Disruption of autosomal recessive hypercholesterolemia gene shows different phenotype in vitro and in vivo

We previously characterized the patients with autosomal recessive hypercholesterolemia (ARH) as having severe hypercholesterolemia and retarded plasma low-density lipoprotein (LDL) clearance despite normal LDL receptor (LDLR) function in their cultured fibroblasts, and we identified a mutation in the ARH locus in these patients. ARH protein is an adaptor protein of the LDL and reportedly modulates its internalization. We developed ARH knockout mice (ARH-/-) to study the function of this protein. Plasma total cholesterol level was higher in ARH-/- mice than that in wild-type mice (ARH+/+), being attributed to a 6-fold increase of LDL, whereas plasma lipoprotein was normal in the heterozygotes (ARH+/-). Clearance of 125I-LDL from plasma was retarded in ARH-/- mice, as much as that found in LDLR-/- mice. Fluorescence activity of the intravenously injected 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI)-LDL was recovered in the cytosol of the hepatocytes of ARH+/+ mice, but not in those of ARH-/- or LDLR-/- mice. Also, less radioactivity was recovered in the liver of ARH-/- or LDLR-/- mice when [3H]cholesteryl oleyl ether (CE)-labeled LDL was injected. In contrast, uptakes of [3H]CE-labeled LDL, 125I-LDL, and DiI-LDL were all normal or slightly subnormal when the ARH-/- hepatocytes were cultured. We thus concluded that the function of the hepatic LDLR is impaired in the ARH-/- mice in vivo, despite its normal function in vitro. These findings were consistent with the observations with the ARH homozygous patients and suggested that certain cellular environmental factors modulate the requirement of ARH for the LDLR function.     

Relationship Between Motor Function,DTI, and Neurophysiological Parameters in Patients with Stroke in the Recovery Rehabilitation unit

ObjectivesWe investigated the relationship between pyramidal tract evaluation indexes (i.e., diffusion tensor imaging, transcranial magnetic stimulation (TMS)-induced motor-evoked potential (MEP), and central motor conduction time (CMCT) on admission to the recovery rehabilitation unit) and motor functions at discharge in patients with ischemic or hemorrhagic stroke.Materials and MethodsSeventeen patients were recruited (12 men; 57.9 ± 10.3 years). The mean fractional anisotropy (FA) values of the right and left posterior limbs of the internal capsule were estimated using a computer-automated method. We determined the ratios of FA values in the affected and unaffected hemispheres (rFA), TMS-induced MEP, and the ratios of CMCT in the affected and unaffected hemispheres (rCMCT) and examined their association with motor functions (Fugl–Meyer Assessment (FMA) and Action Research Arm Test (ARAT)) at discharge.ResultsHigher rFA values of the posterior limb of the internal capsule on admission to the recovery rehabilitation unit led to a better recovery of upper limb function (FMA: r = 0.78, p < 0.001; ARAT: r = 0.74, p = 0.001). Patients without MEP had poorer recovery of upper limb function than those with MEP (FMA: p < 0.001; ARAT: p = 0.001). The higher the rCMCT, the poorer the recovery of upper limb function (ARAT: r = ?0.93, p < 0.001). However, no association was observed between the pyramidal tract evaluation indexes and recovery of lower limb motor function.ConclusionsEvaluating the pyramidal tract is useful for predicting upper limb function prognosis, but not for lower limb function prognosis.     

The Maze-Making and Solving Technique for Coil Embolization of Large and Giant Aneurysms

BACKGROUND AND PURPOSE:Despite major progress in treating aneurysms by coil embolization, the complete occlusion of aneurysms of >10 mm in diameter (large/giant aneurysms) remains challenging. We present a novel endovascular treatment method for large and giant cerebral aneurysms called the “maze-making and solving” technique and compare the short-term follow-up results of this technique with those of conventional coil embolization.MATERIALS AND METHODS:Eight patients (65 ± 11.5 years of age, 7 women) with large/giant unruptured nonthrombosed cerebral aneurysm (mean largest aneurysm dimension, 19 ± 4.4 mm) were treated by the maze-making and solving technique, a combination of the double-catheter technique and various assisted techniques. The coil-packing attenuation, postoperative courses, and recurrence rate of this maze group were compared with 30 previous cases (conventional group, 65.4 ± 13.0 years of age; 22 women; mean largest aneurysm dimension, 13.4 ± 3.8 mm).RESULTS:Four maze group cases were Raymond class 1; and 4 were class 2 as indicated by immediate postsurgical angiography. No perioperative deaths or major strokes occurred. Mean packing attenuation of the maze group was significantly higher than that of the conventional group (37.4 ± 5.9% versus 26.2 ± 5.6%). Follow-up angiography performed at 11.3 ± 5.4 months revealed no recurrence in the maze group compared with 39.2% in the conventional group.CONCLUSIONS:The maze-making and solving technique achieves high coil-packing attenuation for efficient embolization of large and giant cerebral aneurysms with a low risk of recurrence.

Substantial progress in the endovascular treatment of cerebral aneurysms, such as balloon- and stent-assisted coil embolization, has resulted in the widespread use of these techniques with relatively high efficacy and safety. However, large and giant aneurysms remain difficult to treat by using assist techniques and bioactive coils,^1,2 possibly because the requisite coil-packing attenuation is often not achieved. We recently developed a “maze-making and solving” technique to occlude these large/giant aneurysms by achieving high packing attenuation. Here, we present the technical details of this procedure and compare the clinical outcomes and recurrence rates between large/giant aneurysm cases treated by the maze technique and matched cases treated by conventional coil embolization.     

Critical role of monocyte chemoattractant protein-1 receptor CCR2 on monocytes in hypertension-induced vascular inflammation and remodeling

Activated monocytes are present in the arterial walls of hypertensive patients and animals. Monocyte chemoattractant protein-1 (MCP-1), which controls monocyte function through its receptor (CCR2), is implicated in hypertensive inflammatory changes in the arterial wall. The role of CCR2 expression on monocytes in hypertension-induced vascular remodeling, however, has not been addressed. We hypothesized that CCR2 on monocytes is critical in hypertension-induced vascular inflammation and remodeling. Hypertension was induced by infusion of angiotensin II (Ang II) into wild-type mice, CCR2-deficient (CCR2-/-) mice, and bone marrow-transferred mice with a leukocyte-selective CCR2 deficiency (BMT-CCR2-/-). In wild-type mice, Ang II increased CCR2 intensity in circulating monocytes, which was prevented by an Ang II type-1 (AT1) receptor blocker or blunted in AT1 receptor-deficient mice. Enhanced CCR2 intensity on monocytes was observed in hypertensive patients and rats, and was reduced by treatment with the Ang II receptor blocker, supporting the clinical relevance of the observation in mice. In CCR2-/- and BMT-CCR2-/- mice, Ang II-induced vascular inflammation and vascular remodeling (aortic wall thickening and fibrosis) were blunted as compared with control mice. In contrast, Ang II-induced left ventricular hypertrophy developed in CCR2-/- and BMT-CCR2-/- mice. The present study suggests that CCR2 expression in monocytes has a critical role in vascular inflammation and remodeling in Ang II-induced hypertension, and possibly in other forms of hypertension.     

Influence of mild-to-moderate alcohol consumption on cardiovascular diseases in men from the general population

Background and methodsThere is controversy about the association between mild-to-moderate alcohol consumption and a reduced risk of cardiovascular diseases. The relationships between daily alcohol consumption and the incidence of acute myocardial infarction (MI) or ischemic stroke (IS) were examined in men in a community-based, prospective cohort study (n = 8014, age 40–80 years, mean age = 64.1 years). Alcohol consumption was categorized into 3 groups (A1, none or occasional; A2, ≤25 g/day; A3, >25 g/day as ethanol) at baseline.ResultsDuring the mean follow-up of 5.5 years, 53 MIs and 186 ISs occurred. On Cox regression analysis adjusted for age, hypertension, diabetes, dyslipidemia, smoking index, and body mass index (BMI), the hazard ratio (HR) for incident MI was significantly lower in the A2 group than in the A1 group (HR = 0.49, p = 0.043). The HR for incident MI in the A3 group tended to be lower than in the A1 group (HR = 0.53, p = 0.10). In obese subjects, while a significantly lower HR for incident MI in the A2 group was retained (HR = 0.29, p = 0.049), no significant difference in the HR of the A3 group compared with the A1 group was found. No significant differences were found in the IS-free curve among the 3 groups of alcohol consumption.ConclusionsAlcohol consumption may have a protective effect on the onset of MI but not on IS in the general population. A U-shaped relation between alcohol consumption and incident MI was found in obese subjects. An appropriate limit for daily alcohol consumption, depending on the risk of ischemic heart disease, may need to be established.     

A multi-centered epidemiological study evaluating the reliability of the treatment difficulty indices developed by the Japan Prosthodontic Society

BackgroundThe diagnostic assessment of the level of difficulty in treating patients who need prosthodontic care is useful to establish a medico-economically efficient system with primary care dentists and prosthodontic specialists.Materials and methodsA multi-axis assessment protocol was established using the newly established treatment difficulty indices. The protocol contains Axis I: oral physiological conditions (e.g., teeth damage and/or missing teeth); Axis II: general health and sociological conditions (e.g., medical disorders); Axis III: oral health-related quality of life (OHRQOL; e.g., oral health impact profile: OHIP); and Axis IV: psychological health (e.g., mood, anxiety, somatoform disorders). A preliminary study on the test–retest consistency of the protocol was conducted to check the levels of reliability of the indices prior to a large-scale, multi-center cohort study on the validity of the protocol.ResultsThe test–retest consistency in terms of the oral physiological condition (Axis I) after data reduction was 0.63 for patients with teeth problems, 0.95 for partially edentulous patients, and 0.62 for edentulous patients. The reliability for general health and sociological conditions (Axis II), OHRQOL (Axis III), and psychological health (Axis IV) were 0.88, 0.74, and 0.61, respectively. These values reflect either “sufficient agreement” or “excellent agreement” in accordance with the criteria established by Landis and Koch (1977) [1].ConclusionThis protocol is the first multi-axis assessment scheme introduced for prosthodontic treatment with sufficient reliability. This new system is therefore expected to have a significant impact on future dental diagnostic nomenclature systems.