Accumulation of Plasma-Derived Lipids in the Lipid Core and Necrotic Core of Human Atheroma: Imaging Mass Spectrometry and Histopathological Analyses.

Objective: To clarify the pathogenesis of human atheroma, the origin of deposited lipids, the developmental mechanism of liponecrotic tissue, and the significance of the oxidation of phospholipids were investigated using mass spectrometry-aided imaging and immunohistochemistry.Atherosclerotic lesions in human coronary arteries were divided into 3 groups: pathologic intimal thickening with lipid pool, atheroma with lipid core, and atheroma with necrotic core. The lipid pool and lipid core were characterized by the deposition of extracellular lipids. The necrotic core comprised extracellular lipids and liponecrotic tissue. The proportion of cholesteryl linoleate in cholesteryl linoleate+cholesteryl oleate fraction in the extracellular lipid and liponecrotic regions differed significantly from that of the macrophage foam cell-dominant region, and the plasma-derived components (apolipoprotein B and fibrinogen) were localized in the regions. The liponecrotic region was devoid of elastic and collagen fibers and accompanied by macrophage infiltration in the surrounding tissue. Non-oxidized phospholipid (Non-OxPL), OxPL, and Mox macrophages were detected in the three lesions. In the atheroma with lipid core and atheroma with necrotic core, non-OxPL tended to localize in the superficial layer, whereas OxPL was distributed evenly. Mox macrophages were colocalized with OxPL epitopes.In human atherosclerosis, plasma-derived lipids accumulate to form the lipid pool of pathologic intimal thickening, lipid core of atheroma with lipid core, and necrotic core of atheroma with necrotic core. The liponecrotic tissue in the necrotic core appears to be developed by the loss of elastic and collagen fibers. Non-OxPL in the accumulated lipids is oxidized to form OxPL, which may contribute to the lesion development through Mox macrophages.

Reduced Estimated GFR and Cardiac Remodeling: A Population-Based Autopsy Study.

RATIONALE & OBJECTIVE: Evidence suggests that cardiac remodeling, including left ventricular hypertrophy and myocardial fibrosis, develops with progression of kidney disease. Few studies have examined cardiac pathology across a range of estimated glomerular filtration rates (eGFRs), which was the objective of this investigation. STUDY DESIGN: Population-based cross-sectional study of deceased patients undergoing autopsy. SETTING & PARTICIPANTS: 334 of 694 consecutive deceased patients undergoing autopsy with available cardiac tissue, with a prior health examination within 6 years and without a prior diagnosis of heart disease. EXPOSURE: eGFR. OUTCOMES: The thickness of the left ventricular wall, sizes of cardiac cells, and percentages of fibrosis, estimated from pathology examination of autopsy samples. ANALYTICAL APPROACH: Generalized estimating equations. RESULTS: Lower eGFRs were associated with greater left ventricular wall thickness. Deceased patients with eGFRs≥60, 45 to 59, 30 to 44, and <30mL/min/1.73m2 had left ventricular wall thicknesses of 9.1, 9.5, 9.8, and 10.3mm, respectively (P for trend<0.05). Lower eGFRs were also significantly associated with greater mean values of cardiac cell size in the left ventricular wall after adjusting for confounders: 15.3, 16.1, 16.4, and 17.4µm for eGFRs≥60, 45 to 59, 30 to 44, and <30mL/min/1.73m2 (P for trend<0.01). Patients with lower eGFRs had significantly higher multivariable-adjusted geometric mean values for fibrosis percentage in the left ventricular wall: 3.22%, 4.33%, 3.83%, and 6.14% for eGFRs≥60, 45 to 59, 30 to 44, and <30mL/min/1.73m2 (P for trend<0.001). The negative association of eGFR with multivariable-adjusted mean values of cardiac cell width was stronger among patients with than those without anemia. LIMITATIONS: Cross-sectional study with a high proportion of elderly patients, no available information for severity or duration of hypertension and other cardiovascular risk factors, no information for medication use. CONCLUSIONS: These findings suggest that reduced eGFR is associated with cardiac hypertrophy and fibrosis of the left ventricle, cardiac cell enlargement, and cardiac fibrosis.

[A Case of HER2 Positive Occult Breast Cancer Presenting as Swollen Axillary Lymph Nodes].

Occult breast cancer, which develops as a metastatic lesion with no primary tumor detected in the breast, is a rare breast cancer. A 68-year-old female patient particularly complained of the presence of a right axillary mass. The mass in the right axilla was palpable, but no tumor was found in both the breasts on palpation, ultrasound examination, or MRI. Partial breast resection and axillary lymph node dissection were performed following a diagnosis of invasive ductal carcinoma by core needle biopsy. There was no mammary gland tissue present around the tumor due to the pathology of the disease, and the tumor was diagnosed as occult breast cancer. As the cancer was ER negative and HER2 positive, treatment with a combination of FEC, docetaxel, and trastuzumab was initiated. Radiotherapy, which irradiated the right supraclavicular fossa and the right mammary gland, was administered. No disease recurrence and mammary tumor has been reported in the patient till date. Treatment of occult breast cancer generally includes local therapy such as radiation and surgery. However, in the present case, we did not operate upon the breast; instead we treated the right breast and the right supraclavicular fossa with radiation therapy. As the tumor was HER2 positive, we reasoned that local control of disease would be likely if treatment with chemotherapy and trastuzumab was performed effectively.

[A Case of Noninvasive Ductal Carcinoma of the Breast in a Male].

Breast cancer in male is rare, accounting for 1%of all breast cancers.Among male breast cancers, noninvasive carcinoma is extremely rare.We experienced a case of noninvasive carcinoma of the breast in a male.A 72-year-old male was referred to our hospital with a chief complaint of the tumor and blood secretion from the left nipple.Mammography revealed a highdensity mass.Ultrasound examination revealed low echoic mass at the E area, and it measured 1.5 cm.Core needle biopsy failed to provide a definitive diagnosis, and we performed an excisional biopsy of the tumor.The pathological diagnosis was noninvasive ductal carcinoma.He underwent a mastectomy without sentinel lymph node biopsy because the resection margin was positive.The patient received no adjuvant therapy and the patient's postoperative course was uneventful for 1 year.As there have been few reports on male noninvasive ductal carcinoma, we do not have evidence for indication of the sentinel lymph nodes and postoperative adjuvant therapy such as tamoxifen.We may confuse the treatment policy.

Invasive myoepithelial carcinoma ex pleomorphic adenoma of the major salivary gland: two case reports.

BACKGROUND: Myoepithelial carcinoma (MEC) is a rare salivary gland tumor. Its long-term prognosis remains unknown because of the paucity of reported cases with long-term follow-up. Although some case series exist, the clinical features of MEC vary considerably depending on the site of origin. Therefore, accumulation of these rare cases is important. CASE PRESENTATION: Case 1: An 89-year-old man presented with a 10-year history of a mass originating from the right parotid gland and involving the neck. The mass grew rapidly for 3 months, reaching approximately 8 cm. There was no facial paralysis. MEC ex pleomorphic adenoma (PA) was suspected. Superficial parotid gland resection was performed in 2013; the tumor grade was pT3N0M0, and the resection margins were free of carcinoma. Because of several high-risk factors for metastasis (i.e., invasive carcinoma ex PA, high MIB1 index, and mutant p53 protein positivity), radiotherapy and chemotherapy were recommended as adjuvant therapy. Although the patient refused adjuvant therapy, he was recurrence-free at 36 months after surgery. Case 2: A 54-year-old woman presented with a >10-year history of a right submandibular mass, which grew rapidly for 1 year, reaching approximately 6 cm. Preoperative diagnosis was PA of the right submandibular gland. Submandibular gland resection was performed in 2013. Pathological analysis revealed invasive MEC ex PA, pT3N0M0; in addition, the carcinoma portion had an extra capsule and had invaded the platysma muscle close to the margin. An MIB1 index of 40 % and mutant p53 protein positivity indicated a high risk for metastasis. Additional resection and right neck dissection revealed no residual carcinoma. The patient refused adjuvant chemotherapy. One year after surgery, metastasis to the right pulmonary hilar node and both lungs were detected. Chemotherapy prevented recurrent growth of the lesion and extended survival. The patient was alive with cancer 30 months after the first surgery. CONCLUSIONS: High expression of the Ki67 labeling index might reflect prognosis of these cases. Chemotherapy for distant metastasis was effective, as expected. Further accumulation of cases and long follow-up data are needed to elucidate the pathophysiology and prognosis of MEC ex PA.

Chronic kidney disease is associated with neovascularization and intraplaque hemorrhage in coronary atherosclerosis in elders: results from the Hisayama Study.

There is little information regarding whether patients with chronic kidney disease (CKD) have a high incidence of vulnerable plaques in their coronary arteries. To gain additional evidence on this, we conducted a population-based study by randomly selecting 126 subjects from 844 consecutive autopsies of elderly residents of Hisayama, Japan. We then determined the relationships of CKD with neovascularization and intraplaque hemorrhage in coronary atherosclerosis with the subjects classified into four categories based on their estimated glomerular filtration rate (eGFR). Areas of oxidized low-density lipoprotein (oxLDL) and vascular endothelial growth factor (VEGF) expression, assessed by immunohistochemistry in a total of 375 coronary arteries, increased significantly with decreasing eGFR. A lower eGFR was also associated with increased numbers of newly formed blood vessels. These relationships remained substantially unchanged after adjustment for confounding factors. The multivariate-adjusted odds ratio of the presence of intraplaque hemorrhages was 6.2 (95% confidence interval, 1.1-35.0) in patients with an eGFR <30 ml/min/1.73 m(2) compared with those with an eGFR of ≥ 60 ml/min/1.73 m(2). Thus, elderly patients with CKD have intimal neoangiogenesis and an increased risk of intraplaque hemorrhage in coronary arteries, possibly favored by local accumulation of oxLDL and VEGF.

Giant Patent Ductus Arteriosus Aneurysm Compressing the Esophagus.

It is extremely rare to observe aneurysmal changes in patients with patent ductus arteriosus (PDA), especially in adults. If left untreated, a PDA aneurysm can increase the risk of life-threatening complications, including rupture, dissection, esophageal fistula, and infection. Following is a description of successful surgical repair in a 55-year-old man with PDA aneurysm compressing the esophagus. Histologically, the aneurysmal wall showed mild thickening of the intima and media with hyperplastic smooth muscle cells, but no destructive changes were observed.

Mechanism of sac expansion without evident endoleak analyzed with X ray phase-contrast tomography.

Objective: Synchrotron radiation-based X ray phase-contrast tomography (XPCT) was used in this study to evaluate abdominal aorta specimens from patients with sac expansion without evidence of an endoleak (endotension) following endovascular aortic repair (EVAR) for an abdominal aortic aneurysm (AAA). The aim of this study was to analyze the morphologic structure of the aortic wall in patients with this condition and to establish the cause of the endotension. Methods: Human aortic specimens of the abdominal aorta were obtained during open repair, fixed with formalin, and analyzed among three groups. Group A was specimens from open abdominal aortic aneurysm repairs (n = 7). Group E was specimens from sac expansion without an evident endoleak after EVAR (n = 7). Group N was specimens from non-aneurysmal "normal" cadaveric abdominal aortas (n = 5). Using XPCT (effective voxel size, 12.5 µm; density resolution, 1 mg/cm3), we measured the density of the tunica media (TM) in six regions of each sample. Then, any changes to the elastic lamina and the vasa vasorum were analyzed pathologically. The specimens were immunohistochemically examined with anti-CD31 and vascular endothelial growth factor antibodies. Results: The time from EVAR to open aortic repair was 64.2 ± 7.2 months. There were significant differences in the thickness of the TM among three groups: 0.98 ± 0.03 mm in Group N; 0.31 ± 0.01 mm in Group A; and 0.15 ± 0.03 mm in Group E (P < .005). There were significant differences in the TM density among the groups: 1.087 ± 0.004 g/cm3 in Group N; 1.070 ± 0.001 g/cm3 in Group A; and 1.062 ± 0.007 g/cm3 in Group E (P < .005). Differences in the thickness and density of the TM correlated with the thickness of the elastic lamina; in Group N, uniform high-density elastic fibers were observed in the TM. By contrast, a thinning of the elastic lamina in the TM was observed in Group A. A marked thinness and loss of elastic fibers was observed in Group E. CD31 immunostaining revealed that the vasa vasorum was localized in the adventitia and inside the outer third of the TM in Group N, and in the middle of the TM in Group A. In Group E, the vasa vasorum advanced up to the intima with vascular endothelial growth factor-positive cells in the intimal section. Conclusions: XPCT could be used to demonstrate the densitometric property of the aortic aneurysmal wall after EVAR. We confirmed that the deformation process that occurs in the sac expansion after EVAR without evidence of an endoleak could be explained by hypoxia in the aortic wall.

Hypoxia activates the hedgehog signaling pathway in a ligand-independent manner by upregulation of Smo transcription in pancreatic cancer.

The hedgehog (Hh) signaling pathway is activated in various types of cancer including pancreatic ductal adenocarcinoma. It has been shown that extremely low oxygen tension (below 1% O2) is found in tumor tissue including pancreatic ductal adenocarcinoma cells (PDAC) and increases the invasiveness of PDAC. To investigate the contribution of the Hh pathway to hypoxia-induced invasiveness, we examined how hypoxia affects Hh pathway activation and the invasiveness of PDAC. In the present study, three human PDAC lines were cultured under normoxic (20% O2) or hypoxic (1% O2) conditions. Hypoxia upregulated the transcription of Sonic hedgehog (Shh), Smoothened (Smo), Gli1 and matrix metalloproteinase9 (MMP9) and increased the invasiveness of PDAC. Significantly, neither the addition of recombinant Shh (rhShh) nor the silencing of Shh affected the transcription of these genes and the invasiveness of PDAC. On the other hand, silencing of Smo decreased the transcription of Gli1 and MMP9 and PDAC invasiveness. Silencing of Gli1 or MMP9 decreased PDAC invasiveness. These results suggest that hypoxia activates the Hh pathway of PDAC by increasing the transcription of Smo in a ligand-independent manner and increases PDAC invasiveness.

Objective response with lapatinib in patients with meningitis carcinomatosa derived from HER2/HER1-negative breast cancer.

A 45-year-old woman with HER2(-)/HER1(-) breast cancer underwent radical mastectomy, followed by radiation and chemotherapy. However, her symptoms progressed rapidly owing to meningitis carcinomatosa and she was fitted with a urethral catheter. She also had difficulty in walking. However, immediately after treatment with lapatinib, her symptoms almost completely disappeared. The catheter was removed and she no longer needed a wheelchair. Unfortunately, after treatment was stopped, the bilateral upper limb skin metastases reappeared, the brain metastases relapsed, and she again experienced symptoms of meningitis carcinomatosa. Lapatinib was restarted, resulting in an immediate improvement in the symptoms and a reduction in the skin and brain metastases. Immunohistochemical staining of the lapatinib-sensitive metastatic skin tumor showed it to be HER2(2+), FISH(-)/HER1(-). This result suggested that the lapatinib-sensitive lesions in the brain and meninges were also HER2-positive. Carcinomatosa meningitis has a very poor prognosis and no effective treatment has yet been developed. Here, we report the first case in which lapatinib has been used to effectively treat meningitis carcinomatosa in HER2(-)/HER1(-) relapsed breast cancer.

Development of Unidirectional Cellular Structure with Multiple Pipe Layers and Characterisation of Its Mechanical Properties.

This study is concerned with the development of a new unidirectional cellular (UniPore) copper structure with multiple concentric pipe layers. The investigated UniPore structures were grouped into three main types, each having a different number of pipes (3, 4, and 5 pipes per transversal cross-section) and different pore arrangements. The specimens were fabricated by explosive compaction to achieve tightly compacted structures with a quasi-constant cross-section along the length of the specimens. The bonding between copper pipes was observed by a metallographic investigation, which showed that the pipes and bars were compressed tightly without voids. However, they were not welded together. The mechanical properties were determined by quasi-static compressive testing, where the typical behaviour for cellular materials was noted. The study showed that porosity significantly influences the mechanical properties, even more so than the arrangement of the pipes.

Synchrotron Radiation-based X-ray phase-contrast imaging of the aortic walls in acute aortic dissection.

OBJECTIVE: Synchrotron radiation-based X-ray phase-contrast tomography (XPCT) imaging is an innovative modality for the quantitative analysis of three-dimensional morphology. XPCT has been used in this study to evaluate ascending aorta specimens from patients with acute type A aortic dissection (ATAAD) and to analyze the morphologic structure of the aortic wall in patients with this condition. METHODS: Aortic specimens from 12 patients were obtained during repairs for ATAAD and were fixed with formalin. Five patients had Marfan syndrome (MFS), and seven did not. In addition, six normal aortas were obtained from autopsies. Using XPCT (effective pixel size, 12.5 µm; density resolution, 1 mg/cm3), the density of the tunica media (TM) in each sample was measured at eight points. The specimens were subsequently analyzed pathologically. RESULTS: The density of the TM was almost constant within each normal aorta (mean, 1.081 ± 0.001 g/cm3). The mean density was significantly lower in the ATAAD aortas without MFS (1.066 ± 0.003 g/cm3; P < .0001) and differed significantly between the intimal and adventitial sides (1.063 ± 0.003 vs 1.074 ± 0.002 g/cm3, respectively; P < .0001). The overall density of the TM was significantly higher in the ATAAD aortas with MFS than those without MFS (1.079 ± 0.008 g/cm3; P = .0003), and greater variation and markedly different distributions were observed in comparison with the normal aortas. These density variations were consistent with the pathologic findings, including the presence of cystic medial necrosis and malalignment of the elastic lamina in the ATAAD aortas with and without MFS. CONCLUSIONS: XPCT exhibited differences in the structure of the aortic wall in aortic dissection specimens with and without MFS and in normal aortas. Medial density was homogeneous in the normal aortas, markedly varied in those with MFS, and was significantly lower and different among those without MFS. These changes may be present in the TM before the onset of aortic dissection.

Early atherosclerosis in humans: role of diffuse intimal thickening and extracellular matrix proteoglycans.

This review attempts to define the early events that lead to lesions of human atherosclerosis based on careful morphological studies in human autopsy specimens. In contrast to most small laboratory animals, diffuse intimal thickening (DIT) is present in human arteries before atherosclerosis develops, particularly in the atherosclerosis-prone arteries such as coronary arteries and abdominal aorta. In the earliest stage of atherosclerosis, lipids deposit eccentrically in the deep layer of DIT to form Type I lesions. These layers are enriched in extracellular matrix (ECM) proteoglycans such as biglycan. Following lipid deposition, macrophages appear in these regions and foam cells are observed (Type II lesions). Such observations support the 'response-to-retention' hypothesis that states that a principle early event in the pathogenesis of human atherosclerosis is the trapping and retention of lipoproteins by ECM proteoglycans followed by infiltration and accumulation of macrophages.

A Comparison of Methods to Count Breathing Frequency.

BACKGROUND: Counting breaths for a full minute for all patients to determine breathing frequency could result in excessive work load for many medical staff. The aim of this study was to verify the agreement of 2 quick screening methods with counting breaths for a full minute. METHODS: We conducted a cross-sectional study to compare the breathing frequency estimates from a 15-s period multiplied by 4 (15-s quadruple) and a value which is 60 divided by the time measured for a single breath (ie, breathing time measurement) against counting breaths for a full minute. Subjects of this study included 58 nurses; 1 nurse acted as the patient, and 57 nurses counted the patient's breathing frequency using each of the 3 methods. Each nurse examiner performed the breathing time measurement, the 15-s quadruple method, and the 1-min breath count, in that order. We performed correlation and Bland-Altman analyses between the 15-s quadruple and 1-min breath count methods, and between the breathing time measurement and 1-min breath count methods. Using paired t tests, we compared the absolute difference between the 15-s quadruple and the 1-min breath count methods to the absolute difference between the breathing time measurement and the 1-min breath count methods. RESULTS: The coefficient of correlation between the 15-s quadruple and 1-min breath count was 0.83, while the coefficient of correlation between the breathing time measurement and 1-min breath count methods was 0.90. Brand-Altman analysis indicated that the bias of 15-s quadruple method to the 1-min breath count method was -2.1 ± 2.9 SD, and the limit of agreement was ±5.6; the bias of the breathing time measurement method to the 1-min breath count method was 0.5 ± 2.6 SD, and the limit of agreement was ±5.0. There were statistically significant differences between the 15-s quadruple and 1-min breath count methods and between the breathing time measurement and 1-min breath count methods (P < .001). CONCLUSIONS: The breathing time measurement method had better agreement with the 1-min breath count method than did the 15-s quadruple method in this study setting.

Attenuation of Angiotensin II-Induced Hypertension in BubR1 Low-Expression Mice Via Repression of Angiotensin II Receptor 1 Overexpression.

Background Angiotensin II (Ang II) can cause hypertension and tissue impairment via AGTR1 (Ang II receptor type 1), particularly in renal proximal tubule cells, and can cause DNA damage in renal cells via nicotinamide adenine dinucleotide phosphate oxidase. BubR1 (budding uninhibited by benzimidazole-related 1) is a multifaceted kinase that functions as a mitotic checkpoint. BubR1 expression can be induced by Ang II in smooth muscle cells in vitro, but the relationship between systemic BubR1 expression and the Ang II response is unclear. Methods and Results Twenty 24-week-old male BubR1 low-expression mice (BubR1L/L mice) and age-matched BubR1+/+ mice were used in this study. We investigated how Ang II stimulation affects BubR1L/L mice. The elevated systolic blood pressure caused by Ang II stimulation in BubR1+/+ mice was significantly attenuated in BubR1L/L mice. Additionally, an attenuated level of Ang II-induced perivascular fibrosis was observed in the kidneys of BubR1L/L mice. Immunohistochemistry revealed that the overexpression of AGTR1 induced by Ang II stimulation was repressed in BubR1L/L mice. We evaluated AGTR1 and Nox-4 (nicotinamide adenine dinucleotide phosphate oxidase-4) levels to determine the role of BubR1 in the Ang II response. Results from in vitro assays of renal proximal tubule cells suggest that treatment with small interfering RNA targeting BubR1 suppressed Ang II-induced overexpression of AGTR1. Similarly, the upregulation in Nox4 and Jun N-terminal kinase induced by Ang II administration was repressed by treatment with small interfering RNA targeting BubR1. Conclusions Ang II-induced hypertension is caused by AGTR1 overexpression in the kidneys via the upregulation of BubR1 and Nox4.

Linear mucosal defect may be characteristic of lansoprazole-associated collagenous colitis.

BACKGROUND: Although some cases of collagenous colitis have been induced by lansoprazole (LPZ), the clinicopathologic features of LPZ-associated collagenous colitis have not been elucidated. OBJECTIVE: To elucidate the clinical, endoscopic, and histopathologic features of LPZ-associated collagenous colitis. DESIGN: Retrospective case study. PATIENTS: The subjects were 13 patients with collagenous colitis diagnosed during a period from 2002 to 2007. MAIN OUTCOME MEASUREMENTS: The colonoscopic and histopathologic findings were compared retrospectively between 9 cases of LPZ use (LPZ group) and 4 cases without the use of LPZ (non-LPZ group). RESULTS: A colonoscopy revealed a linear mucosal defect more frequently in the LPZ group (7 of 9 cases [78%]) than in the non-LPZ group (0 of 4 cases [0%], P = .02). Friable mucosa was also noted in 4 patients (44%) in the LPZ group but none in the non-LPZ group. The colonoscopic finding in the non-LPZ group was either normal mucosa or nonspecific minimal abnormalities, whereas patients in the LPZ group had either a linear mucosal defect, mucosal bleeding, or both (P = .001). On histologic examination, the subepithelial collagen band was thicker in patients in the LPZ group than in those in the non-LPZ group (median 45 vs 26.3 mum). All patients in the LPZ group recovered from diarrhea after discontinuance of LPZ. LIMITATION: A small number of patients. CONCLUSIONS: Linear mucosal defects and friable mucosa may be characteristic colonoscopic findings in cases of LPZ-associated collagenous colitis.

Early human atherosclerosis: accumulation of lipid and proteoglycans in intimal thickenings followed by macrophage infiltration.

OBJECTIVE: The present study was designed to clarify the morphological features of early human atherosclerosis and to determine whether specific extracellular matrix proteoglycans play a role in early atherogenesis. METHODS AND RESULTS: Step and serial sections were obtained from right coronary arteries with no or early atherosclerosis. Atherosclerosis was classified into 4 grades according to the amount of lipid deposition. Coronary arteries with Grade 0 showed diffuse intimal thickening (DIT) with no lipid deposits. The extracellular matrix proteoglycans, biglycan and decorin, were localized in the outer layer of DIT. Most cases of Grade 1 and Grade 2 exhibited fatty streaks with extracellular lipids colocalizing with biglycan and decorin in the outer layer of the intima. As lipid grades increased, macrophages increased in number and were present in the deeper layers. Most cases of Grade 3 exhibited pathologic intimal thickening (PIT) with extracellular lipids underneath a layer of foam cell macrophages. CONCLUSIONS: In early human coronary atherosclerosis, fatty streaks develop via extracellular deposition of lipids associated with specific types of proteoglycans in the outer layer of preexisting DIT. As the amount of the lipid increases in fatty streaks, macrophages infiltrate toward the deposited lipid to form PIT with foam cells.

Pathologic intimal thickening in human atherosclerosis is formed by extracellular accumulation of plasma-derived lipids and dispersion of intimal smooth muscle cells.

BACKGROUND AND AIMS: Pathologic intimal thickening (PIT) is an important stage of atherosclerosis that leads to atheroma. The present study aimed to clarify the pathogenesis of PIT in humans. METHODS: Coronary arteries were obtained from 43 autopsy subjects aged 15-49 years. Non-atherosclerotic intima and atherosclerotic intimal lesions were classified into four groups, i.e. diffuse intimal thickening, fatty infiltration, fatty streak, and PIT, and the number and density of macrophages and smooth muscle cells (SMCs) were determined. Components of the lesions and proliferative and apoptotic activities of macrophages and SMCs were investigated by immunohistochemistry and TUNEL assay. RESULTS: Extracellular lipids accumulated mildly in the fatty infiltration and fatty streak, and abundantly in the PIT to form the lipid pool. The extracellular lipids co-localized with apolipoprotein B and fibrinogen. Macrophage foam cells accumulated in the fatty streak and PIT, but no TUNEL-positive macrophages were detected in any lesion. No significant difference in the number of SMCs was found between the four groups, but the density of SMCs decreased in the fatty streak and PIT. The decrease correlated with an increase in the number of macrophages, and the accumulation of extracellular lipids in the lipid pool. Neither Ki-67-positive nor TUNEL-positive SMCs were detected in any lesion. CONCLUSIONS: In PIT in human atherosclerosis, the lipid pool is formed by infiltration and deposition of plasma-derived lipids. Intimal SMCs are dispersed in association with macrophage infiltration and lipid pool formation without undergoing significant proliferation or death.

Bone density of the femoral neck in patients on maintenance dialysis.

BACKGROUND: Our institution recently started using the femoral neck (FN), as well as the non-shunted distal radius (Rd), to measure bone mineral density (BMD) in patients with chronic kidney disease. We examined the utility and characteristics of this measurement in patients on maintenance dialysis. METHODS: We selected 293 patients on chronic dialysis. We measured Rd and FN BMD using dual-energy X-ray absorptiometry, and we reviewed blood test findings, which included hemoglobin, albumin, blood urea nitrogen, creatinine, adjusted calcium, phosphorus, alkaline phosphatase, and intact parathyroid hormone. We conducted a multiple linear regression analysis that was stratified according to sex, age, body weight, height, and dialysis vintage. The Rd and FN BMD values were the dependent variables, and the blood test findings were the independent variables. We compared the areas under the curve (AUCs) of Rd and FN BMD using receiver operating characteristic curve analysis to differentiate between patients with and without fractures. RESULTS: FN BMD was significantly lower than Rd BMD. The general risk factors for osteoporosis, such as low body weight, older age, muscle mass loss, and malnutrition, influenced FN BMD. FN and Rd BMD were not correlated with calcium, phosphorous, or intact parathyroid hormone, whereas a significant, negative correlation with alkaline phosphatase was detected. Both men and women with a history of fragility fractures had significantly lower Rd and FN BMDs than patients without such a history. However, there was no significant difference between the AUCs of FN and Rd BMD for fractures in both men and women. CONCLUSIONS: FN BMD was significantly lower than Rd BMD. Additionally, FN BMD was not inferior to Rd BMD for assessing the risk of fracture in patients on maintenance dialysis.

Long-term treatment with a Rho-kinase inhibitor improves monocrotaline-induced fatal pulmonary hypertension in rats.

Primary pulmonary hypertension is a fatal disease characterized by endothelial dysfunction, hypercontraction and proliferation of vascular smooth muscle cells (VSMCs), and migration of inflammatory cells, for which no satisfactory treatment has yet been developed. We have recently demonstrated that intracellular signaling pathway mediated by Rho-kinase, an effector of the small GTPase Rho, is involved in the pathogenesis of arteriosclerosis. In the present study, we examined whether the Rho-kinase-mediated pathway is also involved in the pathogenesis of fatal pulmonary hypertension in rats. Animals received a subcutaneous injection of monocrotaline, which resulted in the development of severe pulmonary hypertension, right ventricular hypertrophy, and pulmonary vascular lesions in 3 weeks associated with subsequent high mortality rate. The long-term blockade of Rho-kinase with fasudil, which is metabolized to a specific Rho-kinase inhibitor hydroxyfasudil after oral administration, markedly improved survival when started concomitantly with monocrotaline and even when started after development of pulmonary hypertension. The fasudil treatment improved pulmonary hypertension, right ventricular hypertrophy, and pulmonary vascular lesions with suppression of VSMC proliferation and macrophage infiltration, enhanced VSMC apoptosis, and amelioration of endothelial dysfunction and VSMC hypercontraction. These results indicate that Rho-kinase-mediated pathway is substantially involved in the pathogenesis of pulmonary hypertension, suggesting that the molecule could be a novel therapeutic target for the fatal disorder.