfilament lattice spacing increased significantly in C2-/- EDL muscle. Consistent with these findings, we observed a significant reduction of steady-state isometric force during Ca2+-activation, decreased myofilament calcium sensitivity, and sinusoidal stiffness in skinned EDL muscle fibers from C2-/- mice. Finally, C2-/- muscles displayed disruption of inflammatory and regenerative pathways, along with increased muscle damage upon mechanical overload. Together, our data suggest that fMyBP-C is essential for maximal speed and force of contraction, sarcomere integrity, and calcium sensitivity in fast-twitch muscle.

Amino terminus of cardiac myosin binding protein-C regulates cardiac contractility.

Phosphorylation of cardiac myosin binding protein-C (cMyBP-C) regulates cardiac contraction through modulation of actomyosin interactions mediated by the protein's amino terminal (N')-region (C0-C2 domains, 358 amino acids). On the other hand, dephosphorylation of cMyBP-C during myocardial injury results in cleavage of the 271 amino acid C0-C1f region and subsequent contractile dysfunction. Yet, our current understanding of amino terminus region of cMyBP-C in the context of regulating thin and thick filament interactions is limited. A novel cardiac-specific transgenic mouse model expressing cMyBP-C, but lacking its C0-C1f region (cMyBP-C∆C0-C1f), displayed dilated cardiomyopathy, underscoring the importance of the N'-region in cMyBP-C. Further exploring the molecular basis for this cardiomyopathy, in vitro studies revealed increased interfilament lattice spacing and rate of tension redevelopment, as well as faster actin-filament sliding velocity within the C-zone of the transgenic sarcomere. Moreover, phosphorylation of the unablated phosphoregulatory sites was increased, likely contributing to normal sarcomere morphology and myoarchitecture. These results led us to hypothesize that restoration of the N'-region of cMyBP-C would return actomyosin interaction to its steady state. Accordingly, we administered recombinant C0-C2 (rC0-C2) to permeabilized cardiomyocytes from transgenic, cMyBP-C null, and human heart failure biopsies, and we found that normal regulation of actomyosin interaction and contractility was restored. Overall, these data provide a unique picture of selective perturbations of the cardiac sarcomere that either lead to injury or adaptation to injury in the myocardium.

Cryo-EM structure of the inhibited (10S) form of myosin II.

Myosin II is the motor protein that enables muscle cells to contract and nonmuscle cells to move and change shape1. The molecule has two identical heads attached to an elongated tail, and can exist in two conformations: 10S and 6S, named for their sedimentation coefficients2,3. The 6S conformation has an extended tail and assembles into polymeric filaments, which pull on actin filaments to generate force and motion. In 10S myosin, the tail is folded into three segments and the heads bend back and interact with each other and the tail3-7, creating a compact conformation in which ATPase activity, actin activation and filament assembly are all highly inhibited7,8. This switched-off structure appears to function as a key energy-conserving storage molecule in muscle and nonmuscle cells9-12, which can be activated to form functional filaments as needed13-but the mechanism of its inhibition is not understood. Here we have solved the structure of smooth muscle 10S myosin by cryo-electron microscopy with sufficient resolution to enable improved understanding of the function of the head and tail regions of the molecule and of the key intramolecular contacts that cause inhibition. Our results suggest an atomic model for the off state of myosin II, for its activation and unfolding by phosphorylation, and for understanding the clustering of disease-causing mutations near sites of intramolecular interaction.

Driving-Related Adverse Events in the Elderly Men: A Population-Based Prospective Cohort Study.

OBJECTIVE: This study estimated the incidence of driving-related adverse events and examined the association of cognitive function with the risk of future driving-related adverse events in the elderly Korean male population. METHODS: We analyzed 1,172 male drivers aged 60 years or older in the Korean Longitudinal Study on Cognitive Aging and Dementia (KLOSCAD). Using the data from Korean National Police Agency, we classified the participants into three groups: safe driving (drove for 2 years after baseline without a traffic accident or repeated violations), driving cessation (stopped driving), and risky driving (one or more traffic accidents or repeated violations). We estimated the incidences of driving cessation and risky driving, and examined the effect of cognitive function on their risks. RESULTS: The incidence of driving cessation and risky driving in the Korean male drivers aged 60 years or older was 19.3 and 69.9 per 1,000 person-years respectively and increased in the late 80s. Drivers with better baseline Word List Memory Test scores showed less risky driving (OR=0.94, p=0.039). CONCLUSION: Driving-related adverse events increased in late 80s, and better memory function was protective against these events.

Postoperative Intravenous Iron Supplementation Does Not Improve Hemoglobin Level and Transfusion Rate Following Staged Bilateral Total Knee Arthroplasty.

BACKGROUND: We determined whether postoperative intravenous (IV) iron supplementation could reduce transfusion rate in patients undergoing staged bilateral total knee arthroplasty (TKA). Furthermore, we examined whether hemoglobin (Hb) levels and iron profile differed between patients with and without postoperative IV iron supplementation. METHODS: This retrospective, comparative cohort study included 126 patients who underwent primary staged bilateral TKA during a single hospitalization. The second TKA was performed at a week's interval. Group iron (n = 65) received IV iron immediately after each surgery, while patients in group no-iron (n = 61) received no iron after surgery. Transfusion rate, change in Hb levels, and iron profile including serum iron, ferritin, total iron binding capacity, and transferrin saturation were evaluated preoperatively; on postoperative days 1, 2, and 4 after the first TKA; and postoperative days 1, 2, 4, and 7, 6 weeks, and 3 months after the second TKA. RESULTS: There were no significant differences in Hb levels and transfusion rate following staged bilateral TKA between patients with and without postoperative IV iron supplementation although serum iron profiles were improved in patients with IV iron supplementation. CONCLUSION: Postoperative IV iron supplementation immediately after acute blood loss caused by TKA was not effective in improving the transfusion rate. Therefore, surgeons should use protocols other than postoperative IV iron supplementation for reducing the transfusion rate in patients undergoing staged bilateral TKA in a single hospitalization. LEVEL OF EVIDENCE: III.

Is Thumb Proprioception Decreased in Patients With Trapeziometacarpal Joint Osteoarthritis?

Proprioception is thought to be essential for normal joint homeostasis, and its decreased function has been associated with an increased risk of joint diseases. However, only a few studies have been performed on the association between proprioceptive function in the trapeziometacarpal joint (TMCJ) and osteoarthritis. The purpose of this study was to compare TMCJ proprioceptive function in elderly women with radiographic TMCJ osteoarthritis relative to age-matched control women without osteoarthritis. We enrolled 19 women (mean age, 66 years) with symptomatic, radiographic Eaton and Littler grade 2, 3, and 4 TMCJ osteoarthritis and 19 age-matched control women without osteoarthritis. We evaluated thumb proprioception by using a joint-position reproduction test and compared the reposition error (RE) between the groups. We carried out a multivariate analysis for factors potentially associated with increased RE, such as age, body mass index, hand dominance, the presence of diabetes, pain level, and the presence of osteoarthritis. Also, a logistic regression analysis was performed for factors associated with the occurrence of TMCJ osteoarthritis. Patients with TMCJ osteoarthritis had greater RE than did the control patients in the joint-position reproduction test at 20°, 30°, and 40° of thumb palmar abduction. The multivariate analysis indicated that increased RE was associated with the presence of osteoarthritis, but not with the other factors assessed. The occurrence of TMCJ osteoarthritis was associated with increased RE at 20°, 30°, and 40° of thumb palmar abduction. This study showed that decreased proprioceptive function was associated with the presence of osteoarthritis in the TMCJ, although the causality remains unknown. Further studies on the role of proprioception in the pathogenesis of TMCJ osteoarthritis and the potential role of its training for disease prevention or treatment are required.

The myosin interacting-heads motif present in live tarantula muscle explains tetanic and posttetanic phosphorylation mechanisms.

Striated muscle contraction involves sliding of actin thin filaments along myosin thick filaments, controlled by calcium through thin filament activation. In relaxed muscle, the two heads of myosin interact with each other on the filament surface to form the interacting-heads motif (IHM). A key question is how both heads are released from the surface to approach actin and produce force. We used time-resolved synchrotron X-ray diffraction to study tarantula muscle before and after tetani. The patterns showed that the IHM is present in live relaxed muscle. Tetanic contraction produced only a very small backbone elongation, implying that mechanosensing-proposed in vertebrate muscle-is not of primary importance in tarantula. Rather, thick filament activation results from increases in myosin phosphorylation that release a fraction of heads to produce force, with the remainder staying in the ordered IHM configuration. After the tetanus, the released heads slowly recover toward the resting, helically ordered state. During this time the released heads remain close to actin and can quickly rebind, enhancing the force produced by posttetanic twitches, structurally explaining posttetanic potentiation. Taken together, these results suggest that, in addition to stretch activation in insects, two other mechanisms for thick filament activation have evolved to disrupt the interactions that establish the relaxed helices of IHMs: one in invertebrates, by either regulatory light-chain phosphorylation (as in arthropods) or Ca2+-binding (in mollusks, lacking phosphorylation), and another in vertebrates, by mechanosensing.

A retrospective comparative study of infection control rate and clinical outcome between open debridement using antibiotic-impregnated cement beads and a two-stage revision in acute periprosthetic knee joint infection.

The aim of this study was to determine whether the infection control rate of a modified debridement, antibiotics, and implant retention (DAIR) protocol (DAIR with antibiotic-impregnated cement beads) is comparable to that of 2-stage revision for acute periprosthetic joint infection (PJI) after total knee arthroplasty (TKA). We also aimed to determine whether this modified DAIR technique produced better clinical results than those obtained using 2-stage revision in terms of functional outcome, range of motion (ROM), and patient satisfaction at 2 years after surgery.This retrospective comparative study included patients who underwent modified DAIR (7 patients, 9 knees) or 2-stage revision (8 patients, 9 knees) for acute PJI of the knee joint. Infection control rate, functional outcome measured using Western Ontario and McMaster Universities Arthritis Index (WOMAC) score, ROM and patient satisfaction were compared between the two groups.There was no difference in infection control rates between the modified DAIR and 2-stage revision groups (78% vs 78%, respectively). In contrast, surgical outcome in the modified DAIR group was tended to be better than 2-stage revision group, but it did not reach statistical significance. Median maximal range of flexion was 103° in the modified DAIR group and it was 90° in the 2-stage group (P = .191). In addition, the median WOMAC function score was 24 in the modified DAIR group and it was 30 in the 2-stage group (P = .076). Median patient satisfaction measured using visual analogue scale was 8 in the modified DAIR group and 5 in the 2-stage group (P = .069).The infection control rates of the modified DAIR protocol and 2-stage revision protocol were similar for the treatment of acute PJI of the knee joint. However, the modified DAIR protocol could not provide substantially increased functional outcomes and patient satisfaction compared to 2-stage revision. Therefore, the modified DAIR technique should be considered to be of limited use in patients with high surgical morbidity.

Low Diastolic Blood Pressure and Cognitive Decline in Korean Elderly People: The Korean Longitudinal Study on Cognitive Aging and Dementia.

OBJECTIVE: Cardiovascular diseases are representative risk factors for the onset of cognitive decline. The purpose of this study was to confirm the relationship between diastolic blood pressure and cognitive function in elderly people in Korea. METHODS: Data from subjects who were enrolled in the prospective Korean Longitudinal Study on Cognitive Aging and Dementia were used in this study. Data from 701 subjects whose diastolic blood pressure range did not change (≤79 mm Hg or ≥80 mm Hg) over 2 years were analyzed. To analyze the differences in cognitive function between the groups at the 2-year follow-up, an analysis of covariance was performed with covariates, which were significantly different between the two groups, and the baseline cognitive function. RESULTS: Significant differences were observed between the two groups, and the mean scores on the constructional praxis (η2=0.010) and word list recall tests (η2=0.018) in the diastolic blood pressure ≥80 mm Hg group were higher than those in the diastolic blood pressure ≤79 mm Hg group at the 2-year follow-up. CONCLUSION: These results indicate that maintaining a DBP below 79 mm Hg presents a greater risk of cognitive decline in Korean elderly people.

Different Strategies in Making Transseptal Portal for the Different Purposes.

The purpose of this study was to find the most suitable and safe position of the transseptal portal in anatomic anterior cruciate ligament (ACL) and posterior cruciate ligament (PCL) reconstructions. The hypothesis of this study was that area and position of the transseptal portal are different between ACL and PCL reconstructions for the observation of native footprint. A matched-pair comparison study was conducted on the arthroscopic images of 100 consecutive patients who underwent ACL reconstruction and 50 consecutive patients who underwent PCL reconstruction. The transseptum was divided into six compartments. The opened compartments for each surgery were then evaluated to find which anatomical structures are well seen. The anterior middle and upper parts were necessary for the ACL reconstruction, whereas middle and lower portions of the anterior and posterior compartments were necessary for the PCL reconstruction. A larger opening was necessary for PCL reconstruction than that for ACL reconstruction. The ACL posterior one-third, ACL femoral attachment, and apex of the deep cartilage margin (DCM) were viewed in 100% of the patients during ACL reconstruction. The PCL posterior one-third, PCL tibial attachment, PCL fovea margin, and medial meniscus around posterior margin were always viewed during PCL reconstruction. The anterior part of the septum, from the middle to the upper portions of the transseptum, was necessary to be opened for visualization of the femoral footprint and DCM of the lateral femoral condyle during ACL reconstruction. The anterior and posterior parts of the septum, from the middle to the lower portions of the transseptum, were necessary for excellent visualization of the PCL tibial footprint during PCL reconstruction. These paths of the transseptal portal for each surgery will help surgeons obtain both anatomic footprint restoration and maximal remnant preservation through the most suitable and safe means. This is a case-control study; level of evidence is 3.

Lattice arrangement of myosin filaments correlates with fiber type in rat skeletal muscle.

The thick (myosin-containing) filaments of vertebrate skeletal muscle are arranged in a hexagonal lattice, interleaved with an array of thin (actin-containing) filaments with which they interact to produce contraction. X-ray diffraction and EM have shown that there are two types of thick filament lattice. In the simple lattice, all filaments have the same orientation about their long axis, while in the superlattice, nearest neighbors have rotations differing by 0° or 60°. Tetrapods (amphibians, reptiles, birds, and mammals) typically have only a superlattice, while the simple lattice is confined to fish. We have performed x-ray diffraction and electron microscopy of the soleus (SOL) and extensor digitorum longus (EDL) muscles of the rat and found that while the EDL has a superlattice as expected, the SOL has a simple lattice. The EDL and SOL of the rat are unusual in being essentially pure fast and slow muscles, respectively. The mixed fiber content of most tetrapod muscles and/or lattice disorder may explain why the simple lattice has not been apparent in these vertebrates before. This is supported by only weak simple lattice diffraction in the x-ray pattern of mouse SOL, which has a greater mix of fiber types than rat SOL. We conclude that the simple lattice might be common in tetrapods. The correlation between fiber type and filament lattice arrangement suggests that the lattice arrangement may contribute to the functional properties of a muscle.

The central role of the tail in switching off 10S myosin II activity.

Myosin II is a motor protein with two heads and an extended tail that plays an essential role in cell motility. Its active form is a polymer (myosin filament) that pulls on actin to generate motion. Its inactive form is a monomer with a compact structure (10S sedimentation coefficient), in which the tail is folded and the two heads interact with each other, inhibiting activity. This conformation is thought to function in cells as an energy-conserving form of the molecule suitable for storage as well as transport to sites of filament assembly. The mechanism of inhibition of the compact molecule is not fully understood. We have performed a 3-D reconstruction of negatively stained 10S myosin from smooth muscle in the inhibited state using single-particle analysis. The reconstruction reveals multiple interactions between the tail and the two heads that appear to trap ATP hydrolysis products, block actin binding, hinder head phosphorylation, and prevent filament formation. Blocking these essential features of myosin function could explain the high degree of inhibition of the folded form of myosin thought to underlie its energy-conserving function in cells. The reconstruction also suggests a mechanism for unfolding when myosin is activated by phosphorylation.

Anhedonia and Dysphoria Are Differentially Associated with the Risk of Dementia in the Cognitively Normal Elderly Individuals: A Prospective Cohort Study.

OBJECTIVE: We investigated the impact of depressed mood (dysphoria) and loss of interest or pleasure (anhedonia)on the risk of dementia in cognitively-normal elderly individuals. METHODS: This study included 2,685 cognitively-normal elderly individuals who completed the baseline and 4-year follow-up assessments of the Korean Longitudinal Study on Cognitive Aging and Dementia. We ascertained the presence of dysphoria and anhedonia using the Mini International Neuropsychiatric Inventory. We defined subjective cognitive decline as the presence of subjective cognitive complaints without objective cognitive impairments. We analyzed the association of dysphoria and anhedonia with the risk of cognitive disorders using multinomial logistic regression analysis adjusted for age, sex, education, Cumulative Illness Rating Scale score, Apolipoprotein E genotype, and neuropsychological test performance. RESULTS: During the 4-year follow-up period, anhedonia was associated with an approximately twofold higher risk of mild cognitive impairment (OR=2.09, 95% CI=1.20-3.64, p=0.008) and fivefold higher risk of dementia (OR=5.07, 95% CI=1.44-17.92, p=0.012) but was not associated with the risk of subjective cognitive decline. In contrast, dysphoria was associated with an approximately twofold higher risk of subjective cognitive decline (OR=2.06, 95% CI=1.33-3.19, p=0.001) and 1.7-fold higher risk of mild cognitive impairment (OR=1.75, 95% CI=1.00-3.05, p=0.048) but was not associated with the risk of dementia. CONCLUSION: Anhedonia, but not dysphoria, is a risk factor of dementia in cognitively-normal elderly individuals.

Normal-But-Low Serum Folate Levels and the Risks for Cognitive Impairment.

OBJECTIVE: This study aimed to examine the association between normal-but-low folate levels and cognitive function in the elderly population using a prospective cohort study. METHODS: We analyzed 3,910 participants whose serum folate levels were within the normal reference range (1.5-16.9 ng/mL) at baseline evaluation in the population-based prospective cohort study named the "Korean Longitudinal Study on Cognitive Aging and Dementia." The association between baseline folate quartile categories and baseline cognitive disorders [mild cognitive impairment (MCI) or dementia] was examined using binary logistic regression analysis adjusting for confounding variables. The risks of incident MCI and dementia associated with the decline of serum folate level during a 4-year follow-up period were examined using multinomial logistic regression analysis. RESULTS: The lowest quartile group of serum folate (≥1.5, ≤5.9 ng/mL) showed a higher risk of cognitive disorders than did the highest quartile group at baseline evaluation (odds ratio 1.314, p=0.012). Over the 4 years of follow-up, the risk of incident dementia was 2.364 times higher among subjects whose serum folate levels declined from the 2nd-4th quartile group to the 1st quartile than among those for whom it did not (p=0.031). CONCLUSION: Normal-but-low serum folate levels were associated with the risk of cognitive disorders in the elderly population, and a decline to normal-but-low serum folate levels was associated with incident dementia. Maintaining serum folate concentration above 5.9 ng/mL may be beneficial for cognitive status.

Altered C10 domain in cardiac myosin binding protein-C results in hypertrophic cardiomyopathy.

AIMS: A 25-base pair deletion in the cardiac myosin binding protein-C (cMyBP-C) gene (MYBPC3), proposed to skip exon 33, modifies the C10 domain (cMyBP-CΔC10mut) and is associated with hypertrophic cardiomyopathy (HCM) and heart failure, affecting approximately 100 million South Asians. However, the molecular mechanisms underlying the pathogenicity of cMyBP-CΔC10mutin vivo are unknown. We hypothesized that expression of cMyBP-CΔC10mut exerts a poison polypeptide effect leading to improper assembly of cardiac sarcomeres and the development of HCM. METHODS AND RESULTS: To determine whether expression of cMyBP-CΔC10mut is sufficient to cause HCM and contractile dysfunction in vivo, we generated transgenic (TG) mice having cardiac-specific protein expression of cMyBP-CΔC10mut at approximately half the level of endogenous cMyBP-C. At 12 weeks of age, significant hypertrophy was observed in TG mice expressing cMyBP-CΔC10mut (heart weight/body weight ratio: 4.43 ± 0.11 mg/g non-transgenic (NTG) vs. 5.34 ± 0.25 mg/g cMyBP-CΔC10mut, P < 0.05). Furthermore, haematoxylin and eosin, Masson's trichrome staining, as well as second-harmonic generation imaging revealed the presence of significant fibrosis and a greater relative nuclear area in cMyBP-CΔC10mut hearts compared with NTG controls. M-mode echocardiography analysis revealed hypercontractile hearts (EF: 53.4%±2.9% NTG vs. 66.4% ± 4.7% cMyBP-CΔC10mut; P < 0.05) and early diastolic dysfunction (E/E': 28.7 ± 3.7 NTG vs. 46.3 ± 8.4 cMyBP-CΔC10mut; P < 0.05), indicating the presence of an HCM phenotype. To assess whether these changes manifested at the myofilament level, contractile function of single skinned cardiomyocytes was measured. Preserved maximum force generation and increased Ca2+-sensitivity of force generation were observed in cardiomyocytes from cMyBP-CΔC10mut mice compared with NTG controls (EC50: 3.6 ± 0.02 µM NTG vs. 2.90 ± 0.01 µM cMyBP-CΔC10mut; P < 0.0001). CONCLUSION: Expression of cMyBP-C protein with a modified C10 domain is sufficient to cause contractile dysfunction and HCM in vivo.