Long-term follow-up of atrioventricular delay optimization in patients with biventricular pacing.

BACKGROUND: Atrioventricular (AV) delay optimization may be important in patients with biventricular pacing and the optimal AV delay can be predicted using Doppler echocardiography and the formula: optimal AV delay = AV delay-the interval between the end of A wave and complete closure of the mitral valve when the AV delay is set at slightly prolonged AV delay. METHODS AND RESULTS: In the present study the efficacy of this method was evaluated in 5 patients (67.4+/-8.0 (SD) years old) with biventricular pacing. Cardiac output (CO) and diastolic filling time were measured by Doppler echocardiography. When the AV delay was set at the predicted optimal AV delay -25 ms, the predicted optimal AV delay (133+/-66 ms) and predicted optimal AV delay + 25 ms, the respective CO were 4.5+/-0.9, 5.3+/-1.0, 4.8+/-1.0 L/min (p<0.05, ANOVA) and the diastolic filling times were 364 +/-100, 373+/-105, 335+/-84 ms (p<0.05, ANOVA). Congestive heart failure improved from New York Heart Association class 3.6+/-0.5 to 1.4+/-0.5 (p<0.001). CONCLUSIONS: AV delay optimization is important in patients with biventricular pacing and can be easily achieved by the new method.     

Multi-Step Regulation of Interferon Induction by Hepatitis C Virus

Acute hepatitis C virus (HCV) infection evokes several distinct innate immune responses in host, but the virus usually propagates by circumventing these responses. Although a replication intermediate double-stranded RNA is produced in infected cells, type I interferon (IFN) induction and immediate cell death are largely blocked in infected cells. In vitro studies suggested that type I and III IFNs are mainly produced in HCV-infected hepatocytes if the MAVS pathway is functional, and dysfunction of this pathway may lead to cellular permissiveness to HCV replication and production. Cellular immunity, including natural killer cell activation and antigen-specific CD8 T-cell proliferation, occurs following innate immune activation in response to HCV, but is often ineffective for eradication of HCV. Constitutive dsRNA stimulation differs in output from type I IFN therapy, which has been an authentic therapy for patients with HCV. Host innate immune responses to HCV RNA/proteins may be associated with progressive hepatic fibrosis and carcinogenesis once persistent HCV infection is established in opposition to the IFN system. Hence, innate RNA sensing exerts pivotal functions against HCV genome replication and host pathogenesis through modulation of the IFN system. Molecules participating in the RIG-I and Toll-like receptor 3 pathways are the main targets for HCV, disabling the anti-viral functions of these IFN-inducing molecules. We discuss the mechanisms that abolish type I and type III IFN production in HCV-infected cells, which may contribute to understanding the mechanism of virus persistence and resistance to the IFN therapy.     

Early non-convulsive seizures are associated with the development of acute encephalopathy with biphasic seizures and late reduced diffusion

IntroductionChildren with either febrile seizure or acute encephalopathy exhibit seizures and/or impaired consciousness accompanied by fever of unknown etiology (SICF). Among children with SICF, we previously reported those who have refractory status epilepticus or prolonged neurological abnormalities with normal AST levels are at a high risk for the development of acute encephalopathy with biphasic seizures and late reduced diffusion (AESD), considered to be caused by excitotoxicity. Non-convulsive seizures (NCS) are common in critically ill children and cause excitotoxic neuronal injury. The aim of this study was to elucidate the prevalence of NCS in the acute phase of children at a high risk for developing AESD and the relationship between NCS in the acute phase and neurological outcomes.MethodsWe studied 137 children with SICF at a high risk for developing AESD and who underwent continuous electroencephalogram monitoring (cEEG) upon admission to a tertiary pediatric care center at Hyogo Prefectural Kobe Children’s Hospital between October 2007 and August 2018. Patient characteristics and outcomes were compared between patients with NCS and without NCS.ResultsOf the 137 children, NCS occurred in 30 children; the first NCS were detected in cEEG at the beginning in 63.3%, during the first hour in 90%, and within 12 h in 96.7%. Neurological sequelae were more common in NCS patients (20.0%) than in non-NCS patients (1.9%; p = 0.001). Five in 30 NCS patients (16.7%) and 3 in 107 non-NCS patients (2.8%) developed AESD (p = 0.013).ConclusionThe occurrence of NCS is associated with subsequent neurological sequelae, especially the development of AESD.     

Regional differences in facial skin blood flow responses to the cold pressor and static handgrip tests

We have previously reported the unique regional responses of facial skin blood flow (SkBF) to oral application of the basic tastes without simultaneous systemic circulatory changes. In the present study, we determined whether a systemic circulatory challenge due to sympathetic activation induces regional differences in facial SkBF by observing the responses in facial SkBF and blood pressure to a 2-min cold pressor test (CPT) and static handgrip exercise (HG) by right hand in 20 healthy subjects. The CPT significantly increased SkBF in the forehead, eyelid, cheek, upper lip and lower lip by 6 ± 2 to 8 ± 2  % (mean ± SEM) as compared to resting baseline, with a significant simultaneous increase (13 ± 2 %) in mean arterial pressure (MAP), whereas it significantly decreased the SkBF in the nose by 5 ± 2 %. The HG significantly increased SkBF in the forehead, cheek and lower lip by 6 ± 3 to 10 ± 3 %, with a significant simultaneous increase in MAP (13 ± 2 %), while it induced no significant change in the other regions. Increases in SkBF were greater in the right than left cheek during CPT. These results demonstrate that a systemic circulatory challenge via sympathetic activation elicits regional differences in the facial SkBF response.     

Mechanical properties of nerve roots and rami radiculares isolated from fresh pig spinal cords

No reports have described experiments designed to determine the strength characteristics of spinal nerve roots and rami radiculares for the purpose of explaining the complexity of symptoms of medullary cone lesions and cauda equina syndrome. In this study, to explain the pathogenesis of cauda equina syndrome, monoaxial tensile tests were performed to determine the strength characteristics of spinal nerve roots and rami radiculares, and analysis was conducted to evaluate the stress-strain relationship and strength characteristics. Using the same tensile test device, the nerve root and ramus radiculares isolated from the spinal cords of pigs were subjected to the tensile test and stress relaxation test at load strain rates of 0.1, 1, 10, and 100 s^-1 under identical settings. The tensile strength of the nerve root was not rate dependent, while the ramus radiculares tensile strength tended to decrease as the strain rate increased. These findings provide important insights into cauda equina symptoms, radiculopathy, and clinical symptoms of the medullary cone.     

Silent cerebral infarction in patients with type 2 diabetic nephropathy. Effects of antiplatelet drug dilazep dihydrochloride

BACKGROUND: To determine whether diabetic nephropathy is a risk factor for silent cerebral infarction and whether antiplatelet drug dilazep dihydrochloride decreases the occurrence of silent cerebral infarction in type 2 diabetes patients with microalbuminuria. METHODS: Two hundred four type 2 diabetes patients (124 men, 80 women; age, median 56 years, range 42-74 years) and 60 healthy age-matched subjects (no diabetes, normal renal function) were recruited for brain magnetic resonance imaging. The diabetes patients included 40 without nephropathy (group A), 42 with microalbuminuria (20-200 microg/min) (group B), 44 with macroalbuminuria (>200 microg/min) and normal renal function (blood creatinine <132.7 micromol/L) (group C), 33 with chronic renal failure but not undergoing haemodialysis (blood creatinine >132.7 micromol/L; mean creatinine 335.9 micromol/L) (group D) and 45 undergoing haemodialysis (duration; median 4 years, range 3-6 years) (group E). RESULTS: Silent cerebral infarction was found in 20, 29, 34, 45, 53 and 8% of group A, B, C, D, E and control patients respectively. The incidence of silent cerebral infarction was increased with diabetic nephropathy. Thirty group B patients with no silent cerebral infarction were divided into two groups: (B1) 15 treated with dilazep dihydrochloride and (B2) 15 not treated with dilazep dihydrochloride. Treatment continued for 24 months. The incidence of silent cerebral infarction was significantly lower in the dilazep-treated patients (6.7%) than in the untreated patients (33.3%) (p < 0.01). CONCLUSIONS: These data suggest that diabetic renal dysfunction increases the risk of silent cerebral infarction and that dilazep dihydrochloride prevents its onset in early type 2 diabetic nephropathy patients.     

Sphingosine 1-phosphate induces contraction of coronary artery smooth muscle cells via S1P2

OBJECTIVES: Sphingosine 1-phosphate (Sph-1-P), a bioactive lipid derived from activated platelets, may play an important role in coronary artery spasm and hence the pathogenesis of ischemic heart diseases, since we reported that a decrease in coronary blood flow was induced by this lysophospholipid in an in vivo canine heart model [Cardiovasc. Res. 46 (2000) 119]. In this study, metabolism related to and cellular responses elicited by Sph-1-P were examined in human coronary artery smooth muscle cells (CASMCs). METHODS AND RESULTS: [3H]Sphingosine (Sph), incorporated into CASMCs, was converted to [3H]Sph-1-P intracellularly, but its stimulation-dependent formation and extracellular release were not observed. Furthermore, the cell surface Sph-1-P receptors of S1P family (previously called EDG) were found to be expressed in CASMCs. Accordingly, Sph-1-P seems to act as an extracellular mediator in CASMCs. Consistent with Sph-1-P-elicited coronary vasoconstriction in vivo, Sph-1-P strongly induced CASMC contraction, which was inhibited by JTE-013, a newly-developed specific antagonist of S1P(2) (EDG-5). Furthermore, C3 exoenzyme or Y-27632 inhibited the CASMC contraction induced by Sph-1-P, indicating Rho involvement. Finally, exogenously-added [3H]Sph-1-P underwent a rapid degradation. Since lipid phosphate phosphatases, ectoenzymes capable of dephosphorylating Sph-1-P, were expressed in CASMCs, Sph-1-P may be dephosphorylated by the ectophosphatases. CONCLUSIONS: Sph-1-P, derived from platelets and dephosphorylated on the cell surface, may induce the contraction of coronary artery smooth muscle cells through the S1P(2)/Rho signaling.     

Cervical ossification of the posterior longitudinal ligament: Biomechanical analysis of the influence of static and dynamic factors

Objective

Cervical myelopathy due to ossification of the posterior longitudinal ligament (OPLL) is induced by static factors, dynamic factors, or a combination of both. We used a three-dimensional finite element method (3D-FEM) to analyze the stress distributions in the cervical spinal cord under static compression, dynamic compression, or a combination of both in the context of OPLL.

Methods

Experimental conditions were established for the 3D-FEM spinal cord, lamina, and hill-shaped OPLL. To simulate static compression of the spinal cord, anterior compression at 10, 20, and 30% of the anterior–posterior diameter of the spinal cord was applied by the OPLL. To simulate dynamic compression, the OPLL was rotated 5°, 10°, and 15° in the flexion direction. To simulate combined static and dynamic compression under 10 and 20% anterior static compression, the OPLL was rotated 5°, 10°, and 15° in the flexion direction.

Results

The stress distribution in the spinal cord increased following static and dynamic compression by cervical OPLL. However, the stress distribution did not increase throughout the entire spinal cord. For combined static and dynamic compression, the stress distribution increased as the static compression increased, even for a mild range of motion (ROM).

Conclusion

Symptoms may appear under static or dynamic compression only. However, under static compression, the stress distribution increases with the ROM of the responsible level and this makes it very likely that symptoms will worsen. We conclude that cervical OPLL myelopathy is induced by static factors, dynamic factors, and a combination of both.     

Assessment of regional wall motion using strain Doppler imaging during right ventricular bifocal pacing in a patient with severe congestive heart failure: a case report

A 79-year-old man presented with dilated cardiomyopathy and chronic atrial fibrillation. A DDD pacemaker was implanted due to sick sinus syndrome. His left ventricular ejection fraction was 23%. He was repeatedly admitted with congestive heart failure. Although cardiac resynchronization therapy was attempted, insertion of a pacing lead into the coronary sinus failed. Right ventricular bifocal pacing was done. The QRS width was shortened to 155 msec during bifocal pacing and 157 msec during right ventricular outflow pacing from 221 msec during right ventricular apical pacing. Heart failure was improved from New York Heart Association class III to II. Regional wall motion was assessed by strain of the myocardium. Bifocal pacing increased stroke volume due to improvement of longitudinal dyssynchrony of the septal and lateral walls. Bifocal pacing is effective for patients with severe congestive heart failure in whom biventricular pacing therapy has failed. Strain Doppler imaging is useful for the assessment of regional wall motion during cardiac pacing.     

Coexistence of phosphotyrosine-dependent and -independent interactions between Cbl and Bcr-Abl

Cbl is one of the major tyrosine-phosphorylated proteins in Bcr-Abl-expressing cells. A direct association between the SH2 domain of Bcr-Abl and tyrosine-phosphorylated Cbl has been demonstrated. The purpose of this study was to determine if and how unphosphorylated Cbl and Bcr-Abl may associate.Interactions between Cbl and Bcr-Abl were investigated in yeast two- and three-hybrid systems, gel overlay assays, and immunoprecipitates from mammalian cells expressing wild-type and the Y177F mutant of Bcr-Abl.No direct interaction between Bcr-Abl and unphosphorylated Cbl was observed. Bcr-Abl did, however, associate with Grb2, an adaptor protein that binds tyrosine 177 of Bcr-Abl. Additionally, Grb2 interacted with Cbl. In a yeast three-hybrid assay, Grb2 mediated an interaction between Cbl and Bcr-Abl that was dependent on a functional Grb2 binding site. This interaction was confirmed in vitro using purified proteins. In cells expressing Bcr-Abl with a mutation in the Grb2 binding site, binding of Cbl to Bcr-Abl was significantly reduced, but Cbl tyrosine phosphorylation was maintained. Imatinib treatment of these cells further reduced but did not abrogate Cbl binding, reflecting residual kinase activity.Multiple phosphotyrosine-dependent and -independent interactions stabilize the interaction between Cbl and Abl. Grb2 or another, yet unidentified, protein may mediate an initial interaction between Cbl and Bcr-Abl that is independent of Cbl tyrosine phosphorylation. Following this initial interaction, Cbl can then become tyrosine phosphorylated and interact with the SH2 domain of Bcr-Abl, further stabilizing the complex.