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.

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.

[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.

Impact of synchrotron radiation-based X-ray phase-contrast tomography on understanding various cardiovascular surgical pathologies.

At SPring-8, synchrotron radiation-based X-ray phase-contrast tomography (PCXI) has been developed to measure the inner structures of biological soft tissue without destroying them. To resolve the three-dimensional (3D) morphology, we have applied PCXI to various cardiovascular tissue samples, including the thoracic aorta, ductus arteriosus, and cardiac conduction system. In the aortic walls, PCXI demonstrated differences in 3D structures of tunica media of aortic dissection. These findings correlated well with the irregularity of the structure of the media. In the surgically excised sample of coarctation of the aorta, PCXI showed 3D morphological changes in transition from the ductus arteriosus to the descending aorta. PCXI is also useful for examining abnormalities of the cardiac conduction system in congenital heart defects. Synchrotron radiation-based X-ray phase-contrast tomography has strong modality for analyzing 3D morphology and is useful for understanding the pathophysiology of various cardiovascular surgical pathologies.

Morphometric study of the human mitral annulus: guide for mitral valve surgery.

BACKGROUND: during mitral valve surgery, it is important for surgeons to understand the anatomy of the mitral valve annulus to prevent surgical complications. This study aimed to perform morphometry of the mitral annulus to facilitate secure suturing during ring annuloplasty or replacement of the mitral valve. METHODS: an anatomical study was carried out on 7 human hearts. We divided the mitral valve annulus into sections containing 8 different points. It was noted that the annulus was a complex structure which has fibrous continuity with the mitral leaflets, and with or without the aortic annulus. RESULTS: there was always a segment of the annular fibrous structure which was facing directly toward the left ventricular cavity. The length of the segment ranged from 1.0 to 3.4 mm. In terms of the size of the annulus, there were large variations within the subject and among the subjects. The shortest distance between the mitral annulus and left circumflex coronary artery was at the anterolateral commissure, and the length was 3.3 mm. CONCLUSION: this study has improved understanding of the anatomy of the mitral annulus, which could help surgeons to avoid operative complications. Based on this study, several suggestions are made for placing sutures for mitral valve replacement and mitral ring annuloplasty.

Peroxiredoxins, thioredoxin, and Y-box-binding protein-1 are involved in the pathogenesis and progression of dialysis-associated renal cell carcinoma.

Patients with end-stage renal disease are exposed to increased oxidative stress and impairment of antioxidant mechanisms. We focused on dialysis renal cell carcinoma (RCC), including epithelial hyperplasia in acquired cystic disease of the kidney (ACDK). We attempted to obtain insight into the carcinogenesis and tumor progression in terms of cellular defense mechanisms associated with oxidative stress by investigating the expression of antioxidant proteins by immunohistochemistry. We evaluated retrospectively 43 cases of dialysis RCC and, as a control group, 49 cases of sporadic RCC. Peroxiredoxin (Prx) 1, 3, 4, 5, and 6 expression in dialysis RCC was positively correlated with the duration of dialysis. In epithelial hyperplasia, in 17 cases of acquired cystic disease of the kidney, Prxs and thioredoxin were highly expressed. Moreover, in dialysis RCC, Prx 3, 4, and 5 immunoreactivity and nuclear expression of Y-box-binding protein-1 were higher than in sporadic RCC. In dialysis RCC, Prx 3, 4, and 5 immunoreactivity positively correlated with the Fuhrman nuclear grade. These data suggest that oxidative stress during dialysis enhances antioxidant activity, with an inhibiting effect on carcinogenesis. Once cancer has developed, antioxidant activity might have a stimulating effect on the progression of dialysis RCC.

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.

Heterochronic spontaneous rupture of bilateral renal cell carcinomas in a hemodialysis patient.

A 64-year-old man undergoing chronic hemodialysis was admitted under a shock state with macrohematuria and fatigue lasting for two hours. A blood analysis revealed severe anemia. Computed tomography disclosed a large right-sided perirenal hematoma. The patient was successfully treated with radical nephrectomy, leading to a histological diagnosis of spontaneous rupture of renal cell carcinoma (RCC). One year after rupture of the right RCC, he again developed macrohematuria and computed tomography revealed a left-sided perirenal hematoma. Radical nephrectomy followed by a histological examination revealed spontaneous rupture of the left-sided RCC. This case emphasizes the importance of conducting periodic imaging evaluations of chronic hemodialysis patients with renal cystic masses.

Surgical strategy for intracranial endodermal cyst--case report.

Two cases of endodermal cyst of the posterior fossa are reported. A 12-year-old girl presented with severe headache and vomiting caused by increased intracranial pressure. Computed tomography and magnetic resonance (MR) imaging showed a cystic mass occupying the ambient and quadrigeminal cisterns. A 65-year-old woman presented with dizziness, and MR imaging revealed a cystic mass in the posterior fossa. The two patients underwent surgery for decompression and resection of the cyst. Surgical specimens of the cyst walls consisted of a single layer of ciliated columnar epithelium. The diagnoses were endodermal cyst. The optimal surgical goal is total resection of the cyst wall, but the cyst wall sometimes tightly adheres to the adjacent nerves, vessels, and vital structures. The cyst must communicate adequately with the surrounding cerebrospinal fluid space, and a newly closed cyst space must be avoided, by the widest possible resection of the cyst 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.

Gastric adenocarcinoma of fundic gland type (chief cell predominant type): proposal for a new entity of gastric adenocarcinoma.

Only a few cases of gastric adenocarcinoma of fundic gland type have been reported. Gastric adenocarcinoma with chief cell differentiation (GA-CCD) has been recently reported as a new variant of gastric adenocarcinoma. However, its clinicopathologic features are uncertain. To elucidate them, GA-CCDs exhibiting pepsinogen-I expression (10 lesions: Group A) and randomly selected gastric adenocarcinomas of differentiated type (111 lesions: Group B) were evaluated in this study. Cell differentiation by MUC2, MUC5AC, MUC6, CD10, pepsinogen-I, H+/K+-ATPase and chromogranin A, cell proliferation by Ki-67, and overexpression of p53 protein were evaluated immunohistochemically. In Group A, all GA-CCDs were located in the upper third of the stomach. Tumors were small, with the average maximum diameter ranging from 4 to 20 (average, 8.6) mm. Histologically, GA-CCDs were well-differentiated adenocarcinomas composed of pale gray-blue, basophilic columnar cells with mild nuclear atypia, resembling chief cells. Immunohistochemically, scattered positivity for H+/K+-ATPase was observed in addition to expression of pepsinogen-I and MUC6, indicating focal differentiation toward parietal cells. In Group B, pepsinogen-I was very focally expressed in 2 cases. As these 2 cases exhibited different clinicopathological and histologic features, they cannot be categorized as GA-CCD. Mild atypism, no lymphovascular invasion, low proliferative activity, no overexpression of p53, and no recurrence indicated less aggressiveness of GA-CCD. GA-CCD is rare, but it has distinct clinicopathological characteristics, especially in terms of tumor location, histologic features, phenotypic expression, and low-grade malignancy. We propose gastric adenocarcinoma of fundic gland type (chief cell predominant type) as a new entity of gastric adenocarcinoma.

Conjugated linoleic acid suppresses colon carcinogenesis in azoxymethane-pretreated rats with long-term feeding of diet containing beef tallow.

BACKGROUND: We have indicated previously that long-term feeding of beef tallow increases colorectal cancer in rats. In this study, we investigated the effects of conjugated linoleic acid (CLA) on colon carcinogenesis in rats under long-term feeding of beef tallow diets, pretreated with azoxymethane (AOM). METHODS: Six-week-old male Sprague-Dawley rats were fed with 10% beef tallow diet only, 10% beef tallow with 1% CLA in triglyceride form (CLA-TG), or 10% beef tallow with 1% CLA in free fatty acid form (CLA-FFA). Colon carcinogenesis was induced by two intraperitoneal injections of AOM. Aberrant crypt foci (ACFs) were examined at 12 weeks. Cancer, cell proliferation, apoptosis, Wnt signaling, and the arachidonic acid cascade were examined at 44 weeks. RESULTS: At 12 weeks, CLA-TG and CLA-FFA attenuated the increase in ACFs induced by 10% beef tallow and AOM pretreatment. At 44 weeks, both forms of CLA attenuated multiple colon cancers, and CLA-FFA reduced the incidence of colon cancer to 50% of that seen with CLA-TG. CLA-TG and CLA-FFA decreased the number of 5-bromo-2'-deoxyuridine-positive cells in AOM-pretreated rats fed with 10% beef tallow. CLA-FFA increased the number of apoptotic cells and the activity of caspase-3 in the colon mucosa, and CLA-TG enhanced the activity of caspase-3. Both forms of CLA suppressed Wnt signaling and the arachidonic acid cascade in rats treated with beef tallow and AOM. CONCLUSION: These results suggested that CLA-TG and CLA-FFA suppressed colon carcinogenesis in rats with long-term feeding of a 10% beef tallow diet, through several mechanisms. The results of the present study with rats might be applicable to humans.

Risk factors for coronary atherosclerosis in a general Japanese population: the Hisayama study.

To investigate risk factors for coronary atherosclerosis in men and women in the recent general Japanese population, we examined coronary arteries obtained from subjects autopsied in the Hisayama cohort study (autopsy rate: 78.7%). The subjects were over 40 years of age and consisted of 125 men and 108 women. They underwent an antemortem medical examination in 1988 and were subject to autopsy at death during an 8-year follow-up period. Atherosclerosis was globally assessed by examining 14 specimens taken from wide areas of epicardial coronary arteries and classified into 6 grades. The frequency of more severe grades of coronary atherosclerosis increased with age in both genders and was greater in men than in women of the same age. Multiple regression analysis revealed that age, systolic blood pressure, serum total cholesterol, and hemoglobin A(1C) were significant risk factors for men. Age, systolic blood pressure, and waist to hip ratio were risk factors for women. Smoking was not significantly correlated with the grade of coronary atherosclerosis in either gender. Thus, aging, hypertension, hypercholesterolemia, obesity, and glucose intolerance are risk factors for coronary atherosclerosis in recent Japanese populations, and the significance of the metabolic risk factors is different between men and women.

Overexpression of heme oxygenase-1 in coronary atherosclerosis of Japanese autopsies with diabetes mellitus: Hisayama study.

Few studies regarding the topographical expression of heme oxygenase-1 (HO-1) and its pathophysiological role in human coronary atherosclerotic lesions, particularly in relation to type 2 diabetes mellitus (DM) and intimal angiogenesis, have been reported. HO-1 expression was immunohistochemically examined in 312 tissue blocks of coronary arteries obtained from 53 Japanese autopsy cases in Hisayama cohort study that included 19 diabetic subjects and 34 age- and sex-matched non-diabetic subjects (56-93 years old, mean+/-S.D.: 73+/-10). The HO-1 was ubiquitously distributed in atherosclerotic intima, and was mainly expressed by macrophages and endothelial cells, and partly by smooth muscle cells. The prevalence of HO-1 expression increased as the lesion type (as classified by the American Heart Association (AHA) Committee) and stenotic grade progressed (p<0.0001), and was significantly higher in diabetic than in non-diabetic subjects (p<0.01). This HO-1 overexpression was associated with greater CD-68-positive macrophage infiltration (p=0.005). Interestingly, the distribution of HO-1-positive cells was accentuated in coronary atherosclerotic lesions with intimal microvessels in diabetic subjects (p<0.05), particularly those with hypercholesterolemia (p<0.05), and was preferentially distributed in the shoulder region of atherosclerotic lesion type IV in the AHA classification (p<0.01). In conclusion, HO-1 expression was distributed in overall human coronary atherosclerotic lesions, particularly in diabetic subjects, indicating that HO-1 expression is intimately associated with atherogenesis and may play an important role as an adaptive molecule in the inflammatory-repair process. The association of HO-1 overexpression with a greater extent of intraplaque angiogenesis suggests a multi-faceted role for HO-1 in modulating the progression of atherosclerosis.

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 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.

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.