Calcium oxalate crystal deposition in a patient with Aspergilloma due to Aspergillus niger

Discrimination between aspergilloma and chronic necrotizing pulmonary aspergillosis (CNPA) based on radiological findings can difficult. We describe a patient with aspergilloma and organizing pneumonia that was possibly caused by Aspergillus niger infection and radiologically mimicked CNPA. A postmortem histological analysis showed diffuse alveolar damage that had originated in peri-cavitary lung parenchyma. Calcium oxalate or Aspergillus niger was located inside, but not outside the cavity in the right upper lobe. Calcium oxalate or other unknown hyphal bioactive components might provoke severe lung inflammation not only adjacent to the cavity, but also on the contralateral side.KEY WORDS : Calcium oxalate crystal deposition, aspergilloma, black deposits, Aspergillus niger     

Polyunsaturated fatty acid saturation by gut lactic acid bacteria affecting host lipid composition

In the representative gut bacterium Lactobacillus plantarum, we identified genes encoding the enzymes involved in a saturation metabolism of polyunsaturated fatty acids and revealed in detail the metabolic pathway that generates hydroxy fatty acids, oxo fatty acids, conjugated fatty acids, and partially saturated trans-fatty acids as intermediates. Furthermore, we observed these intermediates, especially hydroxy fatty acids, in host organs. Levels of hydroxy fatty acids were much higher in specific pathogen-free mice than in germ-free mice, indicating that these fatty acids are generated through polyunsaturated fatty acids metabolism of gastrointestinal microorganisms. These findings suggested that lipid metabolism by gastrointestinal microbes affects the health of the host by modifying fatty acid composition.Dietary fats are metabolized not only by humans but also by microbes in our gastrointestinal tracts. Microorganisms in the gastrointestinal tract interact with their host in many ways and contribute significantly to the maintenance of host health (1). Lipid metabolism by gastrointestinal microbes generates multiple fatty acid species, such as conjugated fatty acids and trans-fatty acids, that can affect host lipid metabolism (2). However, lipid metabolism by gastrointestinal microbes has not been explored in detail. Saturation metabolism of polyunsaturated fatty acids, a representative mode of lipid metabolism by gastrointestinal microbes, is a detoxifying metabolism of anaerobic bacteria, such as lactic acid bacteria, that reside in colon and intestine. This process transforms growth-inhibiting free polyunsaturated fatty acids into less toxic free saturated fatty acids (3). This saturation metabolism generates characteristic fatty acids (e.g., conjugated fatty acids and trans-fatty acids, which are well known to present in ruminant-derived foods and exert various physiological activities).“Conjugated fatty acid” is a collective term for positional and geometric isomers of fatty acids with conjugated double bonds. In particular, conjugated linoleic acids (CLAs), such as cis-9,trans-11-CLA and trans-10,cis-12-CLA, reduce carcinogenesis (4), atherosclerosis (5), and body fat (6). With regard to lipid metabolism, CLA is a potent peroxisome proliferator-activated receptor (PPAR)α agonist (7), and treatment with CLA increases the catabolism of lipids in the liver of rodents (8). Based on these findings, CLA is now commercialized as a functional food for control of body weight, especially in the United States and European countries.On the other hand, consumption of trans-fatty acids increases the risk of coronary heart disease by increasing LDL and reducing HDL cholesterol levels (9). Consequently, trans-fatty acids are considered to be harmful for health, and nutritional authorities have recommended that consumption of trans-fatty acids be reduced to trace amounts (10). Therefore, it is important to control fatty acid saturation processes that generate these fatty acids (11); however, the precise metabolic pathway and enzymes involved have not been clearly identified.Our analyses on conjugated fatty acid synthesis in representative gut bacteria, the lactic acid bacteria (12–15), demonstrated that Lactobacillus plantarum AKU 1009a (AKU Culture Collection, Faculty of Agriculture, Kyoto University) can transform the cis-9,cis-12 diene structure of C18 fatty acids such as linoleic acid, α-linolenic acid, and γ-linolenic acid into the conjugated diene structures cis-9,trans-11 and trans-9,trans-11 (16–21). In addition, this strain can saturate these conjugated dienes into the trans-10 monoene. Our subsequent metabolic analysis indicated that 10-hydroxy-12-octadecenoic acid is an intermediate of CLA synthesis, and further investigations of hydroxy fatty acid metabolism by lactic acid bacteria revealed that CLA is produced from hydroxy fatty acids such as ricinoleic acid in castor oil (22–25). In cell-free extracts from this strain, we identified the enzymes involved in CLA synthesis (26). Three enzymes, CLA-HY, CLA-DH, and CLA-DC, are necessary for synthesis of conjugated fatty acids such as CLA. Only the combined action of these three enzymes can generate CLA from linoleic acid, with 10-hydroxy-cis-12-octadecenoic acid arising as an intermediate (Fig. 1B, 3). The reactions catalyzed by each enzyme, however, were not revealed in those studies. Through genomic analysis in L. plantarum WCFS1, we found that cla-dh (GenBank accession no. {"type":"entrez-nucleotide","attrs":{"text":"NC_004567","term_id":"380031102","term_text":"NC_004567"}}NC_004567; region: 59613-60473) and cla-dc (GenBank accession no. {"type":"entrez-nucleotide","attrs":{"text":"NC_004567","term_id":"380031102","term_text":"NC_004567"}}NC_004567; region: 60505-61350) are located in a cluster with another gene, cla-er (GenBank accession no. {"type":"entrez-nucleotide","attrs":{"text":"NC_004567","term_id":"380031102","term_text":"NC_004567"}}NC_004567; region: 61378-62031) (Fig. 1A). In light of this, we tried to identify the function of the gene product (CLA-ER) together with those of CLA-HY, CLA-DH, and CLA-DC.Open in a separate windowFig. 1.Gene clusters for polyunsaturated fatty acid metabolism and GC chromatograms. (A) Gene clusters for fatty acid metabolic enzymes in L. plantarum. (B) GC chromatograms of substrate (1); reaction with CLA-HY (2); reaction with CLA-HY, CLA-DH, and CLA-DC together with FAD and NADH (3); and reaction with CLA-HY, CLA-DH, CLA-DC, and CLA-ER together with FAD and NADH (4). I.S., internal standard.     

Efficacy of Alfacalcidol on PEG-IFN/ Ribavirin Combination Therapy for Elderly Patients With Chronic Hepatitis C: A Pilot Study

Background

Serum vitamin D concentration is reported to show a decrease in older age. Patients with chronic hepatitis C (CHC) in Japan are older on average than those in Western countries. Moreover, the outcome of pegylated-interferon (PEG-IFN)/ ribavirin therapy combined with vitamin D in elderly patients is unclear.

Objectives

This pilot study explored the efficacy and safety of alfacalcidol as vitamin D source in PEG-IFN/ ribavirin combination therapy for elderly CHC patients infected with hepatitis C virus genotype 1b.

Patients and Methods

Consecutive twenty CHC patients aged ≥ 65 years were enrolled in this pilot study. Fifteen patients met the inclusion criteria and received PEG-IFN/ ribavirin therapy combined with alfacalcidol. Four-week lead-in of oral alfacalcidol was conducted, and it was subsequently and concurrently administered in PEG-IFN/ ribavirin combination therapy (vitamin D group). Age, gender, and IL28B genotype-matched patients, who received PEG-IFN/ ribavirin alone, were saved as control group (n = 15) to compare the treatment outcome with the vitamin D group.

Results

Subjects consisted of 14 males and 16 females, with a median age of 70 years (65-78). The serum 25 (OH) D3 concentration in females (20 ng/ml, 11-37) was significantly lower than males (27 ng/mL, 13-49) (P = 0.004). Sustained virological response (SVR) rates were 33.3% (5/15) in the control group and 80.0% (12/15) in the vitamin D group, respectively (P = 0.025). While no significant difference was shown in the (SVR) rate between the two groups among males (P = 0.592), in females the SVR rate was significantly higher in the vitamin D group (87.5%, 7/8) than the control group (25.0%, 2/8) (P = 0.041). The relapse rates in the groups with and without alfacalcidol were 7.7% (1/13) and 61.5% (8/13), respectively (P = 0.011). Interestingly, in females, the relapse in the control group was shown in 5 of 7 (71.4%), whereas in the vitamin D group the relapse rate was decreased (1/8, 12.5%) (P = 0.041). No specific adverse events were observed in the vitamin D group.

Conclusions

PEG-IFN/ ribavirin combined with alfacalcidol may be effective and safe in elderly CHC patients. In particular, concomitant administration of alfacalcidol may lead to a reduced relapse rate, and consequently improving the SVR rate in elderly females.     

Diffuse gastroduodenitis associated with ulcerative colitis: Treatment by infliximab

Diffuse gastroduodenitis resembling ulcerative colitis in respect to macro‐ and microscopic findings occurs in ulcerative colitis, although it is rare. Reports of gastroduodenitis associated with ulcerative colitis treated with infliximab are rare. A 58‐year‐old man had tarry stool in March 2011. He had a history of ulcerative colitis that was diagnosed in 1984. He underwent subtotal colectomy in 1991. Endoscopy and radiography revealed diffuse friable mucosa throughout the duodenum and an ulcer in the middle of the descending portion, resulting in a narrow portion.In the stomach, numerous small aphthae were observed in the antrum. Biopsy specimens of the duodenum and antrum showed marked inflammatory cell infiltration in both areas and cryptitis in the duodenum. Standard induction therapy of infliximab was started in April. The ulcer in the descending portion became a scar without diffuse mucosal friability in September 2011.     

Hematopoiesis from pluripotent stem cell lines

Embryonic stem cells (ESCs) can differentiate into various types of hematopoietic cells (HPCs) when placed in an appropriate environment. Various methods for the differentiation of ESCs into specific HPC lineages have been developed using mouse ESCs. These ESC-differentiation methods have been utilized also as an in vitro model to investigate hematopoiesis in embryos and they provided critical perceptions into it. These methods have been adapted for use with human ESCs, which have the possibility of being employed in regenerative medicine; further improvement of these methods may lead to the efficient production of HPCs for use in transfusions. The generation of transplantable hematopoietic stem cells is a medical goal that is still difficult to achieve. Recently, induced pluripotent stem (iPS) cells have been established from differentiated cells. Thereby, iPS cells have expanded further possibilities of the use of pluripotent stem cell lines in clinical application. Indeed, iPS cells have been established from cells with disease genes and those which have undergone reprogramming and targeting have generated phenotypically normal HPCs. Here, we mainly summarize the recent progress in research on hematopoiesis conducted with ESCs and iPS cells.     

Predictors of a better outcome of pneumatic dilatation in patients with primary achalasia

Objective  

Pneumatic dilatation (PD) has been widely used in the treatment of primary achalasia. The aim of this study was to evaluate the effectiveness of PD and its predictive factors in Japanese patients with primary achalasia.     

The use of H1-receptor antagonists and left ventricular remodeling in patients on chronic hemodialysis

Suppression of left ventricular (LV) remodeling secondary to heart failure seems critical to improve the prognosis of hemodialysis (HD) patients. This is a retrospective study on the relationship of an antiallergic drug and antihistamines with LV hypertrophy. A total of 149 patients (88 males and 61 females) were entered in the study. Mean age was 66.7 years and mean duration of dialysis 14.4 years. Twenty-three patients received oral treatment with an antiallergic drug or second-generation antihistamines, 3 with the antiallergic drug and 20 with antihistamines. The multivariate analysis using LV mass index (LVMI) as the objective variable extracted the following independent factors: male sex, erythropoietin (EPO)/w, uric acid (UA), total cholesterol, antihistamines, antiallergic drug, and calcium channel blocker (CCB), with a standard regression coefficient of 0.187, 0.196, 0.212, −0.262, −0.215, −0.149 and −0.173, respectively. This study suggests a suppressive role of second-generation antihistamines on LV remodeling. Male sex, high-dose EPO/w, and elevated UA were considered as aggravating factors, and CCB as a suppressive factor.     

Relation of oral 1α-hydroxy vitamin D3 to the progression of aortic arch calcification in hemodialysis patients

The role of decreased active vitamin D levels on vascular calcification has not been elucidated in hemodialysis (HD) patients. The aim of the present study was to evaluate the relationship between progression of aortic arch calcification (AoAC) and prescribed dose of 1α-hydroxy vitamin D. The enrolled study subjects were 65 (40 men and 25 women) HD patients. Calcification of the aortic arch was semiquantitatively estimated with a score (AoACS) on plain chest radiology. Change in AoACS (ΔAoACS) was obtained by subtracting the baseline AoACS value from the follow-up AoACS value. The second assessment was performed from 2 years after the first determination. The nonprogressors (63.2 ± 14.5 years) were significantly younger than the progressors (68.2 ± 10.8 years) (P = 0.0419). In addition, prescribed dose of 1α-hydroxy vitamin D3 was significantly higher in the nonprogressors (125.5 ± 109.1 μg) than progressors (84.8 ± 81.1 μg) (P = 0.0371). Multiple regression analysis revealed prescribed dose of 1α-hydroxy vitamin D₃ (β value = −0.324, P = 0.0051) as well as DBP (β value = −0.418, P = 0.007), serum levels of P (β value = 0.333, P = 0.006) and C-reactive protein (β value = 0.237, P = 0.0048) to be significant independent determinants of ΔAoACS. In conclusion, the evaluation of AoACS on chest radiography is a very simple tool in HD patients. Active vitamin D therapy seems to protect patients from developing vascular calcification.     

Soluble Fas ligand and atherosclerosis in hypertensive patients

BACKGROUND : The Fas-Fas ligand (FasL) system is involved in apoptosis in many types of cells. Recently, the expression of FasL on endothelial cells was reported. FasL is cleaved by a metalloproteinase and released in serum as soluble FasL (sFasL). Vasoactive substances, including metalloproteinase, are modulated by endothelial dysfunction. Advanced atherosclerosis and impaired endothelial function are seen in hypertensive patients. The inflammatory response has an important role in the development of atherosclerosis, whereas C-reactive protein (CRP) is associated with the presence and severity of atherosclerosis. OBJECTIVE : To measure the intima-media thickness of the common carotid artery and evaluate the relationship between atherosclerosis and serum sFasL concentrations in hypertensive patients. PATIENTS AND MAIN OUTCOME MEASURES : Forty-seven patients with hypertension participated in the study. The intima-media thickness of the common carotid artery was evaluated by ultrasound imaging. Serum concentrations of sFasL were measured by enzyme-linked immunosorbent assay. RESULTS : Intima-media thickness correlated positively with age (r = 0.362, P = 0.012) and sFasL concentrations (r =0.332, P = 0.022), and negatively with creatinine clearance (r = -0.399, P = 0.0055). A general linear model analysis with atherosclerotic risk factors and sFasL revealed that age, sFasL, high-density lipoprotein-cholesterol and systolic blood pressure were significantly associated with intima-media thickness. Furthermore, we demonstrated that serum sFasL is directly associated with CRP concentration (r = 0.316, P = 0.030). CONCLUSIONS : These results indicated that serum sFasL concentration is associated with atherosclerosis and inflammatory disease, in patients with hypertension.     

An assay for long-term engrafting human hematopoietic cells based on newborn NOD/SCID/beta2-microglobulin(null) mice

OBJECTIVE: Of various types of xenograft assays, the use of NOD/SCID mice has been the most popular method for quantitating candidate human stem cells. Limitations of the assay include low levels of engraftment, except when large numbers of cells are injected, and the development of thymic lymphoma, which precluded observation of long-term engraftment. In order to establish an assay that allows long-term in vivo engraftment and higher engraftment levels by a reasonable number of human cells, we tested a model based on "conditioned newborn" NOD/SCID or NOD/SCID/beta2-microglobulin(null) (BMG(null)) mice. MATERIALS AND METHODS: Using human cord blood mononuclear cells, we tested various nonradiation conditioning regimens and cell injection routes. Conditioning with a combination of 5-fluorouracil (5FU) and anti-mouse c-kit blocking antibody (Ack-2) or a combination of busulfan (BU) and cyclophosphamide (CY) and the use of facial vein for the cell injection route yielded the highest levels of multilineage engraftment. RESULTS: At 4-5 months posttransplantation, the median of engraftment level in bone marrow with 5FU/Ack-2 and BU/CY regimens were 0.9% (range: 0.2-40.5%) and 2.1% (range: 0.3-2.4%) in NOD/SCID mice, and 11.3% (range: 0.7-38%) and 14.1% (range: 0.8-52%) in NOD/SCID/BMG(null) mice, respectively. Multilineage engraftment was demonstrated by flow cytometry and by the growth of multilineage colonies in methylcellulose culture. Secondary transplantation of the isolated human CD45(+) cells, also performed at 4-5 months posttransplantation, revealed engraftment at the levels of 1.5 +/- 0.42% at 2 months after secondary transplantation. CONCLUSION: Our assay may provide a quantitative method for analysis of human hematopoietic stem cells.