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.

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.

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.

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.

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.

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.

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.

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.

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).

Activation of peroxisome proliferator-activated receptor α in megakaryocytes reduces platelet-derived growth factor-BB in platelets.

AIM: Platelet-derived growth factor (PDGF)-BB plays a crucial role in atherosclerosis and vascular remodeling by promoting the migration and proliferation of vascular smooth muscle cells. The objective of this study was to clarify the pleiotropic effect of peroxisome proliferator-activated receptor α (PPARα) activators on PDGF-BB expression in megakaryocytes and platelets. METHODS AND RESULTS: The expression of PPARα in a human erythroleukemia (HEL) cells was clearly detected by reverse transcriptase-PCR and immunofluorescence microscopy. The expression level of PPARα in HEL cells was unchanged regardless of differentiation into megakaryocytic cells by treatment with phorbol 12-myristate 13 acetate (TPA). The TPA-induced expression of PDGF-B mRNA and PDGF-BB protein levels in culture media was significantly decreased by treatment with PPARα activators, Wy14643 and fenofibric acid, in a dose-dependent manner. PDGF-BB expression induced by inflammatory cytokines, including interleukin-1ß or interleukin-6, was also significantly suppressed by treatment with PPARα activators. Immunohistochemistry of human bone marrow showed the expression of PPARα in both the nucleus and cytoplasm of megakaryocytes. In addition, PDGF-BB levels in platelets were significantly decreased from 1,800±870 to 1,470±840 pg/10(5) platelets (mean±SD, p<0.05) by treatment with 300 mg fenofibrate once daily for 4 weeks in 13 patients with dyslipidemia. CONCLUSIONS: Activation of PPARα in megakaryocytes reduces PDGF-BB expression in platelets. PPARα activators may exert vasculo-protective action through suppression of PDGF-BB production in a megakaryocyte/platelet pathway.

Dehydroepiandrosterone sulfate is inversely associated with sex-dependent diverse carotid atherosclerosis regardless of endothelial function.

BACKGROUND: Dehydroepiandrosterone sulfate (DHEAS) is thought to be associated with life expectancy and anti-aging. However, its biological significance in atherosclerosis remains controversial. Therefore, the aim of this study was to determine whether DHEAS is associated with development of carotid atherosclerosis in subjects with cardiovascular risk factors. SUBJECTS AND METHODS: A total of 419 Japanese individuals (208 males and 211 females) were recruited from Tokushima University Hospital, Japan. In all subjects, maximum intima-media thickness (max-IMT) in all carotid arteries, and mean-IMT and mean blood flow volume (BFV) in the common carotid arteries (CCA) were measured by ultrasonography; endothelial function was assessed by flow-mediated vasodilation of the brachial artery (%FMD). Serum DHEAS and classical cardiovascular risk factors were also evaluated. Statistical significance was determined by multiple regression analysis to elucidate independent determinants of max-IMT, mean-IMT, mean CCA-BFV, and %FMD. RESULTS: Serum DHEAS levels were higher in males than in females. Multiple regression analysis revealed that DHEAS was an independent negative factor for both max-IMT and mean-IMT in males but not in females. In contrast, DHEAS was the sole positive factor for mean CCA-BFV in females but not in males. In addition, there was no significant relationship between %FMD and DHEAS regardless of sex and other confounding factors. CONCLUSION: Although DHEAS is not involved in endothelial function, DHEAS is inversely associated with sex-dependent diverse carotid atherosclerosis such as increased max-IMT and mean-IMT in males and decreased CCA-BFV in females.

View of physicians on and barriers to patient enrollment in a multicenter clinical trial: experience in a Japanese rural area.

BACKGROUND: Clinical trials in the general practice setting are important for providing evidence on the effectiveness and safety of different agents under various conditions. In conducting these trials, the participation of physicians and patient recruitment are important issues. Various investigations in the literature have reported views and attitudes of physicians on various types of clinical trials. Nevertheless, there is still little information concerning physicians participating in a clinical trial and among them, those who could not recruit any patients (unsuccessful physician recruiters). METHODS: In 2003, we collaborated in a large-scale multicenter study of Japanese hypertensive patients (COPE Trial). In Tokushima University Hospital and 18 other medical institutions, we investigated the views and attitudes of unsuccessful physician recruiters in comparison with successful physician recruiters, using a questionnaire. RESULTS: The questionnaire was provided by mail to 47 physicians and 27 (57%) responded. The response rate was 79% for successful physician recruiters compared to 43% (P = 0.014) for unsuccessful physician recruiters. More successful physician recruiters (73%) than unsuccessful physician recruiters (42%) stated they had participated and enrolled patients in previous multicenter clinical trials. A significantly higher number of successful physician recruiters than unsuccessful physician recruiters (42%; P = 0.040) considered the presence of a support system with clinical research coordinators (CRC) as the reason for participation (80%). A large number of unsuccessful physician recruiters experienced difficulty in obtaining informed consent (67%), whereas a significantly smaller number of successful physician recruiters experienced such difficulty (20%; P = 0.014). The difficulties experienced by unsuccessful physician recruiters in the trial were as follows: inability to find possible participants (100%), difficulty in obtaining informed consent (58%), cumbersome procedures (58%), difficulty in long-term follow up (33%), and insufficient tools for explanation and obtaining informed consent (8%). CONCLUSION: This survey showed that successful physician recruiters consider a support system with CRC of value, and that they are skillful in obtaining informed consent. These views and attitudes may have originated from past experience involving clinical trials. In this regard, we need to develop an infrastructure to enlighten physicians on this support system for the promotion of clinical trials.

Androgen receptor counteracts Doxorubicin-induced cardiotoxicity in male mice.

Doxorubicin (Dox) has been used as a potent anticancer agent, but serious cardiotoxicity precludes its use in a wide range of patients. We have reported that the androgen-androgen receptor (AR) system plays important roles in cardiac growth and protection from angiotensin II-induced cardiac remodeling. The present study was undertaken to clarify whether the androgen-AR system exerts a cardioprotective effect against Dox-induced cardiotoxicity. Male AR knockout (ARKO) and age-matched littermate male wild-type (WT) mice at 25 wk of age were given ip injections of Dox (20 mg/kg) or a vehicle. The survival rate and left ventricular function in Dox-treated male ARKO mice were reduced compared with those in Dox-treated male WT mice. Electron microscopic study showed prominent vacuole formation of myocardial mitochondria in Dox-treated male ARKO mice. Cardiac oxidative stress and apoptosis of cardiomyocytes were increased more prominently by Dox treatment in male ARKO mice than in male WT mice. In addition, Dox-induced reduction in the expression of cardiac mitochondria transcription factor A (Tfam) and phosphorylation of serine-threonine kinase (Akt) was more pronounced in male ARKO mice than in male WT mice. In cardiac myoblast cells, testosterone up-regulated Akt phosphorylation and Tfam expression and exerted an antiapoptotic effect against Dox-induced cardiotoxicity. Collectively, the results demonstrate that Dox-induced cardiotoxicity is aggravated in male ARKO mice via exacerbation of mitochondrial damage and superoxide generation, leading to enhanced apoptosis of cardiomyocytes. Thus, the androgen-AR system is thought to counteract Dox-induced cardiotoxicity partly through activation of the Akt pathway and up-regulation of Tfam to protect cardiomyocytes from mitochondrial damage and apoptosis.

Heparin cofactor II as a novel vascular protective factor against atherosclerosis.

Heparin cofactor II (HCII) specifically inhibits thrombin action at the site of vascular wall injury. We encountered a congenital HCII deficiency patient with advanced multiple atherosclerotic lesions. This patient led us to conduct clinical studies to examine the role of HCII against atherosclerosis. We found that the incidence of in-stent restenosis after percutaneous coronary intervention, severity of carotid atherosclerosis and prevalence of peripheral arterial disease are inversely associated with plasma HCII activity. In order to clarify the vascular protective action of HCII, we generated HCII- deficient mice by gene targeting. In contrast to a previous study, HCII(-/-) mice were embryonically lethal. In HCII(+/-) mice, accelerated intimal hyperplasia and frequent thrombosis were observed after cuff or wire injury of femoral arteries. The number of protease-activated receptor-1 (PAR-1) -positive cells and the gene expression levels of inflammatory cytokines and chemokines were increased in the thickened vascular walls of HCII(+/-) mice. The accelerated intimal hyperplasia in HCII+/- mice with vascular injury was attenuated by human HCII administration. Furthermore, HCII deficiency exaggerated aortic plaque formation with increased oxidative stress in apolipoprotein E(-/-) mice. These results demonstrate that HCII protects against thrombin-induced vascular remodeling in both humans and mice and suggest that HCII is a predictive biomarker and therapeutic target for atherosclerosis.

Heparin cofactor II is an independent protective factor against peripheral arterial disease in elderly subjects with cardiovascular risk factors.

AIM: Heparin cofactor II (HCII) specifically inactivates thrombin action at the injured vascular wall. We have reported that HCII is a protective factor against coronary in-stent restenosis and carotid atherosclerosis; however, it is unclear whether there is any correlation between plasma HCII levels and the development of peripheral arterial disease (PAD). METHODS: Plasma HCII activity and the ankle brachial pressure index (ABI) were determined in 494 elderly subjects with cardiovascular risk factors. PAD was diagnosed by ABI below 0.9, and 62 subjects were diagnosed with PAD. The relationship between factors that affect cardiovascular events and the prevalence of PAD was statistically evaluated. RESULTS: Mean HCII activity in PAD subjects was significantly lower than in non-PAD subjects (87.5+/-19.7% v.s. 94.6+/-17.8%, p=0.009). Multivariate logistic regression analysis showed that age (odds ratio [OR]: 1.062, p=0.0016), current smoking (OR 3.028, p=0.002) and diabetes mellitus (OR 2.656, p=0.008) were independent and progressive determinants of PAD. In contrast, HCII was an independent inhibitory factor of PAD (OR: 0.982, p=0.048). CONCLUSIONS: Plasma HCII activity is inversely related to the prevalence of PAD. HCII may function as the sole protective factor against PAD in elderly people with cardiovascular risk factors.

Androgen-androgen receptor system protects against angiotensin II-induced vascular remodeling.

Age-related andropause promotes cardiovascular disease in males. Although we had previously reported that the androgen-androgen receptor (AR) system plays important roles in cardiac growth and remodeling, the system's involvement in vascular remodeling remains unclear. To clarify this role, 25-wk-old male AR knockout (ARKO) mice and littermate male wild-type (WT) mice were divided into two groups with and without angiotensin II (Ang II) administration (2.0 mg/kg . d) for 14 d, respectively. No morphological differences in the coronary artery and thoracic aorta were observed between the groups without Ang II. Ang II stimulation markedly increased medial thickness and perivascular fibrosis in ARKO mice, with enhanced TGF-beta1, collagen type I, and collagen type III gene expression in the aorta. Ang II stimulation also prominently increased superoxide production, lipid peroxidation, and gene expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase components in ARKO mice compared with WT mice. In addition, phosphorylation of c-Jun N-terminal kinase (JNK) and phosphorylated (Smad2/3) was remarkably enhanced in Ang II-treated ARKO mice compared with Ang II-treated WT mice. Notably, daily urinary nitric oxide (NO) metabolites excretion as a marker of NO bioavailability, aortic endothelial NO synthase expression and phosphorylation, and Akt phosphorylation were significantly reduced in ARKO mice compared with WT mice, regardless of Ang II stimulation. In conclusion, the androgen-AR system is required for the preservation of NO bioavailability through Akt-endothelial NO synthase system activation and exerts protective effects against Ang II-induced vascular remodeling by regulating oxidative stress, c-Jun N-terminal kinase (JNK) signaling, and the TGF-beta-phosphorylated Smad pathway.

Infective endocarditis caused by lactobacillus.

Lactobacillus (LB) is a gram-positive rod-shaped bacterium that inhabits the oral cavity, gastrointestinal tract, vagina and nasal cavity. Although LB plays a role in the prevention of infections caused by pathogenic bacteria, it causes some critical infectious diseases such as infective endocarditis (IE). IE due to LB is rare; however, early diagnosis and early treatment are important because of its high mortality rate. We report the onset of IE after otologic treatment in a heavy drinker of alcohol, the second case of IE due to LB in Japan.

Impact of serum insulin-like growth factor-1 on early prognosis in acute myocardial infarction.

OBJECTIVE: Previous research revealed that a low concentration of serum insulin-like growth factor-1 (IGF-1) is associated with risks of myocardial infarction and heart failure. We hypothesized that the serum IGF-1 level affects clinical outcome in acute myocardial infarction (AMI). We examined the impact of serum IGF-1 in acute phase of AMI on 90-day mortality. PATIENTS AND METHODS: In 54 patients with AMI, we measured serum total IGF-1 concentration on admission, in acute phase (1.9+/-0.5 days) and in chronic phase (28.5+/-6.7 days). We measured plasma brain natriuretic peptide (BNP), glucose and insulin in acute phase, and calculated insulin resistance (HOMA-R). RESULTS: Serum IGF-1 was 135.6+/-51.1 ng/ml on admission and significantly decreased to 105.5+/-42.2 ng/ml in acute phase, and then returned to baseline of 136.7+/-52.2 ng/ml in chronic phase. Five patients died of cardiac reasons within 90 days, all of whom had lower IGF-1 on admission and lower IGF-1 in acute phase than their median of 54 patients. Patients with the concentration of IGF-1 on admission below the median (<131 ng/ml) had significantly lower survival rate than those at or above the median (log-rank test p=0.0169). However, patients with BNP concentration at or above the median (> or =227 pg/ml) had a similar survival rate to those below the median (log-rank test p=0.6797). Multivariate analysis clarified that IGF-1 on admission was the sole independent predictor of 90-day mortality (p=0.007, risk ratio=0.927). CONCLUSION: A low concentration of serum IGF-1 on admission was associated with a poor early prognosis of acute myocardial infarction.