Compression-associated injuries using CLOVER3000 device in non-survivor patients of OHCA: A retrospective cohort study.

AIM: The incidence of compression-associated injuries from using the CLOVER3000, a new mechanical cardiopulmonary resuscitation (CPR) device, is not well studied in the context of out-of-hospital cardiac arrest (OHCA). Thus, we aimed to compare compression-associated injuries between CLOVER3000 and manual CPR. METHODS: This single-center, retrospective, cohort study used data from the medical records of a tertiary care center in Japan between April 2019 and August 2022. We included adult non-survivor patients with non-traumatic OHCA who were transported by emergency medical services and underwent post-mortem computed tomography. Compression-associated injuries were tested using logistic regression models adjusting for age, sex, bystander CPR performance, and CPR duration. RESULTS: A total of 189 patients (CLOVER3000, 42.3%; manual CPR, 57.7%) were included in the analysis. The overall incidence of compression-associated injuries was similar between the two groups (92.5% vs. 94.54%; adjusted odds ratio (AOR), 0.62 [95% confidence interval (CI), 0.06-1.44]). The most common injury was anterolateral rib fractures with a similar incidence between the two groups (88.7% vs. 88.9%; AOR, 1.03 [95% CI, 0.38 to 2.78]). The second most common injury was sternal fracture in both groups (53.1% vs. 56.7%; AOR, 0.68 [95% CI, 0.36-1.30]). The incidence rates of other injuries were not statistically different between the both groups. CONCLUSION: We observed a similar overall incidence of compression-associated injuries between the CLOVER3000 and manual CPR groups on small sample size.

X-linked Alport Syndrome with Type IV Collagen α5 Chain Staining Revealing Normal Expression in the Glomerular Basement Membrane and Negative on Bowman's Capsule and Distal Tubular Basement Membrane: A Case Report.

X-linked Alport syndrome is a hereditary progressive renal disease resulting from the disruption of collagen α3α4α5 (IV) heterotrimerization caused by pathogenic variants in the COL4A5 gene. This study aimed to report a male case of X-linked Alport syndrome with a mild phenotype accompanied by an atypical expression pattern of type IV collagen α5 [α5 (IV)] chain in glomerulus. A 38-year-old male presented with proteinuria (2.3 g/day) and hematuria. He has been detected urinary protein and occult blood since childhood. A renal biopsy was performed at the age of 29 years; however, a diagnosis of Alport syndrome was not considered. A renal biopsy 9 years later revealed diffuse thinning and lamellation of the glomerular basement membrane. Α staining for α5 (IV) revealed a normal expression pattern in the glomerular basement membrane and a complete negative expression in Bowman's capsule and distal tubular basement membrane. Using next-generation sequencing, we detected a COL4A5 missense variant within exon 35 (NM_000495.5: c.3088G>A, p. G1030S). The possibility of X-linked Alport syndrome should be considered when negative expression of α5 (IV) staining on Bowman's capsule was observed.

Displaced anterior pelvic fracture on initial pelvic radiography predicts massive hemorrhage.

INTRODUCTION: Massive hemorrhage is often associated with unstable pelvic fractures with posterior ring injury. Initial pelvic radiography alone may not detect these posterior lesions. We examined whether the presence of an anterior pelvic fracture on initial pelvic radiography alone may identify patients who are at a high risk of major hemorrhage. MATERIALS AND METHODS: A total of 288 patients with pelvic fractures were admitted to the Fukui Prefectural Hospital during an 11-year period. After excluding 33 patients who were in cardiopulmonary arrest on arrival and nine with concomitant abdominal organ injuries requiring emergency laparotomy, 246 eligible patients were retrospectively reviewed. Anterior pelvic fractures were defined as displacement of the obturator ring, obturator ring with laterality, or displacement of the pubic symphysis on pelvic radiography. RESULTS: Massive hemorrhage was identified in 106 of 246 patients. Patients with massive hemorrhage had a higher frequency of anterior pelvic fractures on pelvic radiography and higher frequency of posterior pelvic fractures on computed tomography than those without massive hemorrhage. Logistic regression analysis identified displacement of the obturator ring by ≥5mm, obturator ring with laterality of ≥5mm, and displacement of the pubic symphysis by ≥4mm on pelvic radiography as predictors of massive pelvic hemorrhage. CONCLUSION: The results of the present study suggested that the presence of displaced anterior lesions of the pelvic ring on pelvic radiography alone, without the use of computed tomography during the initial treatment stage, may promptly identify patients at high risk of massive pelvic hemorrhage who require intervention for hemorrhage control.

Machine-Learning Approaches for Predicting the Need of Oxygen Therapy in Early-Stage COVID-19 in Japan: Multicenter Retrospective Observational Study.

Background: Early prediction of oxygen therapy in patients with coronavirus disease 2019 (COVID-19) is vital for triage. Several machine-learning prognostic models for COVID-19 are currently available. However, external validation of these models has rarely been performed. Therefore, most reported predictive performance is optimistic and has a high risk of bias. This study aimed to develop and validate a model that predicts oxygen therapy needs in the early stages of COVID-19 using a sizable multicenter dataset. Methods: This multicenter retrospective study included consecutive COVID-19 hospitalized patients confirmed by a reverse transcription chain reaction in 11 medical institutions in Fukui, Japan. We developed and validated seven machine-learning models (e.g., penalized logistic regression model) using routinely collected data (e.g., demographics, simple blood test). The primary outcome was the need for oxygen therapy (≥1 L/min or SpO2 ≤ 94%) during hospitalization. C-statistics, calibration slope, and association measures (e.g., sensitivity) evaluated the performance of the model using the test set (randomly selected 20% of data for internal validation). Among these seven models, the machine-learning model that showed the best performance was re-evaluated using an external dataset. We compared the model performances using the A-DROP criteria (modified version of CURB-65) as a conventional method. Results: Of the 396 patients with COVID-19 for the model development, 102 patients (26%) required oxygen therapy during hospitalization. For internal validation, machine-learning models, except for the k-point nearest neighbor, had a higher discrimination ability than the A-DORP criteria (P < 0.01). The XGboost had the highest c-statistic in the internal validation (0.92 vs. 0.69 in A-DROP criteria; P < 0.001). For the external validation with 728 temporal independent datasets (106 patients [15%] required oxygen therapy), the XG boost model had a higher c-statistic (0.88 vs. 0.69 in A-DROP criteria; P < 0.001). Conclusions: Machine-learning models demonstrated a more significant performance in predicting the need for oxygen therapy in the early stages of COVID-19.

Success rate of anterior shoulder dislocation reduction by emergency physicians: a retrospective cohort study.

Aim: Emergency physicians (EPs) often treat anterior shoulder dislocation, but epidemiology of anterior shoulder dislocation in the emergency department of Japan remains unclear. In this study, we clarified the success rate of anterior shoulder reduction performed by EPs. Methods: This single-center cohort study included patients with anterior shoulder dislocation for whom the EP performed initial reduction. The period was from January 2006 to March 2021 and we used the electronic medical record data of the tertiary care hospital. Our primary outcome was the success rate of the shoulder reduction performed by EP. The secondary outcome was to compare the success of reduction with the failure of the reduction. Results: In total, 293 eligible patients were identified. Of these patients, 244 were included in this study. The success rate of the shoulder reduction performed by EP was 92.2% (225/244). EPs failed in successfully performing reduction in 19 (7.8%) cases of anterior shoulder dislocations. The failure group was older (P = 0.017), had a higher frequency of fall down in the mechanism of dislocation (P = 0.019), used intravenous analgesics more frequently (P = 0.004), used peripheral nerve blocks more frequently (P = 0.006), and had fewer patients who did not use drugs (P = 0.002). We could not perform statical adjustment because the sample size was small. Conclusion: The success rate of the shoulder reduction performed by EPs was 92.2%. Older age might be associated with failure of shoulder reduction.

Absence of calvarial fracture could predict the need for tracheostomy in traumatic brain injury.

AIM: Tracheostomy is a common procedure for intubated patients with traumatic brain injury (TBI) in the intensive care unit (ICU) but optimal timing and the predictors of tracheostomy are still unclear. The aim of our study was to explore whether the traumatic variables of head injury predict the need for tracheostomy in intubated TBI patients. METHODS: A single-center, retrospective observational study including a series of TBI patients admitted to Fukui Prefectural Hospital from April 1, 2004 to March 31, 2020 was carried out. Our primary outcome was tracheostomy. Patients with TBI who were intubated and admitted into the ICU within 24 h after injury were enrolled. Exclusion criteria were age less than 18 years, pregnancy, mortality within 24 h, post-cardiac arrest syndrome, and patients for whom life-sustaining interventions were withheld. Radiologic images were also reviewed and the morphology of the head injury was categorized. RESULTS: Seventy-six patients were included. Forty-six patients (60.5%) underwent tracheostomy and 30 patients (39.5%) were successfully extubated. Calvarial fracture (odds ratio [OR] 0.34; 95% confidence interval [CI], 0.13-0.88; P = 0.03), Injury Severity Score (OR 1.07; 95% CI, 1.00-1.15; P = 0.04), and Glasgow Comas Scale score (OR 0.84; 95% CI, 0.73-0.96) were statistically significant in the univariable analysis. Multivariate logistic regression identified calvarial fracture as an independent predictor for tracheostomy. The model involving calvarial fracture, Injury Severity Score ≥16, and Glasgow Coma Scale score ≤8 showed the area under the receiver operating characteristic curve for the model was 0.737 (95% CI, 0.629-0.846). CONCLUSIONS: The absence of calvarial fracture could predict the necessity for tracheostomy in intubated TBI patients when combined with other factors. Further prospective randomized trials are necessary to confirm the findings.

Hereditary spherocytosis diagnosed with extremely low glycated hemoglobin compared to plasma glucose levels.

Glycated hemoglobin (HbA1c) is an important indicator of glycemic control in patients with diabetes. High-performance liquid chromatography (HPLC) is the most commonly used method for measuring HbA1c levels; as HPLC measures all hemoglobin types, the values can be influenced by hemoglobin variants. Moreover, as HPLC-HbA1c levels are low in some diseases, including hemolytic anemia, it may be difficult to differentiate hemoglobin variants from these diseases based on HPLC-HbA1c levels alone. Similar HbA1c values using both HPLC and immunoassays (IAs) are noted for these diseases, while discrepancies are noted in the case of hemoglobin variants. Herein, we describe our process of differential diagnosis for hereditary spherocytosis, the most common inherited hemolytic anemia, in a 56-year-old man presenting with a low HPLC-HbA1c level compared to the glucose concentration, concomitant with anemia, jaundice, hyperbilirubinemia, cholelithiasis, and splenomegaly. There was a discrepancy between HbA1c levels measured with HPLC and IAs and glycated albumin levels. The possibility of hemoglobin variants was unlikely, based on the chromatography and isoelectric focusing results. The haptoglobin levels and reticulocyte counts were low and high, respectively. The direct and indirect Coomb's tests were negative. The presence of spherocytes on blood smears and flow cytometric analysis of the eosin-5-maleimide binding test supported a diagnosis of hereditary spherocytosis. We recommend that when a discrepancy between HPLC-HbA1c levels and glucose concentrations is noted, clinicians should consider hemolysis or hemoglobin variants as the diagnosis. It should be considered that a discrepancy between HbA1c levels measured with HPLC and IAs does not specifically exclude hemolysis.

Strain-dependent embryonic lethality and exaggerated vascular remodeling in heparin cofactor II-deficient mice.

Heparin cofactor II (HCII) specifically inhibits thrombin action at sites of injured arterial wall, and patients with HCII deficiency exhibit advanced atherosclerosis. However, the in vivo effects and the molecular mechanism underlying the action of HCII during vascular remodeling remain elusive. To clarify the role of HCII in vascular remodeling, we generated HCII-deficient mice by gene targeting. In contrast to a previous report, HCII(-/-) mice were embryonically lethal. In HCII(+/-) mice, prominent intimal hyperplasia with increased cellular proliferation was observed after tube cuff and wire vascular injury. The number of protease-activated receptor-1-positive (PAR-1-positive) cells was increased in the thickened vascular wall of HCII(+/-) mice, suggesting enhanced thrombin action in this region. Cuff injury also increased the expression levels of inflammatory cytokines and chemokines in the vascular wall of HCII(+/-) mice. The intimal hyperplasia in HCII(+/-) mice with vascular injury was abrogated by human HCII supplementation. Furthermore, HCII deficiency caused acceleration of aortic plaque formation with increased PAR-1 expression and oxidative stress in apoE-KO mice. These results demonstrate that HCII protects against thrombin-induced remodeling of an injured vascular wall by inhibiting thrombin action and suggest that HCII is potentially therapeutic against atherosclerosis without causing coagulatory disturbance.

Pitavastatin, an HMG-CoA reductase inhibitor, exerts eNOS-independent protective actions against angiotensin II induced cardiovascular remodeling and renal insufficiency.

Angiotensin II (Ang II) plays a pivotal role in cardiovascular remodeling leading to hypertension, myocardial infarction, and stroke. Pitavastatin, an HMG-CoA reductase inihibitor, is known to have pleiotropic actions against the development of cardiovascular remodeling. The objectives of this study were to clarify the beneficial effects as well as the mechanism of action of pitavastatin against Ang II-induced organ damage. C57BL6/J mice at 10 weeks of age were infused with Ang II for 2 weeks and were simultaneously administered pitavastatin or a vehicle. Pitavastatin treatment improved Ang II-induced left ventricular hypertrophy and diastolic dysfunction and attenuated enhancement of cardiac fibrosis, cardiomyocyte hypertrophy, coronary perivascular fibrosis, and medial thickening. Ang II-induced oxidative stress, cardiac TGFbeta-1 expression, and Smad 2/3 phosphorylation were all attenuated by pitavastatin treatment. Pitavastatin also reduced Ang II-induced cardiac remodeling and diastolic dysfunction in eNOS-/- mice as in wild-type mice. In eNOS-/- mice, the Ang II-induced cardiac oxidative stress and TGF-beta-Smad 2/3 signaling pathway were enhanced, and pitavastatin treatment attenuated the enhanced oxidative stress and the signaling pathway. Moreover, pitavastatin treatment reduced the high mortality rate and improved renal insufficiency in Ang II-treated eNOS-/- mice, with suppression of glomerular oxidative stress and TGF-beta-Smad 2/3 signaling pathway. In conclusion, pitavastatin exerts eNOS-independent protective actions against Ang II-induced cardiovascular remodeling and renal insufficiency through inhibition of the TGF-beta-Smad 2/3 signaling pathway by suppression of oxidative stress.

Nonuniform sampling pitch acquisition method in myocardial single-photon emission computed tomography.

BACKGROUND: Single-photon emission computed tomography is a tomographic imaging method that acquires a projection image by rotating a gamma camera around by 380° or 180°. For myocardial single-photon emission computed tomography, 180° acquisition is common, but it has limitations including an incomplete reconstruction, which can distort the resulting image. It is possible to produce a complete reconstruction using 360° acquisition, but the testing time is long and is burdensome to patients. METHODS: The nonuniform sampling pitch acquisition (NUSPA) method devised in this study involves reducing the total sampling count using NUSPA that reduces the sampling pitch in the range in which the gamma cameras are closer to the myocardium (RAO45-LPO45) and increases it elsewhere. RESULTS AND CONCLUSION: The NUSPA-1 method based on a 6° sampling pitch had 20 views fewer than 360° acquisition. In addition, the NUSPA-2 method based on a 3.75° sampling pitch had 60 views fewer than 360° acquisition, considerably reducing the testing time. The acquired sinograms from the NUSPA methods were subjected to nonuniform rational B-spline surface interpolation processing, producing data with a uniform sampling pitch, after which image reconstruction was performed. The images after nonuniform rational B-spline interpolation for both the line sources and heart-liver phantom investigated in this study were not found to have the distortion observed from 180° acquisition or a count decrease at the center, resulting in image quality nearly equivalent to 360° acquisition. This method enabled a reduction in testing time without impacting image quality.

Comparison of acute vertigo diagnosis and treatment practices between otolaryngologists and non-otolaryngologists: A multicenter scenario-based survey.

Acute vertigo is a common problem in emergency departments. However, clinical strategies of acute vertigo care vary among care providers. The aim of the study was to investigate differences in diagnosis [Dix-Hallpike test, the head impulse, nystagmus, and the test of skew (HINTS) procedure, and imaging modalities] and treatment (pharmacological treatments and the Epley maneuver) by otolaryngologists and non-otolaryngologists in emergency medicine settings. We used a multicenter case-based survey for the study. Four clinical vignettes of acute vertigo (posterior canal benign paroxysmal positional vertigo, vestibular neuritis, Meniere disease, and nonspecific vertigo) were used. Total 151 physicians from all study sites participated in the study. There were 84 non-otolaryngologists (48 emergency physicians and 36 internists) and 67 otolaryngologists. The multivariate analysis indicated that otolaryngologists ordered fewer CT scans (odds ratio (OR), 0.20; 95% confidence interval (CI), 0.07-0.53) and performed fewer HINTS procedures (OR, 0.17; 95% CI, 0.06-0.46), but used the Dix-Hallpike method more often (OR, 2.36; 95% CI, 1.01-5.52) for diagnosis compared to non-otolaryngologists. For treatment, otolaryngologists were less likely to use the Epley method (OR, 0.19; 95% CI, 0.07-0.53) and metoclopramide (OR, 0.09; 95% CI, 0.01-0.97) and more likely to use sodium bicarbonate (OR, 20.50; 95% CI, 6.85-61.40) compared to non-otolaryngologists. We found significant differences in the acute vertigo care provided by non-otolaryngologists and otolaryngologists from a vignette-based research. To improve acute vertigo care, educational systems focusing on acute vertigo are needed.

A comprehensive validation of very early rule-out strategies for non-ST-segment elevation myocardial infarction in emergency departments: protocol for a multicentre prospective cohort study.

INTRODUCTION: Recent advances in troponin sensitivity enabled early and accurate judgement of ruling-out myocardial infarction, especially non-ST elevation myocardial infarction (NSTEMI) in emergency departments (EDs) with development of various prediction-rules and high-sensitive-troponin-based strategies (hs-troponin). Reliance on clinical impression, however, is still common, and it remains unknown which of these strategies is superior. Therefore, our objective in this prospective cohort study is to comprehensively validate the diagnostic accuracy of clinical impression-based strategies, prediction-rules and hs-troponin-based strategies for ruling-out NSTEMIs. METHODS AND ANALYSIS: In total, 1500 consecutive adult patients with symptoms suggestive of acute coronary syndrome will be prospectively recruited from five EDs in two tertiary-level, two secondary-level community hospitals and one university hospital in Japan. The study has begun in July 2018, and recruitment period will be about 1 year. A board-certified emergency physician will complete standardised case report forms, and independently perform a clinical impression-based risk estimation of NSTEMI. Index strategies to be compared will include the clinical impression-based strategy; prediction rules and hs-troponin-based strategies for the following types of troponin (Roche Elecsys hs-troponin T; Abbott ARCHITECT hs-troponin I; Siemens ADVIA Centaur hs-troponin I; Siemens ADVIA Centaur sensitive-troponin I). The reference standard will be the composite of type 1 MI and cardiac death within 30 days after admission to the ED. Outcome measures will be negative predictive value, sensitivity and effectiveness, defined as the proportion of patients categorised as low risk for NSTEMI. We will also evaluate inter-rater reliability of the clinical impression-based risk estimation. ETHICS AND DISSEMINATION: The study is approved by the Ethics Committees of the Kyoto University Graduate School and Faculty of Medicine and of the five hospitals where we will recruit patients. We will disseminate the study results through conference presentations and peer-reviewed journals.

Small tube thoracostomy (20-22 Fr) in emergent management of chest trauma.

BACKGROUND: The optimal tube size for an emergent thoracostomy for traumatic pneumothorax or hemothorax is unknown. Both small catheter tube thoracostomy and large-bore chest tube thoracostomy have been shown to work for the nonemergent management of patients with traumatic pneumothorax or hemothorax. This study was conducted to compare the efficacy of a small chest tube with that of a large tube in emergent thoracostomy due to chest trauma. Our hypothesis was that there would be no difference in clinical outcomes including tube-related complications, the need for additional tube placement, and thoracotomy, with the replacement of large tubes with small tubes. METHODS: A retrospective review of all patients with chest trauma requiring tube thoracostomy within the first 2h from arrival at our emergency department over a 7-year period was conducted. Charts were reviewed for demographic data and outcomes including complications and initial drainage output. Small chest tubes (20-22 Fr) were compared with a large tube (28 Fr). Our primary outcome was tube-related complications. Secondary outcomes included additional invasive procedures, such as additional tube insertion and thoracotomy. RESULTS: There were 124 tube thoracostomies (small: 68, large: 56) performed in 116 patients. There were no significant differences between the small- and large-tube groups with regard to age, gender, injury mechanism, systolic blood pressure, heart rate, and injury severity score. Both groups were similar in the posterior direction of tube insertion, initial drainage output, and the duration of tube insertion. There was no significant difference in the primary outcomes of tube-related complications, including empyema (small: 1/68 vs. large: 1/56; p=1.000) or retained hemothorax (small: 2/68 vs. large: 2/56; p=1.000). Secondary outcomes, including the need for additional tube placement (small: 2/68 vs. large: 4/56; p=0.408) or thoracotomy (small: 2/68 vs. large: 1/56; p=1.000), were also similar. CONCLUSION: For patients with chest trauma, emergent insertion of 20-22 Fr chest tubes has no difference in the efficacy of drainage, rate of complications, and need for additional invasive procedures compared with a large tube (28 Fr).

Glucocorticoid excess induces superoxide production in vascular endothelial cells and elicits vascular endothelial dysfunction.

Glucocorticoid (GC) excess often elicits serious adverse effects on the vascular system, such as hypertension and atherosclerosis, and effective prophylaxis for these complications is limited. We sought to reveal the mechanism underlying GC-induced vascular complications. Responses in forearm blood flow to reactive hyperemia in 20 GC-treated patients were significantly decreased to 43+/-8.9% (mean+/-SEM) from the values obtained before GC therapy (130+/-14%). An administration of vitamin C almost normalized blood flow responses. In human umbilical vein endothelial cells (HUVECs), production of hydrogen peroxide was increased up to 166.5+/-3.3% of control values by 10(-7) mol/L dexamethasone (DEX) treatment (P<0.01). Concomitant with DEX-induced hydrogen peroxide production, intracellular amounts of peroxynitrite significantly increased and those of nitric oxide (NO) decreased, respectively (P<0.01). Immunoblotting analysis using anti-nitrotyrosine antibody showed that peroxynitrite formation was increased in DEX-treated HUVECs. Using inhibitors against metabolic pathways for generation of reactive oxygen species (ROS), we identified that the major production sources of ROS by DEX treatment were mitochondrial electron transport chain, NAD(P)H oxidase, and xanthine oxidase. These findings suggest that GC excess causes overproduction of ROS and thereby perturbs NO availability in the vascular endothelium, leading to vascular complications in patients with GC excess.

[Vitamin D-vitamin D receptor system regulates antithrombogenicity in vivo].

Although it has been well documented that vitamin D receptor (VDR) activation influences the expression of various genes involved in calcium homeostasis and cell differentiation, the physiological role of VDR action in hemostasis remains unclear. We studied thrombogenicity in normocalcemic VDR knock-out (KO) mice on a high calcium diet in comparison with that in wild-type mice and that in hypocalcemic VDRKO mice fed a regular diet. Platelet aggregation was significantly enhanced in normocalcemic VDRKO mice. Aortic endothelial nitric-oxide (NO) synthase expression and urinary NOx excretion were reduced in hypocalcemic VDRKO mice but not in normocalcemic VDRKO mice. The gene expression of antithrombin in the liver and that of thrombomodulin in the aorta, liver and kidney were down-regulated in hypo- and normocalcemic VDRKO mice, whereas tissue factor gene expression in the liver and kidney was up-regulated in VDRKO mice regardless of plasma calcium level. Furthermore, VDRKO mice manifested an exacerbated multi-organ thrombus formation after exogenous lipopolysaccharide injection regardless of the calcemic conditions. These results demonstrate that the vitamin D-VDR system plays a pivotal role in antithrombogenicity in vivo.

High plasma heparin cofactor II activity is associated with reduced incidence of in-stent restenosis after percutaneous coronary intervention.

BACKGROUND: Thrombin plays an important role in the development of atherosclerosis and restenosis after percutaneous coronary intervention. Because heparin cofactor II (HCII) inhibits thrombin action in the presence of dermatan sulfate, which is abundantly present in arterial wall, HCII may affect vascular remodeling by modulating thrombin action. We hypothesized that patients with high plasma HCII activity may show a reduced incidence of in-stent restenosis (ISR). METHODS AND RESULTS: Sequential coronary arteries (n=166) with NIR stent (Boston Scientific Corp) implantation in 134 patients were evaluated before, immediately after, and at 6 months after percutaneous coronary intervention. Patients were divided into the following groups: high HCII (> or =110%, 45 lesions in 36 patients), normal HCII (> or =80% and <110%, 81 lesions in 66 patients), and low HCII (<80%, 40 lesions in 32 patients). Percent diameter stenosis at follow-up in the high-HCII group (18.7%) was significantly lower (P=0.046) than that in the normal-HCII group (30.3%) or the low-HCII group (29.0%). The ISR rate in the high-HCII group (6.7%) was significantly lower than that in the low-HCII group (30.0%) (P=0.0039). Furthermore, multivariate analysis demonstrated that high plasma HCII activity is an independent factor in reducing the incidence of angiographic restenosis (odds ratio, 0.953/1% increase of HCII; 95% CI, 0.911 to 0.998). CONCLUSIONS: The results demonstrate that HCII may have a hitherto unrecognized effect in inhibiting ISR. The effect of HCII may be mediated by inactivating thrombin in injured arteries, thereby inhibiting vascular smooth muscle cell migration and proliferation.

Heparin cofactor II is a novel protective factor against carotid atherosclerosis in elderly individuals.

BACKGROUND: Thrombin plays a crucial role in atherothrombotic changes. Because heparin cofactor II (HCII) inhibits thrombin actions after binding to dermatan sulfate at injured arterial walls, HCII may negatively regulate thrombin actions in vascular walls. We hypothesized that plasma HCII activity is a preventive factor against atherosclerotic changes, especially in elderly individuals who already have atherosclerotic vascular injuries. METHODS AND RESULTS: Maximum plaque thickness (MPT) in the carotid artery was measured by ultrasonography in 306 Japanese elderly individuals (154 men and 152 women; age, 40 to 91 years; 68.9+/-11.1 years, mean+/-SD). The relevance of cardiovascular risk factors including plasma HCII activity to the severity of MPT was statistically evaluated. Plasma HCII activity decreased with age. Simple linear regression analysis after adjustments for age and sex showed that lipoprotein(a), glycosylated hemoglobin A1c, and presence of diabetes mellitus significantly contributed to an increase in MPT values (r=0.119, P<0.05; r=0.196, P<0.001; and r=0.227, P<0.0001, respectively). In contrast, high-density lipoprotein (HDL) cholesterol and HCII activity were negatively correlated with MPT values (r=-0.117, P<0.05, and r=-0.202, P<0.0005, respectively). Multiple regression analysis revealed that plasma HCII activity and HDL cholesterol independently contributed to the suppression of MPT values and that the antiatherogenic contribution of HCII activity was stronger than that of HDL cholesterol (P<0.001 and P<0.05, respectively). CONCLUSIONS: These results suggest that HCII can be a novel and independent antiatherogenic factor. Moreover, HCII is a stronger predictive factor than HDL cholesterol against carotid atherosclerosis in elderly individuals.

Vascular smooth muscle cell proliferation is dependent upon upregulation of mitochondrial transcription factor A (mtTFA) expression in injured rat carotid artery.

Consistent with the physiological response to increased energy demand in proliferating cells, the number of mitochondria is upregulated in synthetic states of vascular smooth muscle cells (VSMC) in atherosclerotic lesion. We hypothesized that mitochondrial transcription factor A (mtTFA), a prerequisite factor for the transcription and replication of mtDNA, may be upregulated in VSMC of injured rat carotid artery, and that inhibition of its expression can attenuate the intimal thickening. Changes of intimal thickening and mtTFA expression by a treatment with antisense oligodeoxynucleotides (ODN) for mtTFA were investigated in balloon-injured rat carotid artery model. The expression of mtTFA was upregulated as early as 3 h up to 7 days after balloon injury. Delivery of ansisense ODN for mtTFA from adventitia side to injured arterial wall caused a significant decrease in intima-to-media (I/M) ratio. Furthermore, the increase in immunoreactivity and mRNA expression of mtTFA in injured artery as well as the number of mitochondria in intimal VSMC was abrogated by antisense ODN treatment. These data demonstrate that expression of mtTFA is upregulated in intimal VSMC of injured rat carotid artery, and that suppression of mtTFA expression by antisense ODN can attenuate intimal thickening after balloon injury.

Aspirin inhibits thrombin action on endothelial cells via up-regulation of aminopeptidase N/CD13 expression.

OBJECTIVE: We hypothesized that aspirin may exhibit its anti-atherosclerotic effects via mechanisms other than cyclooxygenase inhibition in platelets. METHODS AND RESULTS: Using enhanced subtraction hybridization analysis, we found in human umbilical vein endothelial cells (HUVECs) that aspirin up-regulates the expression of aminopeptidase N (APN/CD13) mRNA and its surface protein levels in a dose-dependent manner. Enzymatic activity of APN/CD13 on HUVECs was increased approximately 1.5-fold by 1 mmol L(-1) of aspirin, and treatment with bestatin, an inhibitor for APN/CD13 metalloprotease activity, attenuated the enhanced activities of APN/CD13. Since activated thrombin receptor is reported to be inactivated by APN/CD13 in vitro, protective actions of aspirin on HUVECs by thrombin stimulation were examined, resulting in the suppression of endothelin-1 and reactive oxygen species productions in HUVECs. These inhibitory actions of aspirin were partially abrogated by bestatin. CONCLUSIONS: Aspirin may exert its anti-atherothrombotic effects in part via the inhibition of thrombin action by up-regulating APN/CD13 on endothelial cells.

Chronic corticosteroid administration causes mitochondrial dysfunction in skeletal muscle.

Corticosteroid myopathy is a major clinical problem in patients undergoing chronic corticosteroid treatment and shows insidious and progressive muscle atrophy in proximal limbs. Although several mechanisms underlying the pathophysiology of muscle injury have been postulated, precise pathogenesis is still not clear. We evaluated the mitochondrial functions in patients receiving corticosteroids compared with those in healthy controls or patients not receiving corticosteroids. The serum levels and total production of lactate were investigated by an aerobic exercise test using a bicycle ergometer. Mitochondrial respiratory activities and oxidative damage in biopsied skeletal muscles were also studied. The results of aerobic exercise tests revealed a significant overproduction of lactate in patients treated with corticosteroids ( p < 0.005), which was positively correlated with total corticosteroid doses administered ( p < 0.0001). In these patients, mitochondrial enzyme activity in complex I was significantly decreased ( p < 0.05) and oxidative damage of biopsied skeletal muscle was remarkable both in mitochondrial and nuclear DNAs ( p < 0.001). The results suggest that chronic corticosteroid administration induces mitochondrial dysfunction and oxidative damage in skeletal muscles, which may be the pathogenesis, at least in part, of corticosteroid-induced myopathy.