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K Toshima

Publications and source records attributed to K Toshima.

At least 37 records · Page 2Linked to original sources
PubMed1994

Predictive DNA testing and prophylactic thyroidectomy in patients at risk for multiple endocrine neoplasia type 2A.

BACKGROUND: Missense germ-line mutations in the RET protooncogene are associated with multiple endocrine neoplasia type 2A (MEN 2A). Detection of these mutant alleles in kindred members predicts disease inheritance and provides the basis for preventative thyroidectomy. METHODS: A polymerase chain reaction (PCR)-based genetic test for the 19 known RET mutations was designed to study 132 members of 7 kindreds with MEN 2A. Haplotypes also were constructed using genetic markers flanking the MEN 2A locus. Plasma calcitonin (CT) concentrations were determined before and after provocative testing. RESULTS: Direct DNA testing and haplotype analysis showed that 21 of 58 kindred members at risk for disease had inherited a mutation in the RET protooncogene associated with MEN 2A. Plasma CT concentrations were elevated in 9 of the 21 family members, but were normal in 12. After genetic counseling, 13 of the 21 kindred members (6 with normal and seven with elevated plasma CT levels), consented to immediate thyroidectomy. In each patient, the resected thyroid gland showed C-cell hyperplasia with or without medullary thyroid carcinoma. There were no metastases to regional lymph nodes, and postoperative stimulated plasma CT levels were normal. CONCLUSION: The PCR-based direct DNA test for RET mutations is accurate, rapid, and reproducible. For all 132 individuals evaluated, the results of direct DNA analysis were consistent with haplotype studies. The direct test for mutations in the RET protooncogene is the preferred method for screening MEN 2A kindreds. In family members who have inherited a RET mutation, total thyroidectomy is indicated, regardless of the plasma CT values.

Adolescent↗
PubMed1994

Predictive testing for multiple endocrine neoplasia type 2A (MEN 2A) based on the detection of mutations in the RET protooncogene.

BACKGROUND: The identification of inherited mutations in the RET protooncogene (RET) associated with multiple endocrine neoplasia type 2A (MEN 2A) has enabled the development of a genetic test to identify asymptomatic carriers of disease. METHODS: Genomic DNA was extracted from 96 members of an MEN 2A kindred. The polymerase chain reaction was used to amplify the RET exon known to contain the associated mutation. The mutation results in a new restriction endonuclease site and is detected by digestion with the appropriate enzyme. Inheritance of the mutation was verified with a previously developed genetic linkage test. RESULTS: We found that (1) mutations vary among kindreds but are consistently inherited within kindreds, (2) invariable correlation exists between mutation and disease (43 mutations in 43 affected individuals), (3) determination of the genetic status by linkage-based testing was precluded by recombination events and the informativeness of genetic markers, and (4) mutation analysis presymptomatically identified two genetically affected individuals. CONCLUSIONS: Direct genetic analysis for mutations in RET circumvents the limitations of linkage-based genetic testing and current biochemical screening assays. This method will be the diagnostic test of choice for the identification of asymptomatic individuals at risk for MEN 2A.

Amino Acid Sequence↗
PubMed1993

[Cases of Graves' disease with falsely high TSH values due to interfering substances which cross-link with mouse monoclonal antibodies in the TSH assay kits].

It has been reported that highly sensitive two-site immunometric assays occasionally indicate falsely high serum TSH values. A possible reason for this is that heterophilic antibodies interfere with these assays. Recently we had a patient in whom the Delfia TSH kit falsely indicated an elevated serum TSH value. A 29-year-old female was diagnosed as having Graves' disease and was referred to Ito Hospital for surgical treatment. Her thyroid hormone values were distinctly high two months before admission (FT3: 20.7pmol/L, FT4: 42.3pmol/L), but her serum TSH level was normal (1.1mU/l). She was clinically hyperthyroid, and T3 and T4 values determined after ethanol extraction and T3 or T4 analog binding rates did not indicate the presence of T3 or T4 antibodies. Her TSH value became undetectable when mouse IgG was added to the assay. These results suggested that the "normal" serum TSH value was caused by interfering substances such as anti-mouse IgG antibodies which had cross-linked with mouse monoclonal antibodies in the Delfia TSH kit. Another 12 patients who were suspected of having the interfering substances were examined because of the discordance between TSH values and thyroid hormone values. All of the serum TSH values measured using the DELFIA TSH kit decreased when mouse IgG was added. In another case, the presence of serum TSH could not be detected using the Delfia TSH kit but could be measured using the RIABEAD II TSH kit.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1993

Follow-up evaluation of patients with Graves' disease treated by subtotal thyroidectomy and risk factor analysis for post-operative thyroid dysfunction.

Eight-year follow-up evaluation and analysis of factors related to postoperative thyroid dysfunction were made in 216 patients with Graves' disease treated by subtotal thyroidectomy. The postoperative status of thyroid function were as follows according to hypersensitive TSH level: 65 patients (30.1%) were euthyroid, 25 (11.5%) had overt hyperthyroidism requiring treatment, 14 (6.5%) had subclinical hyperthyroidism with normal thyroid hormone and suppressed TSH, 21 (9.8%) were overt hypothyroid requiring thyroid hormone replacement and 91 (41.1%) had latent hypothyroidism without hormone replacement. In order to know factors related to postoperative thyroid function, age, sex, preoperative levels of TSH receptor antibody (TRAb), thyroid antibody titers, degree of lymphocyte infiltration, duration of medical treatment, weight of the resected thyroid tissue and weight of the remnant thyroid tissue were determined. No factor except thyroid remnant and antimicrosomal antibody titer was related to postoperative thyroid function. The weight of remnant should be less than 6 g to avoid recurrent hyperthyroidism. As recurrence of hyperthyroidism was observed more than 5 yr after surgery, long follow-up is needed.

Adolescent↗
PubMed1993

Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC.

Multiple endocrine neoplasia type 2A (MEN 2A) and familial medullary thyroid carcinoma (FMTC) are dominantly inherited conditions which predispose to the development of endocrine neoplasia. Evidence is presented that sequence changes within the coding region of the RET proto-oncogene, a putative transmembrane tyrosine kinase, may be responsible for the development of neoplasia in these inherited disorders. Single strand conformational variants (SSCVs) in exons 7 and 8 of the RET proto-oncogene were identified in eight MEN 2A and four FMTC families. The variants were observed only in the DNA of individuals who were either affected or who had inherited the MEN2A or FMTC allele as determined by haplotyping experiments. The seven variants identified were sequenced directly. All involved point mutations within codons specifying cysteine residues, resulting in nonconservative amino acid changes. Six of the seven mutations are located in exon 7. A single mutation was found in exon 8. Variants were not detected in four MEN 2B families studied for all exon assays available, nor were they detectable in 16 cases of well documented sporadic medullary thyroid carcinoma or pheochromocytoma that were tested for exon 7 variants. Coinheritance of the mutations with disease and the physical and genetic proximity of the RET proto-oncogene provide evidence that RET is responsible for at least two of the three inherited forms of MEN 2. Neither the normal function, nor the ligand of RET are yet known. However, its apparent involvement in the development of these inherited forms of neoplasia as well as in papillary thyroid carcinoma suggest an important developmental or cell regulatory role for the protein.

Amino Acid Sequence↗
PubMed1993

A diabetic case of Hb Riyadh with a low HbA1c value.

A 74-year-old male patient with diabetes mellitus and hypertension who had been treated for a long period was admitted to our hospital. Laboratory data on admission revealed high values for fasting blood sugar and fructosamine, 219 mg/dl and 389 mumol/l respectively, while the concentration of glycated hemoglobin (HbA1c) was low (3.0%). High performance liquid chromatography and isoelectric focusing analysis of the patient's Hb disclosed abnormal Hb with the content being 41.3%. The structural analysis indicated that this abnormal Hb was Hb Riyadh [beta 120 (GH3) Lys-->Asn]. The low value of HbA1c despite the high blood glucose level may be attributed to this abnormal hemoglobin.

Aged↗
PubMed1993

[Outcome of surgical treatment for Graves's disease and a correlation between its clinical course and values of TSH receptor antibodies (TRAb)].

Two hundreds and sixteen patients with Graves' disease who underwent subtotal thyroidectomy at Ito Hospital during 1983 and 1984 were studied in order to known about the relationship between the prognosis and preoperative values of TRAb. There were 65 euthyroid patients (30.1%), 112 hypothyroid (51.8%), and 39 hyperthyroid (18.1%). No relationship between postoperative thyroid function and preoperative values of TRAb was observed. Postoperative values of TRAb were significantly higher in hyperthyroid group than in euthyroid group and hypothyroid group at any period. Postoperative values of TRAb were negative in about 90% of the patients of euthyroid group. On the other hand, negative postoperative values of TRAb were also observed in about 40% patients of hyperthyroid group. It is concluded that postoperative thyroid function could not be estimated from preoperative values of TRAb and much care is thought to be necessary to estimate the prognosis from postoperative values of TRAb.

Adolescent↗
PubMed1991

Solid cell nests of the thyroid gland.

The histogenesis and clinical significance of solid cell nests (SCN) of the thyroid are not fully understood. From August 1987 to December 1989 a total of 2544 patients with thyroid and parathyroid diseases underwent surgery at Ito Hospital, and SCN were revealed within the thyroid parenchyma in 21 (0.8%). Distribution of SCN was not limited to the upper one-third of the lateral lobe, and SCN were found even in the isthmus lobe. In 5 cases microcysts were also noted within SCN, and their content was thought to be acidic proteoglycan. Immunohistochemical study revealed that SCN were negative for thyroglobulin and calcitonin but positive for carcinoembryonic antigen. Thirteen of 21 cases showed positive immunostaining with cytokeratin. Scattered calcitonin-positive cells were noted around the SCN. It is suggested from these findings that SCN of the thyroid are closely related to certain cells of ultimobranchial body vestiges which may be not of neuroectodermal origin but of endodermal origin.

Adult↗
PubMed1989

Effect of sodium dichloroacetate on human pyruvate metabolism.

Sodium dichloroacetate (DCA) was administered orally at doses of 12.5 to 50 mg/kg body weight twice or three times per day to a patient with mitochondrial encephalomyopathy associated with congenital lactic acidemia. During therapy, the rates of decarboxylation of (1-14C) pyruvate and (3-14C) pyruvate, which represent the activity of the pyruvate dehydrogenase (PDH) complex and the function of the TCA cycle, respectively, were markedly increased in the platelets and increases in the lactate levels in the blood and urine during exercise were markedly reduced. These results suggest that oral administration of DCA causes significant increases in the activities of the PDH complex and TCA cycle not only in the platelets but also in various tissues of humans, which is important as a pathway for production of energy, resulting in decreases in the lactate and pyruvate levels in the blood and cerebrospinal fluid.

Acetates↗
PubMed1987

Urinary homocystine levels in a newborn infant with cystathionine synthase deficiency.

A boy with homocystinuria due to cystathionine synthase deficiency was found to have hypermethioninaemia by neonatal blood screening, but was not diagnosed as homocystinuric until 3 months of age because urinary homocystine was not detected by the cyanide-nitroprusside test or on two examinations with a sensitive amino acid autoanalyser. These findings indicate that tests for urinary homocystine should be made repeatedly with an amino acid autoanalyser in newborn infants with hypermethioninaemia until the enzyme defect is identified.

Cystathionine beta-Synthase↗
PubMed1987

Muscle involvement in pyruvate dehydrogenase complex (PDHC) deficiency.

Muscle biopsies from a 13-month-old female infant with a delay in developmental milestones, lactic acidosis and visual disturbance, and a 6 year-old female with frequent epileptic fits are described. Biochemical studies of biopsied muscles and skin fibroblasts demonstrated markedly decreased pyruvate dehydrogenase complex (PDHC) activity to about 16% of normal value. Muscle histochemistry in both patients showed disorganized intermyofibrillar networks containing large diformazan granules on NADH-TR, small angulated fibers with high nonspecific esterase (NSE) activity and basophilic fibers. Ragged-red fibers and increased lipid droplet accumulation were absent. Patient 1 had increased numbers of type 2C fibers (11.3%) and mild fiber type grouping. On electron microscopy, most mitochondria were nearly normal. There were focal aggregates of mildly enlarged mitochondria in the subsarcolemmal areas in both patients. Morphometric study showed that the mean mitochondrial size and the mitochondrial percentage of fiber volume were not significantly different amongst patients and normal controls.

Child↗
PubMed1987

Effects of dichloroacetate on the mechanical function of the isolated ischemic heart.

The effects of sodium dichloroacetate (DCA) on the activity of the pyruvate dehydrogenase complex (PDH) and the mechanical function of the isolated ischemic rat heart were investigated. Ischemia was induced by restriction of coronary flow. Perfusion with DCA caused a decrease in the tension developed (DT) and the maximal rate of tension development (+ dT/dt max), and an increase in the resting tension (RT) at low flow rates (0.6 and 0.15 ml/min). However, it did not affect the DT or +dT/dt max of normoxic hearts (3 ml/min) or hearts at zero flow rate. DCA increased PDH activity in hearts at all flow rates. It was concluded that this effect of DCA was associated with a decrease in lactate production, rather than an increase in the lactate/pyruvate ratio.

Acetates↗
PubMed1986

Rapid diagnosis of vitamin D-dependent rickets type II by use of phytohemagglutinin-stimulated lymphocytes.

The interactions of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] with phytohemagglutinin (PHA)-stimulated lymphocytes from normal subjects and three patients with vitamin D-dependent rickets (DDR) type II were investigated. Impaired nuclear uptake and normal cytosol binding of [3H]1,25-(OH)2D3 were observed with PHA-stimulated lymphocytes of these patients as with their cultured skin fibroblasts. Furthermore, the incorporation of [14C]thymidine into PHA-stimulated lymphocytes of the patients was not reduced by 1,25-(OH)2D3, which is known to inhibit proliferation of various cells. These findings suggest that 1,25-(OH)2D3 receptors are reduced or absent in patients with DDR type II. Thus, the capacities of cytosol binding and nuclear uptake of 1,25-(OH)2D3 in PHA-stimulated lymphocytes seem to reflect those of endo-organs such as the intestine and bone. These findings show that a test of the effect of 1,25-(OH)2D3 on thymidine incorporation into PHA-stimulated lymphocytes is useful for rapid diagnosis of DDR type II.

Calcitriol↗