Lipoprotein glomerulopathy: Significance of lipoprotein and ultrastructural features

Lipoprotein glomerulopathy: Significance of lipoprotein and ultrastructural features.BackgroundLipoprotein glomerulopathy (LPG) is a unique disease characterized by intraglomerular lipoprotein thrombi and type III hyperlipoproteinemia. Recently, we have demonstrated that LPG is associated with inherited apolipoprotein E (apoE) variants including apoE Sendai. On the other hand, electron microscopy shows that intraglomerular lipoprotein thrombi consist of lipid granules of various sizes. To elucidate the relationship between the peculiar histology and abnormal lipid metabolism related to apoE Sendai, we studied lipoprotein profiles and ultrastructural features.MethodsThe subjects were 11 patients with LPG. Four patients were nephrotic, and two others became nephrotic within six months following the biopsy. Eight patients underwent apoE gene analysis and showed apoE Sendai. The other three were presumed to have apoE Sendai because this mutation was demonstrated in their kindreds. Under electron microscopy, diameters of more than 1000 lipid granules were measured in several glomeruli, and a mean value was calculated in each case. Lipoprotein profiles were analyzed by the ultracentrifugation methods.ResultsThe mean diameter of intraglomerular lipid granules correlated inversely with the levels of plasma triglyceride (TG; rs = -0.73, P < 0.05), TG (rs = -0.77, P < 0.01) and cholesterol (Chol; rs = -0.75, P < 0.05) in very low-density lipoprotein (VLDL) fraction and TG in high-density lipoprotein (HDL) fraction (rs = -0.75, P < 0.05). The inverse correlation was also seen between the mean lipid diameter and TG/Chol ratios in whole plasma (rs = -0.80, P < 0.01) and in HDL (rs = -0.80, P < 0.01). In addition, the cases showing smaller lipid granules and higher TG/Chol ratios in plasma and in HDL were nephrotic or became nephrotic within six months.ConclusionThese results suggest that the size of lipid granules in LPG may become smaller under the influence of hypertriglyceridemia and particularly elevated plasma VLDL and HDL-TG, which may lead to heavy proteinuria

Long-term observation of fibrillation cycle length in patients under angiotensin II receptor blocker therapy for chronic atrial fibrillation

AbstractIntroductionThe long-term effect of angiotensin II receptor blockers (ARBs) on atrial fibrillation (AF) is unclear. In this study, we evaluated the change in the fibrillation cycle length (FCL) in patients under long-term ARB therapy for chronic AF.Methods and resultsThe study population consisted of 25 chronic AF patients who were prescribed the same medication for more than 6 years and in whom specific ECG recording for FCL evaluation could be performed before and after the 6-year observation period. The patients were divided into 2 groups: those with and without ARB (ARB group and non-ARB group and n=15 and 10, respectively). FCL was calculated by the spectral analysis of the fibrillation waves in the surface ECG. There was no significant difference in the clinical characteristics between the 2 groups. In the ARB group, the mean FCL was prolonged from 154±20ms to 187±37ms (p=0.005), whereas it remained unchanged in the non-ARB group (150±12ms vs. 149±10ms). In the comparison between patients with and those without FCL prolongation (>30ms; n=6 and 19, respectively), a significant difference was observed only in those prescribed ARBs.ConclusionIn cases of chronic AF, FCL might be prolonged under long-term ARB treatment

Five Amino Acid Residues Responsible for the High Stability of Hydrogenobacter thermophilus Cytochrome c552

Five amino acid residues responsible for extreme stability have been identified in cytochrome c552 (HT c552) from a thermophilic bacterium, Hydrogenobacter thermophilus. The five residues, which are spatially distributed in three regions of HT c552, were replaced with the corresponding residues in the homologous but less stable cytochrome c551 (PA c551) from Pseudomonas aeruginosa. The quintuple HT c552 variant (A7F/M13V/Y34F/Y43E/I78V) showed the same stability against guanidine hydrochloride denaturation as that of PA c551, suggesting that the five residues in HT c552 necessarily and sufficiently contribute to the overall stability. In the three HT c552 variants carrying mutations in each of the three regions, the Y34F/Y43E mutations resulted in the greatest destabilization, by –13.3 kJ mol–1, followed by A7F/M13V (–3.3 kJ mol–1) and then I78V (–1.5 kJ mol–1). The order of destabilization in HT c552 was the same as that of stabilization in PA c551 with reverse mutations such as F34Y/E43Y, F7A/V13M, and V78I (13.4, 10.3, and 0.3 kJ mol–1, respectively). The results of guanidine hydrochloride denaturation were consistent with those of thermal denaturation for the same variants. The present study established a method for reciprocal mutation analysis. The effects of side-chain contacts were experimentally evaluated by swapping the residues between the two homologous proteins that differ in stability. A comparative study of the two proteins was a useful tool for assessing the amino acid contribution to the overall stability.This work was supported in part by grants from Hiroshima University, the Noda Institute for Scientific Research, and the Japanese Ministry of Education, Science and Culture (grants-in-aid for Scientific Research on Priority Areas)

Prevalence of the metabolic syndrome in elderly and middle-aged Japanese

AbstractBackground/PurposeDiagnosis and management of the metabolic syndrome (MetS) are beneficial for successful aging. In spite of several criteria for MetS, there is little information on cardiometabolic risk clustering in elderly Japanese. The purpose of this study was, therefore, to determine the relationship between age-associated changes in obesity and metabolic components in the Japanese.MethodsWe analyzed data from the nationwide survey conducted in 2000. Using Adult Treatment Panel III (ATP III) and Japanese diagnostic criteria for MetS, we analyzed 2366 people aged from 40 to 79 years (men, 1425 and women, 941) from the total participants.ResultsThe prevalence of MetS was almost three fold higher by modified ATP III, International Diabetes Federation, and Japanese criteria, in elderly women than in middle-aged women, whereas no difference was found between middle-aged and elderly men by the three criteria. A marked increase in the prevalence of MetS was found by modified ATP III and International Diabetes Federation criteria compared with that by the Japanese criteria in women. Among the risk factors, the prevalence of central obesity and dyslipidemia increased only in women and that of high fasting glucose and high blood pressure increased in both genders with aging. Among the MetS subjects who fulfilled the modified ATP III criteria, more clustering of risk was observed in elderly than in middle-aged subjects, especially in women. Blood pressure increased and triglyceride decreased in both genders, and non-high-density-lipoprotein cholesterol decreased in elderly men. The prevalence of dyslipidemia decreased in elderly men.ConclusionAging is an important factor that affects the metabolic abnormality, and aging of the population would lead to increase in the prevalence of MetS. Therefore, the development of better approaches to the prevention and management of MetS is necessary for successful aging in our society

Beat-to-beat alterations of acoustic intensity and frequency at the maximum power of heart sounds are associated with NT-proBNP levels

BackgroundAuscultatory features of heart sounds (HS) in patients with heart failure (HF) have been studied intensively. Recent developments in digital and electrical devices for auscultation provided easy listening chances to recognize peculiar sounds related to diastolic HS such as S3 or S4. This study aimed to quantitatively assess HS by acoustic measures of intensity (dB) and audio frequency (Hz).MethodsForty consecutive patients aged between 46 and 87 years (mean age, 74 years) with chronic cardiovascular disease (CVD) were enrolled in the present study after providing written informed consent during their visits to the Kitasato University Outpatient Clinic. HS were recorded at the fourth intercostal space along the left sternal border using a highly sensitive digital device. Two consecutive heartbeats were quantified on sound intensity (dB) and audio frequency (Hz) at the peak power of each spectrogram of S1–S4 using audio editing and recording application software. The participants were classified into three groups, namely, the absence of HF (n = 27), HF (n = 8), and high-risk HF (n = 5), based on the levels of NT-proBNP &lt; 300, ≥300, and ≥900 pg/ml, respectively, and also the levels of ejection fraction (EF), such as preserved EF (n = 22), mildly reduced EF (n = 12), and reduced EF (n = 6).ResultsThe intensities of four components of HS (S1–S4) decreased linearly (p &lt; 0.02–0.001) with levels of body mass index (BMI) (range, 16.2–33.0 kg/m2). Differences in S1 intensity (ΔS1) and its frequency (ΔfS1) between two consecutive beats were non-audible level and were larger in patients with HF than those in patients without HF (ΔS1, r = 0.356, p = 0.024; ΔfS1, r = 0.356, p = 0.024). The cutoff values of ΔS1 and ΔfS1 for discriminating the presence of high-risk HF were 4.0 dB and 5.0 Hz, respectively.ConclusionsDespite significant attenuations of all four components of HS by BMI, beat-to-beat alterations of both intensity and frequency of S1 were associated with the severity of HF. Acoustic quantification of HS enabled analyses of sounds below the audible level, suggesting that sound analysis might provide an early sign of HF

p90RSK Targets the ERK5-CHIP Ubiquitin E3 Ligase Activity in Diabetic Hearts and Promotes Cardiac Apoptosis and Dysfunction

RATIONALE: Cardiomyocyte apoptosis is one of the key events in the development and progression of heart failure, and a crucial role for ICER (inducible cAMP early repressor) in this process has been previously reported. ERK5 is known to inhibit cardiac apoptosis after myocardial infarction (MI), especially in hyperglycemic states, via association with CHIP ubiquitin (Ub) ligase and subsequent up-regulation of CHIP ligase activity, which induces ICER ubiquitination and subsequent protein degradation. The regulatory mechanism governing ERK5/CHIP interaction is unknown. OBJECTIVE: We previously demonstrated increased p90RSK activation in the diabetic heart. As a logical extension of this work, we now investigate whether p90RSK activation inhibits ERK5-mediated CHIP activation, and subsequently increases ICER levels and apoptosis. METHODS AND RESULTS: p90RSK activation inhibits ERK5/CHIP association and CHIP Ub ligase activity. p90RSK and CHIP share a common binding site in the ERK5 C-terminal domain (aa571-807). Overexpression of either p90RSK or an ERK5 fragment (aa571-807) inhibits ERK5/CHIP association, suggesting that p90RSK and CHIP competes for ERK5 binding and that p90RSK activation is critical for inhibiting ERK5/CHIP interaction. We also identified ERK5-S496 as being directly phosphorylated by p90RSK, and demonstrated that an ERK5-S496A mutant significantly impairs Angiotensin II-mediated inhibition of CHIP activity and subsequent increase in ICER levels. In vivo, either cardiac specific depletion of ERK5 or overexpression of p90RSK inhibits CHIP activity and accelerates cardiac apoptosis after MI--a phenomenon fully reversible by activating ERK5. CONCLUSION: These data suggest a role for p90RSK in inhibiting CHIP activity and promoting cardiac apoptosis through binding to and phosphorylation of ERK5-S496

Pregabalin for Refractory Radicular Leg Pain due to Lumbar Spinal Stenosis: A Preliminary Prospective Study

We investigated the efficacy of pregabalin (PGB) for neuropathic leg pain in lumbar spinal stenosis (LSS) patients with disturbed activities of daily living (ADL)/quality of life (QOL) in a prospective observational study. Subjects were a total of 104 LSS patients with neuropathic pain (NeP) in leg and neurological intermittent claudication (IMC) refractory to nonsteroidal anti-inflammatory drugs (NSAIDs) for at least a month. NeP was identified using screening tool, Pain DETECT questionnaire. Visual analog scale (VAS) scores and responses to the Japanese Orthopaedic Association Back Pain Evaluation Questionnaire (JOABPEQ) were assessed before and 6 weeks after PGB treatment initiation. Changes in IMC distance and adverse events were also recorded. PGB significantly improved their VAS scores for pain and sleep quality (P<0.001). With respect to JOABPEQ, significant improvements were observed with regard to the following dimensions: pain-related disorders (P<0.01), lumbar spine dysfunction (P=0.031), gait disturbance (P=0.028), and psychological disorders (P=0.014). The IMC distance showed an improvement tendency after PGB treatment, albeit with no significance (P=0.063). Minor adverse events such as dizziness were observed. PGB can be effective for neuropathic leg pain refractory to NSAIDs in LSS patients, resulting in not only pain control but also improving lower back pain-related ADL/QOL scores