Association of Heart Valve Calcification With Malnutrition‐Inflammation Complex Syndrome, β2‐Microglobulin,and Carotid Intima Media Thickness in Patients on Hemodialysis

Heart valve calcification is an important predictor for all‐cause and cardiovascular mortality in hemodialysis patients. Recently, serum β₂‐microglobulin has been associated with cardiovascular disease in the non‐hemodialysis population, but the relationship between serum β₂‐microglobulin and valve calcification remains unknown. In this cross‐sectional study, we recorded the patients' clinical parameters, including serum β₂‐microglobulin, and related these parameters to the number of calcified valves detected by echocardiography. The patients included 80 males and 35 females (age 67 ± 10 years; duration on hemodialysis 96 ± 67 months). Calcification of the aortic and mitral valves was observed in 89 (77.4%) and 59 patients (51.3%), respectively. Fifty‐one patients (44.3%) showed calcification of both valves. In univariate analysis, age (r = 0.301, P = 0.001), serum albumin (r = ?0.219, P = 0.01), calcium (r = 0.205, P = 0.02), high sensitivity C‐reactive protein (r = 0.209, P = 0.02), and β₂‐microglobulin (r = 0.206, P = 0.02) significantly correlated with the number of calcified valves. Stepwise multiple regression analysis showed that age (β = 0.389, P < 0.001) and calcium (β = 0.223, P = 0.01) were independent determinants for valve calcification (r² = 0.195). In addition, carotid intima media thickness was significantly higher in patients with valve calcification compared with those without valve calcification. Our results suggested the impacts of calcium metabolism and malnutrition‐inflammation complex syndrome on valve calcification. In addition, serum β₂‐microglobulin may be another potential marker of cardiovascular complications in patients on hemodialysis.     

Relationship between an activated N-ras oncogene and chromosomal abnormality during leukemic progression from myelodysplastic syndrome

The relationship between chromosomal abnormality and oncogene activation was investigated during leukemic progression in two patients with myelodysplastic syndrome (MDS). Both patients had partial or complete deletion of chromosome 5 in metaphase cells obtained throughout the progression to leukemia. Analysis with specific oligonucleotide probes revealed that bone marrow cells containing an activated N-ras oncogene proliferated in a dominant manner during the process of leukemic conversion in both patients. These observations suggest that the chromosomal abnormality may precede activation of the N-ras gene in these patients, and that both the chromosomal abnormality and the activated N-ras oncogene contribute to the development of leukemia.     

Histological changes of superficial esophageal squamous cell carcinoma after preoperative chemotherapy

Introduction

We aimed to analyze the clinical and histological effects of chemotherapy in superficial esophageal squamous cell carcinoma (SESCC).

Methods

We analyzed tumor samples from five patients with cT1bN1M0 who underwent subtotal esophagectomy following two courses of a new triplet chemotherapy regimen including docetaxel, cisplatin, and 5-fluorouracil (DCF). To assess the histological effects of chemotherapy, resected specimens were analyzed by macroscopic examination, hematoxylin & eosin (HE) staining, immunohistochemical (IHC) staining (p53, Ki-67 and cytokeratin) and periodic acid-Schiff (PAS) staining.

Results

All five patients had a pathological T stage of T0/1a-LPM/1a-MM/1b (1/2/1/1) and histological grade of grade1a/1b/2/3 (1/1/2/1). Endoscopic examination revealed substantial shrinkage of lugol-voiding lesions (LVLs) in all cases. One case showed complete LVL disappearance, and resected specimen examination confirmed pathological complete response (pCR). IHC and PAS staining revealed that most initial LVLs were PAS-negative. Obvious viable cells were confirmed in two cases. The other three cases exhibited nuclear atypia and strong expression of p53 and Ki-67 in the basal layer of mucosa or lamina propria mucosae, even though the superficial layer of mucosa showed no obvious LVLs with PAS-positive. p53-positive lesions were also observed in Ki-67-positive. This indicated discordance between the endoscopic findings and histopathological evaluation.

Conclusion

DCF chemotherapy alone had a substantial therapeutic effect on SESCC in all cases. However, despite the normal appearance of the mucosal surface, viable cancer cells remained below the basal layer of mucosa. Careful attention should be paid when diagnosing clinical CR, or securing a resection margin of SESCC after DCF chemotherapy.

     

Hyperbaric oxygen induces basic fibroblast growth factor and hepatocyte growth factor expression, and enhances blood perfusion and muscle regeneration in mouse ischemic hind limbs.

BACKGROUND: It is not clear how hyperbaric oxygen therapy (HBO) affects ischemia-induced pathophysiological responses such as angiogenesis and skeletal muscle regeneration. In the present study the effects of HBO on the functional and morphological recovery of ischemic hind limbs, blood perfusion and the local production of angiogenic growth factors were studied in a mouse model. METHODS AND RESULTS: Mice were placed in pure oxygen under 3 atm for 1 h/day for 14 days after the removal of a segment of the left femoral artery. HBO-treated mice showed better functional recovery and greater blood flow in the ischemic hind limb than untreated mice. Histological examination revealed unatrophied muscle fibers with islands of small regenerating muscle cells only in HBO-treated mice. Regeneration of muscle was confirmed by the increase in myf5 mRNA. The amount of mRNA for vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF) and basic fibroblast growth factor (bFGF) was slightly increased in the ischemic hind limbs. HBO eliminated the increase in VEGF mRNA. In contrast, the amount of mRNA for bFGF and HGF was further increased by HBO treatment. HBO transiently increased early growth response protein 1 (Egr-1) in the ischemic hind limbs. CONCLUSIONS: HBO accelerates the recovery of ischemic hind limbs by increasing the production of bFGF and HGF and by promoting muscle regeneration in mice.     

Morphological changes of the aortic valve leaflets in non-compliant aortic roots: in-vivo experiments

BACKGROUND AND AIM OF THE STUDY: Age-related loss of elasticity of the naturally compliant aortic root disrupts the coordinated function of the valve leaflets. Morphological changes that developed over time in the aortic valve leaflets of non-compliant aortic roots were studied. METHODS: Stiffening of the aortic roots was achieved in vivo by applying Super Glue around the sinus of Valsalva in 27 New Zealand White rabbits. In nine animals, glue was applied only partially, and eight untreated rabbits served as controls. Histological evaluation of the aortic valves was performed at 8-11 months after surgery, and included immunohistochemistry and confocal microscopy with quantitative tissue assessment. Levels of collagen I, as a main component of fibrosis, and matrix metalloproteinases (MMP)-1 and MMP-9 and angiotensin-converting enzyme (ACE), as regulators of fibrosis, were analyzed. The morphological structure of the aortic valve leaflets was studied, and the length, thickness and area of leaflets were measured. RESULTS: Leaflects in all groups were found to be composed of a continuous layer of collagen fibers at the mural side, and loose connective tissue containing fibroblasts and few capillaries on the aortic luminal aspect. In stiffened aortic roots, the length and area of the leaflets were increased. The area occupied by collagen was elevated in non-compliant aortic root leaflets, but collagen fluorescence intensity was decreased, indicating less densely packed collagen fibers. Degradation and synthesis of collagen as reflected by MMP-1, MMP-9 and ACE levels was up-regulated. CONCLUSION: Loss of compliance in aortic roots leads to elongation of the leaflets which, combined with a decrease in collagen density, may render leaflets more susceptible to mechanical stress. In time, this may promote the development of degenerative changes in the aortic valve.     

Pulmonary Talcosis: Imaging Findings

Talc is a mineral widely used in the ceramic, paper, plastics, rubber, paint, and cosmetic industries. Four distinct forms of pulmonary disease caused by talc have been defined. Three of them (talcosilicosis, talcoasbestosis, and pure talcosis) are associated with aspiration and differ in the composition of the inhaled substance. The fourth form, a result of intravenous administration of talc, is seen in drug users who inject medications intended for oral use. The disease most commonly affects men, with a mean age in the fourth decade of life. Presentation of patients with talc granulomatosis can range from asymptomatic to fulminant disease. Symptomatic patients typically present with nonspecific complaints, including progressive exertional dyspnea, and cough. Late complications include chronic respiratory failure, emphysema, pulmonary arterial hypertension, and cor pulmonale. History of occupational exposure or of drug addiction is the major clue to the diagnosis. The high-resolution computed tomography (HRCT) finding of small centrilobular nodules associated with heterogeneous conglomerate masses containing high-density amorphous areas, with or without panlobular emphysema in the lower lobes, is highly suggestive of pulmonary talcosis. The characteristic histopathologic feature in talc pneumoconiosis is the striking appearance of birefringent, needle-shaped particles of talc seen within the giant cells and in the areas of pulmonary fibrosis with the use of polarized light. In conclusion, computed tomography can play an important role in the diagnosis of pulmonary talcosis, since suggestive patterns may be observed. The presence of these patterns in drug abusers or in patients with an occupational history of exposure to talc is highly suggestive of pulmonary talcosis.     

Autoantibody against caspase-3, an executioner of apoptosis, in patients with systemic sclerosis

The objective of the study was to determine the presence or levels of antibodies (Abs) against caspase-3 and their clinical relevance in systemic sclerosis (SSc). Anti-caspase-3 Ab was examined by enzyme-linked immunosorbent assay and immunoblotting. IgG anti-caspase-3 Ab levels in SSc patients were higher than in normal controls. SSc patients positive for IgG anti-caspase-3 Ab had significantly longer disease duration, more frequent presence of decreased %VC and %DLco, and elevated levels of serum immunoglobulin and erythrocyte sedimentation rates. IgG anti-caspase-3 Ab levels correlated positively with serum IgG levels, renal vascular resistance, and serum levels of 8-isoprostane. Immunoblotting analysis confirmed the presence of anti-caspase-3 Ab in sera from SSc patients. Caspase-3 enzymatic activity was inhibited by IgG isolated from SSc sera containing IgG anti-caspase-3 Ab. These results suggest that autoantibody against caspase-3 is generated in SSc and that this Ab is related to the severity of pulmonary fibrosis, vascular damage, and inflammation.     

Ubiquitination regulates MHC class II-peptide complex retention and degradation in dendritic cells

The expression and turnover of MHC class II-peptide complexes (pMHC-II) on the surface of dendritic cells (DCs) is essential for their ability to activate CD4 T cells efficiently. The half-life of surface pMHC-II is significantly greater in activated (mature) DCs than in resting (immature) DCs, but the molecular mechanism leading to this difference remains unknown. We now show that ubiquitination of pMHC-II by the E3 ubiquitin ligase membrane-associated RING-CH 1 (March-I) regulates surface expression, intracellular distribution, and survival of pMHC-II in DCs. DCs isolated from March-I-KO mice express very high levels of pMHC-II on the plasma membrane even before DC activation. Although ubiquitination does not affect the kinetics of pMHC-II endocytosis from the surface of DCs, the survival of pMHC-II is enhanced in DCs obtained from March-I-deficient and MHC-II ubiquitination-mutant mice. Using pMHC-II-specific mAb, we show that immature DCs generate large amounts of pMHC-II that are remarkably stable under conditions in which pMHC-II ubiquitination is blocked. Thus, the cellular distribution and stability of surface pMHC-II in DCs is regulated by ubiquitin-dependent degradation of internalized pMHC-II.