Value of renal biopsy in the prognosis of liver transplantation in familial amyloid polyneuropathy ATTR Val30Met patients

Liver transplantation for familial amyloid polyneuropathy (FAP) patients has been carried out worldwide and the outcomes seem to be promising. To clarify the severity of amyloid deposits on visceral organs, we evaluated the histopathological findings of biopsied renal and sural nerve specimens in 13 FAP patients with ATTR Val30Met by quantitative analysis, and compared them with the outcome of transplantation. Renal dysfunction with proteinuria seemed to correlate with the degree of amyloid deposits in glomeruli, not with that in medullary tissues. The severity of renal amyloid deposition did not consistently parallel that of myelinated nerve fiber loss in sural nerve. Three patients with proteinuria and severe amyloid deposits in glomeruli were considered to be unsuitable for transplantation. Ten patients underwent living donor liver transplantation and three resulted in unfavorable outcomes. These three had heavy amyloid deposits on renal tissues, especially in glomerular areas, but the severity of myelinated nerve fiber loss in their sural nerves was very similar to that in patients who made a good recovery. The prognosis after operation might be closely related to the severity of amyloid deposits in renal glomeruli. Renal biopsy is, therefore, recommended when determining the indications and contraindications for liver transplantation in FAP patients, although this biopsy is not routinely required.     

Effects of Transdermal Tulobuterol in Pediatric Asthma Patients on Long-Term Leukotriene Receptor Antagonist Therapy: Results of a Randomized,Open-Label,Multicenter Clinical Trial in Japanese Children Aged 4–12 Years

BackgroundFew studies have examined the efficacy or safety of a transdermal β2 agonist as add-on medicationto long-term leukotriene receptor antagonist (LTRA) therapy in pediatric asthma patients.MethodsIn this randomized, open-label, multicenter clinical trial, children aged 4-12 years on long-term LTRA therapy were treated with tulobuterol patches (1-2 mg daily) or oral sustained-release theophylline (usual dose, 4-5 mg_kg daily) for 4 weeks. LTRAs were continued throughout the trial. Outcomes included volume peak expiratory flow (% PEF), fractional exhaled nitric oxide (FeNO), clinical symptoms and adverse events.ResultsThirty-three and 31 patients were treated with tulobuterol patches and theophylline, respectively. % PEF measured in the morning and before bedtime was significantly higher at all times in the treatment period compared with baseline in the tulobuterol patch group (p < 0.001), and was significantly higher in the tulobuterol patch group compared with the theophylline group. FeNO was similar and unchanged from baseline in both groups. There were no drug-related adverse events in either group.ConclusionsThese results suggest that short-term use of a transdermal β2 agonist is an effective therapy for pediatric asthma without inducing airway inflammation in children on long-term LTRA therapy.     

A case of IgG4-related disease associated with diffuse large B cell lymphoma

In June 2008, a 74-year-old male was diagnosed with IgG4-related disease including histologically proven IgG4-related prostatitis, and then followed as an outpatient. In July 2011, cervical, chest, and abdominal computed tomography (CT) revealed right parotid gland swelling and lymph node enlargement of the supraclavicular, mediastinal, left hilar, porta hepatis, and para-aorta. A biopsy of the right parotid gland was performed, and we diagnosed diffuse large B-cell lymphoma (DLBCL). As malignancies are possible complications for patients with IgG4-related disease, we must be careful in the follow-up of IgG4-related disease patients.     

Drug-induced liver injury associated with Agaricus blazei Murill which is very similar to autoimmune hepatitis

Agaricus blazei Murill (ABM) is one of the most popular complementary alternative medicines (CAM). We experienced a case of a 60-year-old woman with severe hepatitis associated with extract of ABM and extract of Ganoderma lucidum, and a case of a 75-year-old man with drug-induced liver injury (DILI) associated with extract of ABM and fucoidan. Their clinical courses from the start of CAM until the onset of DILI were observed unexpectedly, because they were under observation for stable malignant neoplasms: stage III malignant thymoma and stage IV lung cancer, respectively. However, they did not talk about taking CAM with their physicians. There were two common points between these two cases. First, they were diagnosed as compatible with DILI by using an international diagnostic scale, the Roussel Uclaf Causality Assessment Method. The second point was that histological findings of the liver were very similar to autoimmune hepatitis (AIH). In addition, serum immunoglobulin G and zinc sulfate turbidity tests gradually increased from the start of CAM to the onset of DILI. Their clinical course and liver histology suggested that the immunostimulating action of ABM caused liver injury which was very similar to that seen in AIH.     

Novel compound heterozygous mutations of the growth hormone-releasing hormone receptor gene in a case of isolated growth hormone deficiency

ObjectiveTo elucidate the pathogenesis of isolated growth hormone (GH) deficiency in a Japanese girl without consanguinity.DesignA 2-year-old girl of height 77.2 cm (? 3.0 SD for Japanese girls) was found to have an insulin-like growth factor (IGF)-1 level of 7 ng/mL and IGF binding protein-3 (IGFBP-3) level of 0.41 μg/mL. GH responded modestly to a series of pharmacological stimulants, increasing to 2.81 ng/mL with insulin-induced hypoglycemia, 3.78 ng/mL with arginine, and 3.93 with GH-releasing hormone (GHRH). Following direct sequencing of the GHRH receptor (GHRHR) gene, evaluation by the luciferase reporter assay, immunofluorescence study, and in vitro splicing assay with minigene constructs was conducted.ResultsNovel compound heterozygous GHRHR gene mutations were identified in the patient. A p.G136V substitution elicited no luciferase activity increment in response to GHRH stimulation, with normal membranous expression. Splicing assay demonstrated that the IVS2 + 3a > g mutation would lead to aberrant splicing.ConclusionsA case of isolated GH deficiency due to novel GHRHR gene mutations was identified.     

Esophageal schwannoma of the upper mediastinum: report of a case

Esophageal schwannoma is extremely rare, and it is difficult to confirm a definitive diagnosis preoperatively. We report the case of a 67-year-old male with an asymptomatic esophageal schwannoma with a major axis of 6 cm. Computed tomographic angiography was very useful for determining a safe and efficient route of access to the tumor. Although high 18F-fluorodeoxyglucose uptake and high signal were revealed by diffusion-weighted images, a malignant potential was denied by low-grade clinical symptoms and surgical findings. The patient underwent tumor excision via a cervical collar incision and median sternotomy. This procedure was very useful and was shown to be safe for tumor exfoliation from the main blood vessel and nerve.     

Successful treatment of acute promyelocytic leukemia in a patient under hemodialysis with arsenic trioxide

A man with chronic kidney disease (CKD) under hemodialysis was diagnosed with acute promyelocytic leukemia (APL). He received arsenic trioxide as a single agent and achieved complete molecular remission without severe adverse events. Arsenic trioxide (ATO) can be used safely and effectively for APL with CKD.     

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.