Electrogram characteristics of the coronary sinus in cases requiring epicardial ablation within the coronary sinus for creating a conduction block at the left lateral mitral isthmus

Purpose

We aimed to evaluate the late clinical outcomes of percutaneous LAA closure in patients with atrial fibrillation (AF) and contraindication to oral anticoagulation.

Methods

Consecutive AF patients with contraindications to oral anticoagulation who underwent successful LAA closure between December 2008 and March 2013 at four centers were included.

Results

A total of 101 patients (median age 76 [IQR 69–80] years, 48% women, mean CHA₂DS₂-VASc 5?±?2; HAS-BLED 4?±?1) were included. Eighty-six (85.1%) patients received an Amplatzer Cardiac Plug/Amulet device and 15 (14.9%) patients a Watchman device. The mean follow-up period was 4?±?1 years. During 358.6 patient-years of follow-up, 7 (6.9%) patients suffered a major stroke (2 cases per 100 person-years; expected rate: 6.2 cases per 100 person-years), and 20 (19.8%) patients experienced at least one episode of major bleeding (6.4 cases per 100 person-years; expected rate: 9.0 cases per 100 person-years). There were no cases of late adverse events related to the device. A total of 34 (33.7%) patients died during follow-up (9.5 cases per 100 person-years). Older age, male sex, low ejection fraction, and chronic kidney disease were identified as predictive factors of late mortality.

Conclusions

Percutaneous LAA closure is safe and effective in the long term in patients with AF with contraindications to anticoagulation. However, a high long-term mortality rate was observed in this high-risk population. Comprehensive patient assessment prior to undergoing LAA closure should identify patients in whose comorbidities limit their overall prognosis.

     

Structural views of the ligand-binding cores of a metabotropic glutamate receptor complexed with an antagonist and both glutamate and Gd3+

Crystal structures of the extracellular ligand-binding region of the metabotropic glutamate receptor, complexed with an antagonist, (S)-(alpha)-methyl-4-carboxyphenylglycine, and with both glutamate and Gd3+ ion, have been determined by x-ray crystallographic analyses. The structure of the complex with the antagonist is similar to that of the unliganded resting dimer. The antagonist wedges the protomer to maintain an inactive open form. The glutamate/Gd3+ complex is an exact 2-fold symmetric dimer, where each bi-lobed protomer adopts the closed conformation. The surface of the C-terminal domain contains an acidic patch, whose negative charges are alleviated by the metal cation to stabilize the active dimeric structure. The structural comparison between the active and resting dimers suggests that glutamate binding tends to induce domain closing and a small shift of a helix in the dimer interface. Furthermore, an interprotomer contact including the acidic patch inhibited dimer formation by the two open protomers in the active state. These findings provide a structural basis to describe the link between ligand binding and the dimer interface.     

Protein kinase A inhibits a consolidated form of memory in Drosophila

Increasing activity of the cAMP/protein kinase A (PKA) pathway has often been proposed as an approach to improve memory in various organisms. However, here we demonstrate that single-point mutations, which decrease PKA activity, dramatically improve aversive olfactory memory in Drosophila. These mutations do not affect formation of early memory phases or of protein synthesis-dependent long-term memory but do cause a significant increase in a specific consolidated form of memory, anesthesia-resistant memory. Significantly, heterozygotes of null mutations in PKA are sufficient to cause this memory increase. Expressing a PKA transgene in the mushroom bodies, brain structures critical for memory formation in Drosophila, reduces memory back to wild-type levels. These results indicate that although PKA is critical for formation of several memory phases, it also functions to inhibit at least one memory phase.     

Attractant binding alters arrangement of chemoreceptor dimers within its cluster at a cell pole

Many sensory systems involve multiple steps of signal amplification to produce a significant response. One such mechanism may be the clustering of transmembrane receptors. In bacterial chemotaxis, where a stoichiometric His-Asp phosphorelay from the kinase CheA to the response regulator CheY plays a central role, the chemoreceptors (methyl-accepting chemotaxis proteins) cluster together with CheA and the adaptor CheW, at a pole of a rod-shaped cell. This clustering led to a proposal that signal amplification occurs through an interaction between chemoreceptor homodimers. Here, by using in vivo disulfide crosslinking assays, we examined an interdimer interaction of the aspartate chemoreceptor (Tar). Two cysteine residues were introduced into Tar: one at the subunit interface and the other at the external surface of the dimer. Crosslinked dimers and higher oligomers (especially a deduced hexamer) were detected and their abundance depended on CheA and CheW. The ligand aspartate significantly reduced the amounts of higher oligomers but did not affect the polar localization of Tar-GFP. Thus, the binding of aspartate alters the rate of collisions between Tar dimers in assembled signaling complexes, most likely due to a change in the relative positions or trajectories of the dimers. These collisions could occur within a trimer-ofdimers predicted by crystallography, or between such trimers. These results are consistent with the proposal that the interaction of chemoreceptor dimers is involved in signal transduction.     

Clinical characteristics of anti-glucose-6-phosphate isomerase antibody-positive Japanese patients with rheumatoid arthritis

Anti-glucose-6-phosphate isomerase (GPI) antibodies (Abs) are known to be arthritogenic in mice. These Abs are elevated in several forms of arthritic condition in humans, although their prevalence in rheumatoid arthritis (RA) patients is still in debate. Some RA patients have increased levels of anti-GPI Abs, but their clinical manifestation and relevance to other Abs are not clearly elucidated. The aims of this study were to explore the clinical and hematological characteristics of RA with anti-GPI Abs, and to compare their prevalence in RA patients, systemic lupus erythematosus (SLE) patients, and healthy subjects (HS) in a Japanese population. Anti-GPI Abs were positive in 16 patients with RA (12%, n = 137), in 10 patients with SLE (8%, n = 131), and in 6 HS (4%, n = 139). C-reactive protein (CRP), immunoglobulin G, and the antinuclear antibody titer were higher in anti-GPI-positive patients than in those who were negative (P = 0.049, P = 0.0003, and P = 0.002, respectively). Moreover, the positivity of anti-GPI Abs was correlated with CRP more than with rheumatoid factor in RA patients. It is unclear whether anti-GPI Abs can predict the progress of disease, but the prevalence of these Abs was higher in active RA patients with severe arthritis, suggesting that anti-GPI Abs may be related to the pathogenesis of severe forms of arthritis.     

Familial pseudohyperkalemia: a rare cause of hyperkalemia

A previously healthy 19-year-old girl was admitted to our hospital because of hyperkalemia. Pseudohyperkalemia was diagnosed because there was a marked difference between levels of serum and plasma potassium. Her plasma potassium level was markedly increased after 6-hour in vitro incubation of blood at room temperature, suggesting excessive potassium release from red blood cells without coagulation. The plasma potassium levels of the patient and her father were markedly elevated in blood specimens incubated in vitro at 4 degrees C, but not at 37 degrees C. These data indicated pseudohyperkalemia syndrome caused by abnormal leakage of potassium from red blood cells at the lower temperatures.     

Epimorphin expression and stellate cell status in mouse liver injury.

Epimorphin, a mesenchymal morphogenic protein expressed by hepatic stellate cells, is considered important to liver morphogenesis in both healthy and pathologic conditions. However, the stellate cell phenotype, quiescent versus activated, that expresses epimorphin is unknown. We studied the relationship between epimorphin expression and stellate cell status in carbon tetrachloride-induced acute and chronic injury to mouse liver and in mouse liver regeneration following 70% partial hepatectomy. Epimorphin-positive cells in sinusoids expressed desmin, indicating that they are stellate cells. Epimorphin-positive cells were more numerous and larger in pericentral than periportal sinusoids in normal liver. In early-phase acute liver injury and liver regeneration, epimorphin expression transiently decreased while alphaSMA-positive stellate cells increased. In the recovery phase of acute and chronic injury as well as the late phase of liver regeneration, epimorphin expression was strikingly enhanced while alphaSMA-positive stellate cells decreased. This expression pattern was seen in both Balb/c and C57BL6 mouse strains irrespective of their differences in response to the hepatotoxin. In conclusion, stellate cells express epimorphin in their quiescent state and in the recovery phase, respectively associated with maintenance and reconstruction of microscopic liver structure.     

Delayed diagnosis of ankylosing spondylitis in a Japanese population

Objectives: This study was conducted to evaluate the period from symptom onset to diagnosis of ankylosing spondylitis (AS) in Japanese patients and to examine possible reasons for delayed diagnosis.

Methods: Seventy-two consecutive patients with AS were studied. Diagnostic delay was defined as the gap between the first spondyloarthropathic symptom and diagnosis of AS according to the modified New York criteria.

Results: The mean patient ages at disease onset and diagnosis were 25.6?±?11.3 and 33.3?±?13.2 years old, respectively, resulting in diagnostic delay of 6.7 years. The number of medical institutions to which patients were referred before diagnosis was 2.4, and orthopedic surgeons were most commonly visited (62%). Non-specific low back pain or lumbar spondylitis (33%) and degenerative arthritis (28%) were the primary diagnoses preceding that of AS. Absence of articular symptoms significantly correlated with diagnostic delay. The patients with disease onset on year 2000 or later had significantly shorter periods until diagnosis than those before 2000 (3.6 vs. 7.5 years).

Conclusions: The present study showed a marked diagnostic delay among Japanese patients with AS. Although it has been improved, continuing medical education focusing on inflammatory back pain in adolescent is required for early diagnosis of AS.     

Two cases of systemic lupus erythematosus complicated with colonic ulcers

We report two cases of systemic lupus erythematosus (SLE) complicated with colonic ulcerations. One patient was successfully cured by steroid therapy, while the other did not respond to steroid but oral mesalazine was effective. Systemic lupus erythematosus is frequently accompanied by gastrointestinal symptoms, but colonic lesions are quite rare, and the regular treatment is not fixed yet. The high-dose steroidal regimen may be effective for microvasculitis, although it may increase the risk of perforated ulcer of the intestinal tract, which is a life-threatening complication. Further analysis of its outcomes, and establishment of the regular guideline for its treatment are expected.