Successful use of long-acting octreotide for protracted gastrointestinal bleeding related to protein-losing enteropathy after the Fontan procedure: a case report.

Gastrointestinal bleeding complicated with protein-losing enteropathy after the Fontan procedure has been often reported in recent years, but there is no established therapy for it.We report the case of an 18-year-old boy who suffered from abdominal pain, melena, and anaemia due to intractable haemorrhagic protein-losing enteropathy after the Fontan procedure. He was successfully treated with octreotide therapy.

Clinical assessment of upper airway and its complications in Hunter syndrome.

BACKGROUND: Hunter syndrome (HS) is an X-linked, recessive, lysosomal storage disease caused by a deficiency of the lysosomal enzyme, iduronate sulfatase (IDS). It is characterized by multisystem accumulations of glycosaminoglycans and upper airway obstruction is one of the major causes of death. While the current disease severity classifications for HS are mainly based on the degree of neurocognitive impairment, its association with the level of upper airway obstruction has not been assessed. METHODS: A retrospective chart review of HS patients who were followed at the Jikei University School of Medicine was performed. Association between the degree of airway obstruction and the currently used disease severity scores was evaluated. RESULTS: We identified eight HS patients and they were enrolled in the study. The Modified Mallampati classification (MMC) score, used to predict difficulties for oropharyngeal procedures, was significantly correlated with the HS severity. It was also correlated with the Apnea-Hypopnea Index (AHI). No significant correlation between IDS enzymatic activity and the severity of HS disease was identified. CONCLUSIONS: Variable clinical expressivities exist in HS, but the risk of respiratory complications is likely to be associated with disease severity, assessed by the previously recognized neurocognitive function-based severity scoring systems. MMC can be a simple supplementary tool to evaluate disease severity as well as predict difficulties for oropharyngeal procedures and respiratory function complications in HS, such as sleep apnea.

Emergence and Characterization of Acute Coronary Syndrome in Adults After Confirmed or Missed History of Kawasaki Disease in Japan: A Japanese Nationwide Survey.

Background: Acute coronary syndrome (ACS), which is emerging in adults long after confirmed (followed-up or lost-to-follow), or missed Kawasaki disease (KD), is poorly characterized. Methods and Results: A Japanese retrospective nationwide hospital-based questionnaire survey of ACS during 2000-09 was conducted to characterize such patients. Among a total of 67 patients (median age 35, male 76%) recruited, low conventional coronary risks (≤1/6) was noted in 75%, a diagnosis of ST-elevation and myocardial infarction or cardiac arrest in 66%, medication before ACS in 22% (warfarin in 4%), and no prior history of acute myocardial infarction in 94%. One-month mortality was 19%. KD diagnosis was made in 32 during acute illness (Group A), in which 17 were lost to follow, and retrospectively in the other 35 from coronary imaging at ACS (Group B). Group A developed ACS at lower coronary risks (≤2/5 in 87 vs. 65% in group B, p = 0.043) at a younger age (26.5 vs. 40 yo, p < 0.001). In group A, followed-up patients developed ACS under medication before ACS (87 vs. 0% in lost-to-follow patients, p < 0.001) for giant aneurysm in culprit lesions (69 vs. 29%, p = 0.030). One-month mortality was comparable between groups A and B, and between patients followed-up and lost-to-follow in group A. The culprit lesion in group A was characterized by the association of an aneurysm ≥6 mm in acute KD (100%), lack of significant stenosis (61%) or giant aneurysm (50%) in the long-term (median interval 16 y), and the presence of intravascular ultrasound-derived calcification at ACS (86%). Conclusions: The present retrospective nationwide questionnaire survey demonstrated nationwide emergence of initial ACS in young adults at low coronary risks, who are followed-up or lost-to-follow after confirmed KD and initial coronary aneurysms ≥6 mm.

Biochemical evidence of cell starvation in diabetic hemodialysis patients.

Recently, the ratio of patients with diabetes mellitus (DM) among hemodialysis (HD) patients has increased to become the largest sub-population. Their prognoses are significantly worse than those of patients without diabetes (non-DM). In the present study, 10 DM patients who did not take meals and 10 non-DM patients who took meals during HD sessions were investigated. The time courses of the change in plasma levels of metabolites during HD were determined. DM patients exhibited decreased plasma levels of lactate, pyruvate and alanine and dramatically increased levels of ketone bodies. At the end of HD, the plasma levels of lactate, pyruvate, alanine and ketone body were 0.46 ± 0.07, 0.026 ± 0.01, 0.12 ± 0.04 and 0.26 ± 0.04 mM (mean ± standard error), respectively. The profile was 'hypolactatemia and hyperketonemia', indicating non-homeostasis. Glycolysis and tricarboxylic acid cycle were suppressed, and the oxidation of fatty acid was accelerated, indicating starvation, even though high amounts of glucose (150 mg/dl) in dialysate were supplied continuously to the bloodstream. In contrast, the plasma levels of lactate, pyruvate, and alanine in the non-DM patients were increased, with the levels of ketone body remaining low during HD to maintain homeostasis, indicating accelerated glycolysis. Furthermore, their plasma levels of insulin increased from 8.1 ± 1.4 to 19.8 ± 3.4 µU/ml, which indicated endogenous secretion stimulated by glucose in dialysate and meal intake. In contrast, in the DM patients, the levels decreased from 19.2 ± 3.4 to 5.5 ± 1.1 µU/ml. This value was the lower limit of the normal range. The depletion of the insulin through extracorporeal circulation may inhibit the transportation of glucose from the blood into the muscles, with the consequence of cell starvation. Such cell starvation along with lipolysis every two days may accelerate proteolysis and affect the prognosis of DM patients.

P-Tau and Subunit c Mitochondrial ATP Synthase Accumulation in the Central Nervous System of a Woman with Hurler-Scheie Syndrome Treated with Enzyme Replacement Therapy for 12 Years.

We report an autopsy case of a woman with mucopolysaccharidosis type I (MPS I) Hurler-Scheie syndrome who was treated with enzyme replacement therapy (ERT) for 12 years. This was the first case of MPS I treated with ERT in Japan. Pathological analysis showed no glycosaminoglycan accumulation in the liver and spleen as a result of long-term ERT, although severe aortic stenosis, diffuse intimal hyperplasia of the coronary artery, and fibrous hypertrophy of the endocardium were observed. Additionally, we detected subunit c mitochondrial ATP synthase (SCMAS) accumulation and mild tauopathy (hyperphosphorylated tau or p-tau, both 3-repeat and 4-repeat tau accumulation) in the same area of the cerebral limbic system and central gray matter of the mid brain and pons. Tauopathy is an important pathological finding in Alzheimer's disease and other neurodegenerative disorders; however, in MPS I, it is unclear whether tauopathy is a primary or secondary phenomenon. Thus, in this report, we describe pathological accumulation of p-tau and SCMAS in the context of MPS I and discuss the mechanisms and importance of these findings in the pathogenesis of MPS I.

Low risk of treatment resistance in Down syndrome with Kawasaki disease.

BACKGROUND: A Japanese nationwide survey has reported that Down syndrome (DS) is a less-frequently occurring comorbidity in Kawasaki disease (KD). Although altered immune responses are frequently observed in DS, no studies have focused on the treatment response and risk for coronary artery abnormalities (CAA) in DS patients with KD. The aim of this study was therefore to evaluate the clinical manifestations, treatment response and prevalence of CAA in DS with KD. METHODS: We retrospectively reviewed the medical records of DS patients with KD from 2005 through 2012. The survey questionnaires were sent to facilities nationwide, and clinical data regarding KD in DS were collected. A control group consisted of non-DS patients with KD who were managed at Toho University. RESULTS: Of the 94 233 children diagnosed with acute KD from 2005 to 2012, 16 children with acute KD also had DS (0.017%). The DS-KD patients were significantly older than the non-DS patients (median, 8 years vs 1 year, P < 0.05, respectively). Half of the DS patients had incomplete KD. Although 50% of the DS children were at high risk of immunoglobulin resistance, all children responded to initial treatment and none had CAA. CONCLUSIONS: All DS-KD patients responded to initial i.v. immunoglobulin (IVIG) or aspirin despite having a high risk of IVIG resistance, and none of the DS patients had CAA. This suggests that the risk of treatment resistance and development of CAA may be not higher in DS patients with acute KD.

Prognostic predictive value of gene mutations in Japanese patients with hypertrophic cardiomyopathy.

Although some studies have attempted to find useful prognostic factors in hypertrophic cardiomyopathy (HCM), those results are not fully helpful for use in actual clinical practice. Furthermore, several genetic abnormalities associated with HCM have been identified. However, the genotype-phenotype correlation in HCM remains to be elucidated. Here, we attempted to assess patients with different types of gene mutations causing HCM and investigate the prognosis. A total of 140 patients with HCM underwent a screening test for myofilament gene mutations by direct sequencing of eight sarcomeric genes. Patients with a single mutation in cardiac troponin T, cardiac troponin I, α-tropomyosin, and regulatory and essential light chains were excluded from the study because the number of cases was too small. The clinical presentations and outcomes of the remaining 127 patients with HCM, 31 ß-myosin heavy chain (MYH7) mutation carriers, 19 cardiac myosin-binding protein C (MYBPC3) mutation carriers, and 77 mutation non-carriers were analyzed retrospectively. MYBPC3 mutation carriers had a high frequency of ventricular arrhythmia and syncope. Kaplan-Meier curves revealed no significant difference in prognosis among the three groups, but a lack of family history of sudden death (SD) and a past history of syncope were significantly related to poor prognosis. An absence of family history of SD and past history of syncope are useful prognostic factors in patients with HCM. MYH7 and MYBPC3 mutations did not significantly influence prognosis compared to non-carriers. However, patients with the MYBPC3 mutation should be closely followed for the possibility of SD.

Plasma Levels of Biotin Metabolites Are Elevated in Hemodialysis Patients with Cramps.

Patients with renal failure undergoing hemodialysis (HD) are susceptible to muscle cramps during and after HD. Muscle cramps are defined as the sudden onset of a prolonged involuntary muscle contraction accompanied by severe pain. Through HD, water-soluble vitamins are drawn out with water. Since biotin, a water-soluble vitamin, plays an essential role as one of the coenzymes in producing energy, we have hypothesized that deficiency of biotin may be responsible for HD-associated cramps. We previously reported that biotin administration ameliorated the muscle cramps, despite the elevated plasma biotin levels before HD and biotin administration, as judged by an enzyme-linked immunosorbent assay (ELISA). However, the ELISA measures not only biotin but also total avidin-binding substances (TABS) including biotin metabolites. In the present study, we determined biotin in HD patients as well as healthy controls, using a newly developed method with ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). The plasma samples were collected from 28 HD patients (16 patients with cramps and 12 patients without cramps) before HD and biotin administration and from 11 controls. The results showed that the accumulation of biotin and TABS in plasma of HD patients compared to controls. Importantly, the levels of biotin metabolites, i.e. TABS subtracted by biotin, increased significantly in patients with cramps over those without cramps. Moreover, the levels of biotin metabolites were significantly higher in patients with a poor response to administered biotin, compared to those with a good response. We propose that accumulated biotin metabolites impair biotin's functions as a coenzyme.

Optimal step-down approach for pediatric asthma controlled by salmeterol/fluticasone: A randomized, controlled trial (OSCAR study).

BACKGROUND: Several guidelines, including the Japanese Pediatric Guideline for the Treatment and Management of Asthma (JPGL), recommend salmeterol/fluticasone combination therapy (SFC) as step 3 to 4 treatment for moderate to severe asthma. However, the optimal step-down approach to SFC remains unclear. In the current study, we examined step-down approaches in asthmatic children whose symptoms had been stabilized by SFC 100/200 µg/day. METHODS: This randomized, multicenter, open-label, parallel-group study was conducted over 12 weeks. For step-down therapy, subjects aged 5-15 years were randomly assigned to an SFC group (25/50 µg b.i.d.) or an FP group (100 µg b.i.d.), and treated for 12 weeks. Childhood Asthma Control Test (C-ACT) scores, lung function, and exhaled nitric oxide (FeNO) levels were monitored. RESULTS: Of 131 enrolled subjects, 128 completed the study and were included in the analysis. Decreases in % peak expiratory flow rate and % forced expiratory flow at 50% of vital capacity (V50) were observed in the FP group at each time point. There was a significant difference between the two groups for the change in %V50 from its previous value at each time point. There were no significant changes in FeNO levels (range 15-20 ppb) or C-ACT scores (∼26 points) within or between groups. CONCLUSIONS: A high level of asthma control was maintained with both approaches. The use of SFC step-down resulted in somewhat better respiratory function, with no worsening of airway inflammation. However, halving the dose of SFC and switching to FP alone are both optimal step-down approaches.

Low Cardiac Output Leads Hepatic Fibrosis in Right Heart Failure Model Rats.

BACKGROUND: Hepatic fibrosis progresses with right heart failure, and becomes cardiac cirrhosis in a severe case. Although its causal factor still remains unclear. Here we evaluated the progression of hepatic fibrosis using a pulmonary artery banding (PAB)-induced right heart failure model and investigated whether cardiac output (CO) is responsible for the progression of hepatic fibrosis. METHODS AND RESULTS: Five-week-old Sprague-Dawley rats divided into the PAB and sham-operated control groups. After 4 weeks from operation, we measured CO by echocardiography, and hepatic fibrosis ratio by pathological examination using a color analyzer. In the PAB group, CO was significantly lower by 48% than that in the control group (78.2±27.6 and 150.1±31.2 ml/min, P<0.01). Hepatic fibrosis ratio and serum hyaluronic acid, an index of hepatic fibrosis, were significantly increased in the PAB group than those in the control group (7.8±1.7 and 1.0±0.2%, P<0.01, 76.2±27.5 and 32.7±7.5 ng/ml, P<0.01). Notably, the degree of hepatic fibrosis significantly correlated a decrease in CO. Immunohistological analysis revealed that hepatic stellate cells were markedly activated in hypoxic areas, and HIF-1α positive hepatic cells were increased in the PAB group. Furthermore, by real-time PCR analyses, transcripts of profibrotic and fibrotic factors (TGF-ß1, CTGF, procollargen I, procollargen III, MMP 2, MMP 9, TIMP 1, TIMP 2) were significantly increased in the PAB group. In addition, western blot analyses revealed that the protein level of HIF-1α was significantly increased in the PAB group than that in the control group (2.31±0.84 and 1.0±0.18 arbitrary units, P<0.05). CONCLUSIONS: Our study demonstrated that low CO and tissue hypoxia were responsible for hepatic fibrosis in right failure heart model rats.

A simple and rapid ultra-high-performance liquid chromatography-tandem mass spectrometry method to determine plasma biotin in hemodialysis patients.

A simple, rapid, and selective method for determination of plasma biotin was developed using ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). After single-step protein precipitation with methanol, biotin and stable isotope-labeled biotin as an internal standard (IS) were chromatographed on a pentafluorophenyl stationary-phase column (2.1 × 100 mm, 2.7 µm) under isocratic conditions using 10 mm ammonium formate-acetonitrile (93:7, v/v) at a flow rate of 0.6 mL/min. The total chromatographic runtime was 5 min for each injection. Detection was performed in a positive electrospray ionization mode by monitoring selected ion transitions at m/z 245.1/227.0 and 249.1/231.0 for biotin and the IS, respectively. The calibration curve was linear in the range of 0.05-2 ng/mL using 300 µL of plasma. The intra- and inter-day precisions were all <7.1%. The accuracy varied from -0.7 to 8.2%. The developed UHPLC-MS/MS method was successfully applied to determine plasma biotin concentrations in hemodialysis patients. Copyright © 2016 John Wiley & Sons, Ltd.

Metabolic responses during hemodialysis determined by quantitative (1)H NMR spectroscopy.

A large proportion of patients with end-stage renal disease have lifelong hemodialysis (HD) treatment. HD rapidly and indiscriminately removes necessary small metabolites together with uremic toxins from plasma into dialysate. To investigate metabolic responses to HD, we determined the levels of metabolites through time-course monitoring of (1)H NMR spectroscopy of dialysate during HD. The dialysate sample is stable for analysis because it contains only small metabolites without proteins. It was collected non-invasively from 9 HD patients with chronic glomerular nephropathy, at 6 time points during 4h of HD in 5 sessions. Creatinine, alanine, lactate, pyruvate and valine were simultaneously quantified on a one-dimensional single-pulse spectrum with a single standard compound. The concentration of creatinine exhibited monotonous decay with time, while that of valine decreased slowly and then maintained its levels throughout an HD. Lactate, alanine and pyruvate increased at 2-3h after the initiation of HD. They exhibited remarkable responses to HD with production from the body. The time-course of change in the 4 metabolites of lactate, pyruvate, alanine, and valine had reproducible behavior unique to each patient during the HD. This finding may be applied to distinguish metabolic status in HD patients.

Residual glycosaminoglycan accumulation in mitral and aortic valves of a patient with attenuated MPS I (Scheie syndrome) after 6 years of enzyme replacement therapy: Implications for early diagnosis and therapy.

Mucopolysaccharidosis (MPS) is an inherited metabolic disease caused by deficiency of the enzymes needed for glycosaminoglycan (GAG) degradation. MPS type I is caused by the deficiency of the lysosomal enzyme alpha-l-iduronidase and is classified into Hurler syndrome, Scheie syndrome, and Hurler-Scheie syndrome based on disease severity and onset. Cardiac complications such as left ventricular hypertrophy, cardiac valve disease, and coronary artery disease are often observed in MPS type I. Enzyme replacement therapy (ERT) has been available for MPS type I, but the efficacy of this treatment for cardiac valve disease is unknown. We report on a 56-year-old female patient with attenuated MPS I (Scheie syndrome) who developed aortic and mitral stenosis and coronary artery narrowing. The cardiac valve disease progressed despite ERT and she finally underwent double valve replacement and coronary artery bypass grafting. The pathology of the cardiac valves revealed GAG accumulation and lysosomal enlargement in both the mitral and aortic valves. Zebra body formation was also confirmed using electron microscopy. Our results suggest that ERT had limited efficacy in previously established cardiac valve disease. Early diagnosis and initiation of ERT is crucial to avoid further cardiac complications in MPS type I.

¹H NMR spectroscopic quantification of plasma metabolites in dialysate during hemodialysis.

We used ¹H nuclear magnetic resonance (NMR) spectroscopy to assess metabolic responses in patients undergoing hemodialysis (HD). We collected 71 samples of plasma and dialysate from 10 patients before, during, and after HD. We used the dialysate as a possible substitute for blood plasma to quantify small metabolites by ¹H NMR. We confirmed TSP (sodium 3-(trimethylsilyl) propionate 2, 2, 3, 3-d4) as a reference of NMR intensity in dialysate. We examined TSP sensitivities in various dialysate spectra and the correlation between signal intensities and added quantities of TSP. We used integrations of signal areas on ¹H NMR spectra of plasma and dialysate to quantify concentrations of creatinine, lactate, alanine, and valine and calculate their ratios between plasma and dialysate. The ratios of metabolites in plasma to dialysate were 3.2±0.4 (creatinine), 3.6±0.5 (valine), 3.8±0.7 (alanine), and 4.0±0.8 (lactate) mM (mean±standard deviation [SD]). The broader distributions of ratios in levels of lactate and alanine suggested their de novo production during the HD session. Estimation of blood metabolite levels using dialysate is useful for quantitative analysis of metabolic status in blood during HD.

Massive accumulation of glycosaminoglycans in the aortic valve of a patient with Hunter syndrome during enzyme replacement therapy.

This report describes the pathologic findings for a patient with Hunter syndrome who underwent aortic valve replacement at 10 years of age, 3 years after the initiation of enzyme replacement therapy. Aortic valve pathology showed mild thickening and fibrosis as well as massive glycosaminoglycan accumulation. This suggests that enzyme replacement therapy has limited efficacy for cardiac valve disease both clinically and pathologically.

Biotin ameliorates muscle cramps of hemodialysis patients: a prospective trial.

Patients with renal failure undergoing hemodialysis often have muscle cramps during and after the dialysis therapy. Muscle cramps are defined as the sudden onset of a prolonged involuntary muscle contraction accompanied with severe pain, resulting in early termination of a HD session and inadequate dialysis. The etiology of the cramps is unknown and effective anti-cramp medicine is not available. We have hypothesized that water-soluble vitamins are deficient in HD patients. Accordingly, we administrated biotin to 14 patients who had frequent muscle cramps during HD sessions. Oral administration of 1 mg/day biotin promptly reduced the onset and the severity of cramps in 12 patients both during and after HD. Then, the plasma biotin levels were measured by an enzyme-linked immunosorbent assay method (ELISA) in HD patients, including 14 patients with cramps and 13 patients without cramps, and 11 healthy volunteers. Plasma biotin levels were elevated in 27 HD patients at baseline compared with healthy volunteers [451 (377 - 649) vs. 224 (148 - 308) ng/l, median (lower-upper quartiles); p < 0.0001]. Unexpectedly, among the 14 cramp patients, the biotin levels were significantly higher in biotin-ineffective 7 patients than biotin-effective 7 patients [1,064 (710 - 1,187) vs. 445 (359 - 476) ng/l; p < 0.001]. Thus, the biotins measured by ELISA may consist of not only intact biotin but also its metabolites that do not function as a vitamin. In conclusion, biotin administration is one choice to relieve HD patients from muscle cramps regardless of their elevated plasma biotin levels.

Solution structure of polytheonamide B, a highly cytotoxic nonribosomal polypeptide from marine sponge.

Polytheonamide B (pTB), a highly cytotoxic polypeptide, is one of the most unusual nonribosomal peptides of sponge origin. pTB is a linear 48-residue peptide with alternating D- and L-amino acids and contains a total of eight types of nonproteinogenic amino acids. To investigate the mechanisms underlying its cytotoxic activity, we determined the three-dimensional structure of pTB by NMR spectroscopy, structure calculation, and energy minimization. pTB adopts a single right-handed ß(6.3)-helical structure in a 1:1 mixture of methanol/chloroform with a length of approximately 45 A and a hydrophilic pore of ca. 4 A inner diameter. These features indicate that pTB molecules form transmembrane channels that permeate monovalent cations as gramicidin A channels do. The strong cytotoxicity of pTB can be ascribed to its ability to form single molecule channels through biological membranes.

Quantification of molecules in (1)H-NMR metabolomics with formate as a concentration standard.

Quantitative analysis of metabolites is important in (1)H-nuclear magnetic resonance (NMR)-based metabolomics of plasma. Human plasma contains a high density of proteins which heavily adsorb the commonly-used standard compound of sodium 3-(trimethylsilyl) propionate 2, 2, 3, 3-d(4) (TSP). We have evaluated calcium formate as an alternative standard in 1D single-pulse (1)H-NMR spectra to quantify plasma metabolites. Formate did not interact with either plasma metabolites or proteins under adequate conditions. Linear relations between the signal intensities and the added formate have been demonstrated in (1)H spectra. The quantifications of glucose and creatinine by this method have shown good accordance with biochemical analysis. Calcium formate is applicable as a concentration standard to NMR metabolomics of plasma.

Prognostic factors for the late onset Pompe disease with enzyme replacement therapy: from our experience of 4 cases including an autopsy case.

We report 4 cases of late onset glycogen storage disease type II (GSD II) or Pompe disease (OMIM #232300), under enzyme replacement therapy (ERT) with recombinant human acid alpha glucosidase (rh-GAA, OMIM *606800). In these 4 cases, we focused on the case of a 28-years-old man, whose condition at the ERT starting was the worst and resulted in poor prognosis. The autopsy was done under his family's permission, and revealed severe accumulation of glycogen in his muscle, especially diaphragm or iliopsoas, and pulmonary veno-occlusive disease (PVOD) which resulted in severe pulmonary hypertension (PH). This is the first report of PVOD as the cause of PH in Pompe disease. We studied this case comparing to another 3 cases of late onset Pompe disease under the same course of ERT in our hospital, and the average data of the group of late onset Pompe disease with severe pulmonary insufficiency receiving ERT, supposed that low score of the body mass index (BMI) on the baseline, the presence of specific genotype (p.R600C), and signs of pulmonary dysfunction suggesting PH (tachypnea, ultrasound cardiography data) were factors that influenced the prognosis. For a better prognosis in the late onset Pompe disease, an early diagnosis for the early start of ERT before the onset of respiratory failure should be important, and the deliberate management and care should be needed even after the ERT start, especially for severe cases including pulmonary dysfunction.