Impact of brown adipose tissue on body fatness and glucose metabolism in healthy humans.

BACKGROUND: Brown adipose tissue (BAT) is involved in the regulation of whole-body energy expenditure and adiposity. Some clinical studies have reported an association between BAT and blood glucose in humans. OBJECTIVE: To examine the impact of BAT on glucose metabolism, independent of that of body fatness, age and sex in healthy adult humans. METHODS: Two hundred and sixty healthy volunteers (184 males and 76 females, 20-72 years old) underwent fluorodeoxyglucose-positron emission tomography and computed tomography after 2 h of cold exposure to assess maximal BAT activity. Blood parameters including glucose, HbA1c and low-density lipoprotein (LDL)/high-density lipoprotein-cholesterol were measured by conventional methods, and body fatness was estimated from body mass index (BMI), body fat mass and abdominal fat area. The impact of BAT on body fatness and blood parameters was determined by logistic regression with the use of univariate and multivariate models. RESULTS: Cold-activated BAT was detected in 125 (48%) out of 260 subjects. When compared with subjects without detectable BAT, those with detectable BAT were younger and showed lower adiposity-related parameters such as the BMI, body fat mass and abdominal fat area. Although blood parameters were within the normal range in the two subject groups, HbA1c, total cholesterol and LDL-cholesterol were significantly lower in the BAT-positive group. Blood glucose also tended to be lower in the BAT-positive group. Logistic regression demonstrated that BAT, in addition to age and sex, was independently associated with BMI, body fat mass, and abdominal visceral and subcutaneous fat areas. For blood parameters, multivariate analysis after adjustment for age, sex and body fatness revealed that BAT was a significantly independent determinant of glucose and HbA1c. CONCLUSION: BAT, independent of age, sex and body fatness, has a significant impact on glucose metabolism in adult healthy humans.

Effects of clonidine on lidocaine-induced inhibition of axonal transport in cultured mouse dorsal root ganglion neurones.

BACKGROUND: The alpha(2)-adrenoceptor agonist clonidine is used in combination with lidocaine for anaesthesia. Lidocaine inhibits axonal transport and neurite growth, whereas alpha(2)-adrenoceptor agonists have neurotrophic effects. Here we have investigated whether clonidine reduces lidocaine-induced inhibition of axonal transport in cultured mouse dorsal root ganglion neurones. METHODS: Axonal transport of organelles and neurite growth were assessed by video microscopy in cells treated with clonidine and lidocaine for 1 h. Stable responses were achieved within this period. RESULTS: Clonidine (10 and 100 microM) increased and lidocaine (10, 100 microM, and 1 mM) decreased axonal transport. The inhibitory effects of lidocaine were reduced by simultaneous treatment with clonidine. The actions of clonidine were antagonized by the alpha(2)-adrenoceptor antagonist yohimbine. Since clonidine was reported to block N-type channels, we further investigated the role of ion channels in the antagonistic action of clonidine on the lidocaine response. The action of lidocaine on axonal transport was not mimicked by the Na+ channel blocker tetrodotoxin and not blocked by the Na+ channel activator veratridine. The action of lidocaine was not blocked by the L-type Ca2+ channel blocker nifedipine, but was blocked by the N-type channel blocker omega-conotoxin MVIIA. These effects on axonal transport correlated with the effects on neurite growth. CONCLUSIONS: Inhibition of axonal transport induced by lidocaine, which may be mediated by N-type channel activation, can be blocked by clonidine. Clonidine may alleviate the effects of lidocaine on neuronal dysfunction.

Phosphoglycerate kinase deficiency: an adult myopathic form with a novel mutation.

The authors report a 36-year-old man with exertional myoglobinuria and muscle cramp without hemolytic anemia or CNS symptoms. They found a deficiency of phosphoglycerate kinase (PGK) activity in muscle and erythrocytes and a 4-base pair deletion in exon 6 of the PGK gene. This mutation may cause a frameshift, yielding an abnormal stop codon in exon 6 by which a truncated PGK protein was produced. This phenotype is caused by a novel mutation of the PGK gene.

Infantile muscle glycogen storage disease: phosphoglucomutase deficiency with decreased muscle and serum carnitine levels.

We report a 5-month-old boy with recurrent vomiting, lethargy, and poor weight gain. He had profound metabolic acidosis and nonketotic dicarboxylic aciduria. The serum and muscle carnitine levels were significantly low (60% and 10% of the control means, respectively), suggesting that the patient had a systemic carnitine deficiency syndrome. The patient showed apparent clinical improvement on oral carnitine administration. A quadriceps muscle biopsy revealed a slight increase in intrafiber lipid droplets and mild accumulation of glycogen in the subsarcolemmal portion. An anaerobic glycolysis in vitro study showed a block after glucose-1-phosphate and before glucose-6-phosphate. Direct measurement of individual glycolytic enzymes in muscle of the patient demonstrated a marked decrease in phosphoglucomutase (PGM) activity (13% of the control mean). The specific defect of PGM activity in this patient suggests that the block in the anaerobic glycolytic pathway is the primary abnormality. PGM deficiency can be added as a newly recognized cause of secondary systemic carnitine deficiency syndromes.

Frequent mutations in Japanese patients with acid maltase deficiency.

We screened 22 Japanese patients with acid maltase deficiency (seven with the infantile type, eight with the juvenile type and seven with the adult type) for three previously described mutations, D645E, S529V and R672Q, and a novel mutation, R600C. Although D645E has been reported to be common in Chinese patients with the infantile type, only three of 44 alleles (two of 14 infantile type alleles) from Japanese patients harbored the D645E mutation. The S529V mutation was identified in six of 14 alleles from adult-onset patients. None of the infantile or juvenile patients harbored the S529V mutation. Therefore, S529V apparently results in the adult type disease and is common in Japanese adult-onset patients. R672Q was identified in two pairs of siblings with the juvenile type. A novel mutation, R600C, was identified in eight of 22 patients (nine of 44 alleles). Therefore, R600C is another common Japanese mutation occurring at a CpG dinucleotide "hot spot". Homozygosity for this mutation apparently results in the infantile phenotype. Genetic diagnosis by detecting these four mutations might be feasible for most Japanese patients with acid maltase deficiency.

A case of MERRF associated with chronic pancreatitis.

We report the first case to our knowledge of chronic pancreatitis associated with mitochondrial encephalopathy with the A8344G mitochondrial DNA (mtDNA) mutation. This 10-year-old-girl had suffered from recurrent abdominal pain with elevated serum amylase and lipase since the age of 6, and easy fatigability, tremor and astatic seizures since the age of 8. A biopsy of quadriceps muscle revealed ragged-red-fibers and cytochrome c oxidase deficiency. Analysis of mtDNA in peripheral blood identified an A8344G mutation in the mitochondrial tRNA(Lys) gene. Taken together with physical signs of myoclonic seizures and cerebellar dysfunction, we diagnosed her as myoclonic epilepsy with ragged-red fibers associated with chronic pancreatitis. Although no association between mitochondrial disease and pancreatitis has yet been established, this case suggests it is necessary to consider the participation of mitochondrial abnormality in the pathogenesis of recurrent pancreatitis.

High efficacy of monomethoxypolyethylene glycol-conjugated L-asparaginase (PEG2-ASP) in two patients with hematological malignancies.

Two patients with hematological malignancies were successfully treated with monomethoxypolyethylene glycol-conjugated Escherichia coli L-asparaginase (PEG2-ASP), which reportedly lacks both antigenicity and immunogenicity but retains catalytic activity as well as slow clearance in an experimental animal model. A 20-year-old male patient with leukemic lymphoma was refractory to conventional chemotherapy but responsive to L-asparaginase (L-ASP) followed, however, by severe adverse effects. On relapse, an intravenous infusion of 100-200 IU/day dose of PEG2-ASP alone led to a complete remission 2 months later without hypersensitivity or other significant adverse reactions. Surprisingly, he remained in a complete remission for over one year with a regular weekly infusion of PEG2-ASP, combined with a weekly small dose of Ara-C. During this period, blood asparagine was not detectable. The other patient, a 64-year-old woman with chronic myelogenous leukemia in blast crisis achieved, within 6 weeks, a complete remission with twice-weekly infusions of PEG2-ASP. Thus, PEG2-ASP is a highly effective antitumor agent overcoming the limitations in therapeutic use of L-ASP.

Cerebral oxygen and glucose metabolism in glycogen storage disease with normal acid maltase: case report.

A 26-year-old male with cardiomyopathy, cervical muscle weakness and mental retardation was diagnosed as having glycogen storage disease with normal acid maltase on the basis of his clinical, pathological and biochemical findings. Positron emission tomography showed that cerebral oxygen metabolism was normal, while cerebral glucose metabolism was decreased in the cerebral cortexes. The decrease of the glucose metabolic rate may reflect an abnormality of cerebral glucose metabolism in this disorder and may be related to mental retardation, which is one of the characteristic symptoms.

Genetic analysis of Japanese patients with myophosphorylase deficiency (McArdle's disease): single-codon deletion in exon 17 is the predominant mutation.

We report molecular genetic analysis of 11 Japanese patients with myophosphorylase deficiency (McArdle's disease). Four reported mutations, frequently observed in patients with McArdle's disease, in exons 1, 5, 14 and 17 were investigated. Seven patients out of 11 were homozygous for a single-codon deletion at codon 708/709 in exon 17 and one patient was heterozygous for a single-codon deletion with an unknown mutant allele. In contrast, the predominant mutation reported in US and UK patients (CGA to TGA at codon 49 in exon 1), accounting for 75% and 83% of the cases, respectively, was not found in any of the Japanese patients. Results suggest that the predominant mutation in Japanese patients is a single-codon deletion at codon 708/709 in exon 17 (found in 73% of our patients) and differs from the most common mutation in US or UK patients.

Recurrent myoglobinuria in a child with mental retardation: phosphoglycerate kinase deficiency.

We report the case of an 11-year-old mentally retarded boy with recurrent myoglobinuria precipitated after a generalized tonic-clonic convulsion. No hemolysis was noted. Ischemic forearm test revealed no rise of venous lactate, suggesting a metabolic defect in an anaerobic glycolytic pathway. Histochemistry studies of the quadriceps muscle showed a normal appearance, but electron microscopy confirmed a moderate increase of the glycogen content in muscle. Direct measurement of glycolytic enzymes demonstrated a marked decrease of phosphoglycerate kinase (PGK) activity in muscle (4.4% of control mean) and hemolysate (8% of control mean). Enzyme characteristics of PGK from our patient (PGK Hamamatsu) using hemolysate demonstrated that it had normal Michaelis constants (Km), normal thermal stability, and a normal pH curve. The reason that hemolytic anemia was absent is uncertain. We concluded that a systematic enzyme analysis of the glycolytic pathway, especially of PGK, should be performed on myoglobinuric patients who are males, or who have an X-linked inheritance as suggested by the family history.

Adult onset type II fiber centronuclear neuromyopathy with segmented demyelination.

We report a 54-year-old male with progressive, adult onset distal muscle weakness and intermittent paresthesia associated with preferential type II fiber centronuclear (myotubular) change and segmental demyelination in sural nerve. Morphometric analysis, single fiber teasing and graphic analysis of internode lengths confirms the segmental demyelination with no evidence of ongoing repetitive Schwann cell remyelination. Cases of adult onset centronuclear myopathy are reviewed. This cas provides evidence for a neurogenic component in the pathogenesis of the centronuclear neuromyopathies.

A case of polymyositis associated with Kawasaki disease.

We report a 3-year-old boy with proximal painful muscle weakness associated with Kawasaki disease. The muscle biopsy revealed inflammatory cell infiltration with vasculopathy. This unique coexistence of polymyositis and Kawasaki disease is quite uncommon and suggests a newly recognized complication during Kawasaki disease.

Computed tomography and magnetic resonance imaging of affected muscle in childhood acid alpha-glucosidase deficiency: a case report.

A 13-year-old boy with the juvenile type of acid alpha-glucosidase deficiency is presented. Muscle CT scans performed before muscle biopsy revealed high image density over the entire rectus femoris, and partial high density over the iliopsoas, adductor magnus and tibialis anterior. MRI of the rectus femoris in the transaxial plane showed high image intensity over the entire length of the muscle in both T1- and T2-weighted images. A biopsy revealed a surprising histological difference between the rectus femoris, which showed pronounced vacuolar myopathy with excessive glycogen, and the vastus lateralis, in which deposition of glycogen was minimal and the CT image indicated a normal muscle density. The findings in this case suggest that CT scanning and MRI are useful in recognizing muscle involvement in acid alpha-glucosidase deficiency, which is characterized by images of increased density compared to normal muscle, presumably because excessive deposition of glycogen and lysosomal membranes cause high X-ray absorption on CT and high signal intensity on MRI.

Evaluation of patients with lactic acidosis using microphotometric mitochondrial enzyme assay in single muscle fibers.

Microphotometric enzyme assay in single muscle fibers was performed on two patients with lactic acidosis. Neither case showed ragged red fibers upon histochemical evaluation. Biochemical analysis of mitochondrial enzymes demonstrated low normal cytochrome c oxidase (COX) activity in Case 1 and deficient COX in Case 2. Quantitative single muscle fiber analysis in patients showed marked variation in COX activity in Case 1, reflecting mosaic distribution of fibers with near-normal COX activity and with defective COX activity. These data suggest that this microphotometric assay may be valuable for elucidating the significance of 'partial enzyme deficiency'. In addition, this assay method may be applied to needle biopsy specimens.