Familial idiopathic hypoparathyroidism, sensorineural deafness and renal dysplasia.

We describe a 27-year-old woman with familial idiopathic hypoparathyroidism, bilateral sensorineural deafness and right renal aplasia. There was a family history of deafness in her father and two other family members with sensorineural deafness, one of whom had hypoparathyroidism. To our knowledge, there have been four previous reports of idiopathic hypoparathyroidism associated with sensorineural deafness and renal dysplasia. The clinical features were not identical to any of the four previous reports. Although no chromosome abnormalities were present in the patient using standard trypsin G-banding analysis, we speculate that some common genetic mutation caused hypoparathyroidism, sensorineural deafness and renal dysplasia.

McCune-Albright syndrome associated with non-autoimmune type of hyperthyroidism with development of thyrotoxic crisis.

We report on a patient having McCune-Albright syndrome (MAS) associated with non-autoimmune hyperthyroidism associated with thyrotoxic crisis. Polyostotic fibrous dysplasia developed at age 8, and café-au-lait pigmentation was noted on the skin. At age 18, he developed hyperthyroidism with multiple adenomatous changes. The hyperthyroidism had been controlled with an antithyroid drug, but the antithyroid medication was discontinued by the patient at age 23. One year later, thyrotoxic crisis developed with fever, convulsions and loss of consciousness. Thyroid function tests showed serum concentrations of free T(4) of 5.1 ng/dl, and serum TSH of <0.1 microU/ml. Serum thyroglobulin concentrations were markedly increased (1,280 ng/ml). Three major thyroid-related autoantibodies (TSH receptor antibody, antithyroglobulin, and antimicrosomal antibodies) were not detected in serum. Serum GH concentrations were increased, and not suppressed by the glucose tolerance test, but increased paradoxically by TRH. The thyrotoxic crisis was ameliorated by treatment with a beta-adrenergic receptor-blocking agent, glucocoroticoid, iodine, antithyroid drug, and antibiotics. The cause of thyroidal defect in our patient is not considered to be autoimmune hyperthyroidism, but hyperthyroidism due to constitutive activation of G(s)alpha by inhibition of its GTPase. This paper describes, as far as we know, the first case of MAS associated with thyrotoxic crisis. Because hyperthyroidism in this patient recurred quickly after discontinuation of the antithyroid drug, the mode of treatment for MAS-associated hyperthyroidism appears to be total surgical ablation or repetitive radioiodine therapy.

Calcifying fibrous pseudotumor: an ultrastructural study.

To clarify the pathogenesis of calcification in calcifying fibrous pseudotumor (CFT), the lesion arising in the chest wall of a 16-month-old boy was ultrastructurally investigated. Fibroblasts were surrounded by large amounts of collagen fibrils. The dystrophic and psammomatous calcifications were observed as electron-dense amorphous masses and laminated bodies, respectively, within the cytoplasm of fibroblasts and in the collagenous stroma. The degeneration of cytoplasm seemed to be an initial event of intracytoplasmic calcification. Extracellular calcified substances often abutted to fibroblasts. Fibroblasts may play an important role in both intracellular and extracellular calcifications of CFT.

[A case of atypical Miller Fisher syndrome associated with antiphospholipid antibodies].

We report a 56-year-old man with external ophthalmoplegia and ataxic gait following a diarrhea, being diagnosed atypical Miller Fisher syndrome (FS). On admission, he had severe diplopia and bilateral external ophthalmoplegia were observed. The deep tendon reflexes were decreased on the right upper extremity. He could not walk straight and his tandem gait was impaired. Serum IgG anticardiolipin antibody (aCL) and APTT-lupus anticoagulant (LA) were found to be increased. The serum of the patient had low titer of anti-GQ 1 b and anti-GM 1 antibodies. After the first immunoadsorption therapy, his ophthalmoplegia was improved moderately, but peripheral facial palsy appeared. He was treated with immunoadsorption again, then all neurologic symptoms improved and a follow-up study revealed normalized aCL and LA titers. There have been no previous reports of FS associated with antiphospholipid antibody. The low titer of serum anti-GQ1b and anti-GM 1 antibodies in this patient suggests that the antiphospholipid antibodies, such as aCL and LA, may be linked to the pathogenesis of FS.

Pulmonary diffusing capacity, serum angiotensin-converting enzyme activity and the angiotensin-converting enzyme gene in Japanese non-insulin-dependent diabetes mellitus patients.

We investigated the independent change in pulmonary diffusing capacity (DLCO) as one manifestation of pulmonary microangiopathy and to analyze the correlation between DLCO and serum ACE. We also examined the association between DLCO and the ACE genes. We examined pulmonary functions, especially %DLCO/VA (DLCO corrected by alveolar volume, percent predicted) in 54 NIDDM patients and 34 age-matched normal control subjects. Subjects were subdivided according to the degree of retinopathy. Serum ACE level was assayed by a colorimetric method in 54 patients and an insertion/deletion polymorphism in the ACE gene was amplified using the polymerase chain reaction in 52 of the 54 patients. There was a significant reduction of %DLCO/VA (percent predicted P < 0.05) in diabetic patients. In the proliferative retinopathy (PDR) group. %DLCO/VA was significantly (P < 0.05) lower than in the no diabetic retinopathy (NDR) and simple diabetic retinopathy (SDR) groups. Although the levels of serum ACE were within normal ranges in all diabetic groups, %DLCO/VA was negatively correlated with serum ACE values (r = 0.49, P < 0.0002, y = -1.4x + 109.3). Differences among DD, ID and II type of the ACE gene, with respect to the incidence of abnormal values of each clinical parameter, were not significant. DLCO was significantly reduced in patients with PDR and the serum ACE was significantly related to impaired DLCO. Our study suggests the existence of microangiopathic involvement of pulmonary vessels in NIDDM patients.

Critical behavior of a random diode network.

We study the percolation properties of a random diode network (RDN) which contains two kinds of directed bonds on a square lattice. This network is a special case of the random insulation-resistor-diode network. Both Monte Carlo simulations and series expansion for the percolation probability show that an estimated critical exponent, beta=0.1794+/-0.008, is different from known values for a conventional insulation-resistor-diode network. RDN belongs to neither the isotropic percolation universality class nor to the directed percolation universality, which we attribute to a difference of symmetry breakdown around the critical point.

Novel mitochondrial DNA mutation in tRNA(Lys) (8296A-->G) associated with diabetes.

Mutation in the mitochondrial gene at position 3243 was recently identified in a large pedigree of diabetes mellitus and deafness. As the mitochondria play an important role in glucose-stimulated insulin secretion in pancreatic beta-cells, we therefore searched for such mutations to detect a candidate gene for diabetes. We screened 10 diabetic subjects with clinical features suggesting mitochondrial DNA mutations. An adenine to guanine point mutation in tRNA(Lys) in at position 8296 (the 8296 mutation) was newly identified. Subsequently, we screened 1216 diabetic subjects, 44 patients with sensorineural deafness subjects and 300 non-diabetic control subjects for this mutation. We identified the mutation in 11 (0.90%) unrelated diabetic subjects, one (2.3%) patient with deafness and no non-diabetic control subject. Seven of these 12 subjects showed maternal inheritance. Deafness was seen in 7 of 12 probands. Four family pedigrees showed maternal inheritance of diabetes over two or three generations. Subjects carrying the 8296 mutation may develop diabetes and the mutation can explain as high as ca. 1% of the causes of diabetes.

Screening of patients with maternally transmitted diabetes for mitochondrial gene mutations in the tRNA[Leu(UUR)] region.

To investigate the prevalence and clinical characteristics of diabetes mellitus caused by mitochondrial gene mutations in the tRNA[Leu(UUR)] region, a known 'hot spot' for pathogenic mutations, we screened 440 diabetic patients with diabetic mothers for 11 mitochondrial gene mutations reported in mitochondrial neuromuscular disorders; nucleotide pairs (np) 3250, 3251, 3252, 3254, 3256, 3260, 3271, 3291, 3302 and 3303 in addition to an A to G transition at np 3243. The dot-blot hybridization method using 32P-labelled sequence-specific oligonucleotides as probes was used. One subject carrying a T to C transition at np 3271 and seven carrying the A to G transition at np 3243 were identified, while none of the other diabetic patients screened had these mutations in the tRNA[Leu(UUR)] region. The patient with the 3271 mutation, a 39-year-old male, had excellent glycaemic control with diet alone and had neither hearing impairment nor symptoms suggesting mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). Thus, among patients with maternally transmitted diabetes, the prevalence of the 3271 mutation was approximately one-seventh that of the 3243 mutation, and other mutations are even more rare in the mitochondrial tRNA[Leu(UUR)] region.

Daily profile of serum leptin in Prader-Willi syndrome complicated by diabetes mellitus--a case report.

High leptin levels in Prader-Willi (P-W) syndrome may occur as a result of the existence of leptin resistance, because a hypothalamic disturbance may underlay this disorder. In order to study whether there is a defective action of leptin on the hypothalamus in P-W syndrome, we have measured leptin and insulin twice during the daily profile of blood glucose, comparing the results with the recent reports. The patient was a 22-year-old female, who showed the typical feature of P-W syndrome complicated overt diabetes. This case of P-W syndrome was only made to maintain a diet of 1840 kcal/day of examination under hospitalization and was not made to maintain a calorie diet on any other day of examination in clinic. There was no reduction of leptin observed during the day, especially around noon and mid-afternoon, both under hospitalization and in clinic. Our experience suggests that an absence of the normal fall in leptin during the day was not related to eating pattern in this case, but to the defective action of leptin on the hypothalamus as well as excessive production by adipose tissue.

A patient with diabetes mellitus, cardiomyopathy, and a mitochondrial gene mutation: confirmation of a gene mutation in cardiac muscle.

A 44-year-old woman with diabetes mellitus, cardiomyopathy, and a mitochondrial gene mutation, was reported. She was diagnosed as having diabetes at 33 years of age and was treated with insulin. However, she stopped treatment 6 months later and had no medical care until she developed diabetic ketoacidosis at 41 years of age. She had diabetic foot, diabetic retinopathy, and nephropathy with low insulin secretory capacity, leading to insulin treatment. A point mutation of the mitochondrial tRNA(Leu(UUR)) gene was identified in peripheral leukocytes at 43 years of age, and sensorineural hearing impairment was detected at the same time. Her mother also suffered from diabetes mellitus with deafness and her son, who was not diabetic at age 19, had the same mitochondrial DNA (mtDNA) mutation. At 44 years of age, she developed congestive heart failure due to cardiomyopathy, and the same mtDNA mutation was identified in the cardiac muscle. Thus, it is very likely that in this patient, diabetes and cardiomyopathy was caused by the same abnormality, the point mutation of mitochondrial tRNA(Leu(UUR)) gene.

Differential expression of colony-stimulating factor (CSF) in murine macrophage clones: interferon-gamma-mediated inhibition of CSF production.

Bioassay and northern blot analyses revealed that, among several functional murine macrophage (M phi) clones, lipopolysaccharide (LPS) stimulation generated in distinct induction levels of granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and macrophage colony-stimulating factor (M-CSF). When compared with these induction profiles, the M phi clones could be classified into two types; G type (G-CSF GM-CSF-M-CSF+) and GM type (G-CSF +/- GM-CSF M-CSF+) of M phi clones. Unlike G-CSF and GM-CSF that were inducible factors, M-CSF mRNA was constitutively expressed without stimulation and was differentially controlled between the G and GM types; LPS induction decreased M-CSF mRNA in the former, but increased it in the latter. Further northern blot analysis revealed that interferon-gamma (IFN-gamma) suppressed constitutive expression of M-CSF mRNA, and that costimulation with both LPS and IFN-gamma reduced expression of G-CSF and M-CSF mRNA in the G type of M phi clone, but induced higher expression of GM-CSF and M-CSF mRNAs in the GM type of M phi clone compared with LPS alone. However, in either case, IFN-gamma completely inhibited LPS-induced production of active CSF of the M phi clones, which was observed even in IFN-gamma pretreatment, and also abrogated autoactivation of GM-CSF. Our present results suggested that murine M phi clones had differentially regulated expression of CSFs and that IFN-gamma had a regulatory function of inhibiting CSF production of murine M phi s.

Effects of long- and medium-chain triglycerides on amino acid uptake in rat intestinal brush border membrane vesicles.

1. Uptake of L-leucine, L-phenylalanine, L-proline and L-lysine into brush border membrane vesicles from rats fed either a medium-chain triglyceride (MCT) or a long-chain triglyceride (LCT) diet was studied under conditions of the presence of absence of a Na+ gradient. 2. From the results of initial rate, Na(+)-dependent transport in LCT feeding were lower than in feeding MCT. The Na(+)-independent transport did not vary in either group except for L-lysine uptake. 3. For L-leucine, L-phenylalanine and L-proline in Na+ dependence, kinetic analysis revealed 4-6-fold smaller Vmax values in LCT group than in MCT group. L-Lysine in Na(+)-independent transport was 10-fold lower in LCT group than in MCT group. The Km values were not affected by feeding the LCT or MCT diet. 4. It is clear that amino acid transport is regulated by different types of dietary fat. We consider that the alteration of transport activity is attributable to the changes in number of membrane-bound transport carriers but not to their affinity.