Untersuchungen über die geschwulsthemmende Wirkung verschiedener Aminozucker

Zusammenfassung Die anaerobe Glykolyse bei Ehrlich-Ascitestumorzellen wurde durch GA und GAL (10^–2 M) um etwa 45% bzw. 35% gehemmt. N-Acetyl-d-Glucosamin und NGAL-Zusatz hatte keine Wirkung. Durch Hefehexokinase wurden GA und GAL in einem geringeren Ausmaß phosphoriliert als Glucose. Die Phosphorilierung der Glucose wurde durch GA um 28%, durch GAL um 20% gehemmt.Die endogene Atmung von Tumorzellen des Ehrlich-Ascitestumors und des Asciteshepatoms (AH-130) wurde durch GA in etwa dem gleichen Ausmaß wie durch Glucose (um etwa 45%) gehemmt. Der Crabtree-Effekt wurde durch GA verstärkt, durch GAL dagegen etwas abgeschwächt. Die atmungshemmende Wirkung von Glucose und GA wurde durch IAA bzw. KF nur wenig verändert. Die hemmende Wirkung von GA wurde durch DNP fast völlig aufgehoben, die der Glucose nur in den ersten 30 min.Die Glutaminase-I Aktivität bei Ehrlich-Ascitestumorzellen war vier- bis fünfmal höher als in der Leber von krebstragenden und gesunden Mäusen. Die Fermentaktivität wurde durch Glucose um 45%, durch GA um 35%, durch GAL um 10% und durch Glutaminsäure fast völlig gehemmt. Bei Inkubation der Tumorzellen mit GA eine größere Menge Ammoniak freigesetzt.Die Überlebenszeit von Ehrlich-Ascitestumor tragenden Mäusen wurde durch eine intraperitoneale Behandlung der Tiere mit GA verlängert.

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Summary Glucosamine and GAL inhibited the anaerobic glycolysis of Ehrlich ascites tumor cells by 45% and 35% respectively, but NGA and NGAL showed no effect. GA and GAL were phosphorylated less by yeast-hexokinase than was glucose. The phosphorylation of glucose was inhibited about 28% by GA and about 20% by GAL. The endogenous respiration of the cells of Ehrlich ascites tumor and of ascites hepatoma (AH-130) was inhibited by GA to about the same degree as by glucose (about 45%). The Crabtree effect of glucose control was increased by GA; in contrast, it was somewhat decreased by GAL. The respiratory inhibiting effect of glucose and GA were changed little with IAA or KF. The inhibiting effect of GA was almost completely abolished by DNP; that of glucose only in the first 30 min.The activity of glutaminase-I of Ehrlich ascites tumor cells was 4–5 times greater than that of the liver of tumor-bearing or healthy mice. The enzymatic activity was inhibited by glucose about 45%, by GA about 35%, by GAL about 10%, and by glutaminic acid completely. When the tumor cells were incubated with GA, NH₃ was liberated in large amounts, probably as the result of enzymatic deamination.The mice with Ehrlich ascites tumors survived longer after intraperitoneal injection of GA than control animals.

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Mit 4 Textabbildungen

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Mitteilung 40 der pharmakologischen Untersuchungen über den Stoffwechsel von Geschwulstgewebe.

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Diese Arbeit erfolgte mit der Unterstützung von U.S. Public Health Service Grant No. CY-5257.

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Herren Dr. G. Hertting, Dr. E. Stocklasker, Dr. O. Hornykiewicz und Dr. H. Iwata danken wir heirmit für ihre Hilfe bei der Übersetzung dieser Abhandlung.     

Amendment of the Japanese Consensus Guidelines for Autoimmune Pancreatitis, 2013 III. Treatment and prognosis of autoimmune pancreatitis

The standard treatment for autoimmune pancreatitis (AIP) is steroid therapy, although some patients improve spontaneously. Indications for steroid therapy in AIP patients are symptoms such as obstructive jaundice, abdominal pain, back pain, and the presence of symptomatic extrapancreatic lesions. Prior to steroid therapy, obstructive jaundice should be managed by biliary drainage, and blood glucose levels should be controlled in patients with diabetes mellitus. The recommended initial oral prednisolone dose for induction of remission is 0.6 mg/kg/day, which is administered for 2–4 weeks. The dose is then tapered by 5 mg every 1–2 weeks, based on changes in clinical manifestations, biochemical blood tests (such as liver enzymes and IgG or IgG4 levels), and repeated imaging findings (US, CT, MRCP, ERCP, etc.). The dose is tapered to a maintenance dose (2.5–5 mg/day) over a period of 2–3 months. Cessation of steroid therapy should be based on the disease activity in each case. Termination of maintenance therapy should be planned within 3 years in cases with radiological and serological improvement. Re-administration or dose-up of steroid is effective for treating AIP relapse. Application of immunomodulatory drugs is considered for AIP patients who prove resistant to steroid therapy. The prognosis of AIP appears to be good over the short-term with steroid therapy. The long-term outcome is less clear, as there are many unknown factors, such as relapse, pancreatic exocrine or endocrine dysfunction, and associated malignancy.     

Amendment of the Japanese Consensus Guidelines for Autoimmune Pancreatitis, 2013 I. Concept and diagnosis of autoimmune pancreatitis

Background

In response to the proposal of the international consensus diagnostic criteria (ICDC) for autoimmune pancreatitis (AIP) and the Japanese diagnostic criteria in 2011, the 2009 Japanese consensus guidelines for managing AIP required revision.

Methods

Three committees [the professional committee for making clinical questions (CQs) and statements by Japanese specialists, the expert panelist committee for rating statements by the modified Delphi method, and the evaluating committee by moderators] were organized. Fifteen specialists for AIP extracted the specific clinical statements from 1,843 articles published between 1963 and 2012 (obtained from Pub Med and a secondary database, and developed the CQs and statements. The expert panel individually rated the clinical statements using a modified Delphi approach, in which a clinical statement receiving a median score greater than seven on a nine-point scale from the panel was regarded as valid.

Results

The professional committee created 13 CQs and statements for the current concept and diagnosis of AIP, 6 for extra-pancreatic lesions, 6 for differential diagnosis, and 11 for treatment.

Conclusion

After evaluation by the moderators, amendments to the Japanese consensus guidelines for AIP have been proposed for 2013.     

A primigravida with very‐long‐chain acyl‐CoA dehydrogenase deficiency

Introduction: Valosin‐containing protein (VCP) is a ubiquitously expressed, multifunctional AAA‐ATPase protein. Its dominant mutations cause hereditary inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD) or amyotrophic lateral sclerosis. The pattern of muscle weakness in IBMPFD patients is variable and includes limb‐girdle, scapuloperoneal, distal, or axial distributions. Case Report: We report a 63‐year‐old man with progressive scapuloperoneal weakness, head drop, and hyperCKemia since age 40 years. Electromyography showed myopathic changes and rare myotonic discharges. Muscle biopsy revealed numerous lobulated fibers, few fibers with glycogen accumulation, and rare fibers with polyglucosan bodies. Rimmed vacuoles and congophilic inclusions, often seen in IBMPFD, were absent. VCP sequencing identified a novel heterozygous c. 1160G>A mutation resulting in p.Asn387Ser substitution. Conclusions: Our patient broadens the pathological spectrum of VCP‐myopathy and emphasizes the importance of VCP analysis in patients with scapuloperoneal muscular dystrophy despite the absence of Paget disease, dementia, rimmed vacuoles, or intracellular amyloid deposition. Muscle Nerve 50:295–299, 2014     

The muscle findings in a pediatric patient with live attenuated oral polio vaccine-related flaccid monoplegia

A pediatric patient, who was given live-attenuated oral polio vaccine twice without distinct gait disturbance during infancy, begun to present limp at 3 years. His gait disturbance became remarkable with aging. At 7 years, he was unable to dorsiflex the left ankle, and presented flaccid monoplegia of the left lower extremity, and the left Achilles tendon reflex was diminished. Magnetic resonance imaging revealed multiple crack-lines in the left anterior tibial muscle, but was unable to detect any distinct lesion at responsible level of L4, L5 and S1 anterior horn cells’ degeneration. Electromyography showed continuous fibrillation potentials, but muscle biopsy presented nearly normal in this muscle. The serum levels of polio antibody type 1 and type 2 titers were elevated 64× respectively, while the type 3 antibody titer was not elevated 4×. This patient was diagnosed as live attenuated oral polio vaccine-related flaccid monoplegia, with mild clinical course.     

Muscle‐specific calpain‐3 is phosphorylated in its unique insertion region for enrichment in a myofibril fraction

CAPN3 (also called p94/calpain‐3) is a skeletal muscle‐specific calpain, an intracellular cysteine protease. Loss of CAPN3 protease activity and/or structural functions cause limb‐girdle muscular dystrophy type 2A (LGMD2A). However, the precise mechanism of action of CAPN3 in skeletal muscles in vivo remains largely elusive. By studying the protein modifications that regulate CAPN3 activity, we found that CAPN3 was phosphorylated. By performing mutagenesis and mass spectrometry analyses, we identified two Ser residues at positions 629 and 636 in human CAPN3 that are phosphorylated and showed that S629 is a major phosphorylation site. Intriguingly, rapid and exhaustive autolysis of CAPN3 was slightly attenuated by the substitution of S629. In skeletal muscles, phosphorylated CAPN3 was enriched in the myofibril fraction. These results imply that phosphorylated CAPN3 is a myofibril structural component and/or participates in myofibril‐based signaling pathways, rather than functions as a protease. We evaluated the relationship between phosphorylated CAPN3 and the pathology of LGMD2A. The level of phosphorylated CAPN3 was greatly reduced in LGMD2A muscles. Our findings suggest that phosphorylated CAPN3 is involved in the pathology of LGMD2A through defects in myofibril integrity and/or signaling pathways. This is the first report that phosphorylation of CAPN3 may be involved in its physiological function.     

Proteome analysis of human placentae: pre-eclampsia versus normal pregnancy

Although placental proteins play multiple roles in fetal and placental development and in the maintenance of pregnancy, many remain inadequately characterized. In the present study, we comprehensively analyzed these proteins by using a proteomic approach. Samples were denatured with guanidine hydrochloride, which was found to be superior to the commonly used urea for the present purpose, and subjected to 2-dimensional (2D) electrophoresis (2-DE) to obtain placental proteome maps. The identified protein spots (ca. 60% of the total) on the proteome maps included several pregnancy-related proteins (PRPs). Furthermore, a novel 2D immunoblotting (2-DI) analysis of molecules related to pre-eclampsia revealed three immunopositive spots that appeared to correspond to dynactin p-50, a protein related to cell turn-over. The rate of positivity for dynactin p-50-reactive antibodies was significantly (P=0.0024) higher in 26 pre-eclamptic women than in 58 normally pregnant women. These results indicate that dynactin p-50 may be involved in the pathophysiology of pre-eclampsia.