Patients homozygous for the T435N mutation of succinyl-CoA:3-ketoacid CoA Transferase (SCOT) do not show permanent ketosis

Succinyl-CoA:3-ketoacid CoA transferase (SCOT; locus symbol OXCT; E.C. 2.8.3.5) is the main determinant of the ketolytic capacity of tissues. Hereditary SCOT deficiency causes episodic ketoacidosis. Permanent ketosis has been regarded as a pathognomonic feature of SCOT deficiency. There are three SCOT-deficient patients from a small region in Japan and they have not manifested permanent ketosis, even though their ketoacidotic crises were as severe as those of other SCOT-deficient patients. All three were homozygous for the T435N mutation. Transient expression analysis of wild-type and mutant cDNA showed that the T435N mutant retained significant residual SCOT activities (20% for that of the wild-type at 39.5 degrees C, 25% at 37 degrees C, and 50% at 30 degrees C). The difference of residual SCOT activities at these temperatures in expression analyses was due to differences in the level of the mutant protein. SCOT activity of the T435N protein was more vulnerable than the wild-type to heat treatment at 42 degrees C and 55 degrees C. These temperature-sensitive characteristics of the mutant protein may explain, in part, why the patients developed ketoacidotic crises during febrile illness. In SCOT-deficient patients retaining some residual activity, permanent ketosis may be absent.     

Succinyl-CoA:3-ketoacid transferase (SCOT) deficiency in a new patient homozygous for an R217X mutation

SCOT deficiency presents with persistent excess of ketones leading to ketoacidosis. Here we report patient GS15, homozygous for a novel R217X mutation, who had the first apparent ketoacidotic crisis at 8 months of age. Before confirmation of diagnosis, daily dialysis was the only mechanism by which to normalize her persistent metabolic acidosis of unknown aetiology.     

Simvastatin enhances the regeneration of endothelial cells via VEGF secretion in injured arteries

The search for a novel therapy for endothelial regenerating is an area of intensive investigation. Recent experimental and clinical evidence strongly suggests that 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors (statins) have several physiological effects independent of low-density lipoprotein cholesterol reduction. We here report that the carotid arterial blood flow after endothelial injury in hamsters treated with simvastatin was restored, in contrast to the situation in nontreated hamsters. Histologic observations showed a prompt recovery of endothelial cells with a much higher DNA synthesis index in repaired endothelium of hamsters treated with simvastatin. The amount of secreted vascular endothelial cell growth factor (VEGF) by cultured vascular smooth muscle cells from hamsters treated with simvastatin was significantly increased. Mevalonate reduced the amount of VEGF secretion by simvastatin in vitro. Finally, an injection of either an anti-VEGF antibody or an anti-VEGF receptor-1 (Flt-1) antibody, but not anti-VEGF receptor-2 (Flk-1), reduced the prompt endothelial healing. Simvastatin regulates endothelial regenerating by an over-release of VEGF and by this may result in prompt endothelial healing after vascular injury. Our results provide new insights into the role of statin and VEGF in the pathogenesis of vascular diseases.     

Ulcerative colitis occurring in the course of rheumatoid arthritis: a case successfully treated with mesalamine enema

We report a case of ulcerative colitis (UC) that occurred during the course of rheumatoid arthritis (RA). A 29-year-old woman with a 25-year history of RA was hospitalized for high fever, abdominal pain and hematochezia. Colonoscopy revealed erosive and reddish mucosa from the distal transverse colon to rectum. Histology revealed cryptitis (mainly caused by neutrophils), mild crypt abscess and goblet cell depletion. She was diagnosed with left-sided UC and treated with mesalamine enema. The abdominal symptoms and colonoscopic findings were greatly ameliorated. We conclude that the mesalamine enema was effective in this case of UC occurring during the course of RA.     

Phenylarsine oxide (PAO) more intensely induces apoptosis in acute promyelocytic leukemia and As2O3-resistant APL cell lines than As2O3 by activating the mitochondrial pathway

We studied the cytotoxic effect of an organic arsenical compound, phenylarsine oxide (PAO) on an acute promyelocytic leukemia (APL) cell line (NB4) and an As₂O₃-resistant NB4 subline (NB4/As). Cell growth was inhibited by 50% (IC₅₀) upon 2-day treatment with As₂O₃ or PAO at 0.54 and 0.06 μM, respectively in NB4 cells (P = 0.025), and 2.80 and 0.08 μM, respectively in NB4/As (P = 0.030). 0.1 μM PAO increased the proportion of hypodiploid cells (50.3%) by a greater degree than the same dose of As₂O₃ (3.8%) in NB4 cells. In NB4 cells, 0.1 μM PAO reduced the mitochondrial transmembrane potential (20.5% in a PI^negative-Rhodamine123^low fraction) by a greater degree than 1 μM As₂O₃ (7.1%). Western blotting showed that 0.1 μM PAO downregulated the expression of both Bcl-2 and Bcl-X_L proteins, whereas I μM As₂O₃ downregulated only Bcl-2 expression. These results suggest that the cytotoxic effect of PAO on an APL cell line and As₂O₃-resistant subline is significantly higher than that of As₂O₃. PAO-induced apoptosis seems to be related to the activation of the mitochondrial pathway and downregulation of both Bcl-2 and Bcl-X_L. PAO is a considerable agent for relapsed/refractory APL and for purging APL cells following stem cell transplantation.     

Evaluation of psychological factors in orthodontic patients with TMD as applied to the "TMJ Scale"

Physical and psychological evaluation have been required for TMD patients whose problems are multi dimensional. The questionnaire named the "TMJ Scale" was created to differentiate subjective TMD symptoms of patients. The purpose of this study was to clarify the reliability of the TMJ Scale for Japanese orthodontic patients with TMD and to differentiate the symptoms. Fifty orthodontic patients (average age 21y4m) with a chief complaint of TMD symptoms were compared with thirty patients (average age 21y1m) without TMD symptoms. The results were as follows: female patients in the symptom group in particular showed a higher degree of stress due to the chronic pain and abnormalities than those in the non-symptom group. Significant differences were observed in Pain Report, Joint Dysfunction and Global Scale at the 0.1% significant level, in Non-TM Disorder, Psychological Factor and Chronicity at the 1% level, and in Palpation Pain and Perceived Malocclusion at the 5% level in females. Few psychological problems were observed in male patients in the symptom group. Significant differences were observed in Range of Motion limitation at the 5% level in males. The differences in the psychological factors between male and female patients were clarified by using the TMJ Scale. These findings suggested that it was useful to differentiate the multiple symptoms, especially the psychological factors, by using the TMJ Scale for orthodontic patients with TMD.     

Schwannoma of the spinal accessory nerve in the cisterna magna

BACKGROUND: Intracranial schwannoma of the accessory nerve can be divided into two types. One is a jugular foramen type arising from the accessory nerve of the jugular foramen, while the other is an intracisternal type, which arises from the spinal root of the accessory nerve and is separate from the jugular foramen. The latter type is rare, and only 9 cases have been reported previously. CASE DESCRIPTION: A 46-year-old female presented with a large, midline mass lesion in the posterior fossa manifesting as foramen magnum syndrome. Magnetic resonance imaging (MRI) revealed a huge tumor with cystic lesion located in the cisterna magna with extension to the C1 spinal level. The tumor was totally removed by a suboccipital craniectomy and C1 laminectomy. It originated from the spinal root of the right accessory nerve. Temporary slight atrophy of the right sternocleidomastoid muscle was observed, but the patient was free of disease 2 years after treatment. CONCLUSIONS: We report a schwannoma of the spinal accessory nerve in the cisterna magna. The clinical and neuroradiological findings are discussed with a review of the literature. The initial symptoms were variable without loss of function of the cranial nerve, and the tumor tended to grow in the cisterna magna without laterality. Because of the absence of typical neurologic symptoms, early neuroradiological investigation by MRI is recommended for accurate diagnosis of these tumors.     

Relation of diabetic macular edema to cytokines and posterior vitreous detachment

PURPOSE: To investigate whether angiotensin II (AII) or vascular endothelial growth factor (VEGF) is related to diabetic macular edema (DME) in patients with and without posterior vitreous detachment (PVD). DESIGN: A case-control study. METHODS: Vitreous fluid samples were obtained at vitreoretinal surgery from 28 eyes of 28 DME patients without PVD, 8 eyes of 8 DME patients with PVD, 14 eyes of 14 nondiabetic patients, and 8 eyes of diabetic patients without retinopathy. The VEGF levels in vitreous fluid and plasma were determined by enzyme-linked immunosorbent assay, while AII levels were measured by radioimmunoassay.RESULTS: The vitreous levels of AII and VEGF were significantly higher in DME patients with or without PVD than in nondiabetic patients or diabetic patients without retinopathy (without PVD: P < .0061, P < .0001, P = .0261, and P < .0001; with PVD: P < .0012, P < .0001, P = .0473, and P < .0001, respectively). There was no significant difference in the vitreous levels of AII or VEGF between patients with or without PVD (P = .4948 and P = .6642, respectively). The vitreous level of AII significantly correlated with that of VEGF in DME patients without PVD (P = .576) or with PVD (P = .488). AII and VEGF levels in vitreous fluid were significantly higher than the respective plasma levels. CONCLUSIONS: We found that the vitreous levels of AII and VEGF were elevated in DME patients irrespective of the status of PVD. Angiotensin II and VEGF may be induced in the eyes and be related to the pathogenesis of DME.     

Relationship between human leukocyte antigen status and proliferative diabetic retinopathy in patients with younger-onset type 1 diabetes mellitus

PURPOSE: To investigate the relationship between human leukocyte antigen (HLA) status and proliferative diabetic retinopathy (PDR) to assess the genetic basis of PDR in younger type 1 diabetic patients. DESIGN: Retrospective, nonrandomized, comparative trial. METHOD: Patients who were diagnosed with type 1 diabetes under 30 years of age (range, 13-28) and had a disease duration of more than 10 years were studied. The patients were divided into two groups: 30 patients who had undergone vitreous surgery younger than 40 years old (the PDR group) and 50 patients without retinopathy (the non-DR group). The duration of diabetes and the level of glycemic control were matched between the two groups. The control group consisted of 50 healthy patients. HLA-A, -B, -C, -DR, and -DQ typing of blood samples was done using the standard microcytotoxicity method. RESULTS: The frequency of HLA-B62, Cw4, and DQ4 was significantly higher in the PDR group than in the non-DR group (P =.0020, P =.048, and P =.0026, respectively). The Cw4-DR4-DQ4 haplotype frequency was significantly higher in the PDR group than in the control group and the non-DR group (P =.0059). CONCLUSIONS: Our results suggests that HLA-B62, Cw4, and DQ4 may be useful for predicting the prognosis of retinopathy in patients with younger-onset type 1 diabetes.