Graves' Disease after Adrenalectomy for Cushing's Syndrome.

A 44-year-old woman presented with a 3-month history of back pain, gait disturbance, and insomnia. She had moon face and central obesity but no goiter. Cushing's syndrome due to left adrenal adenoma was diagnosed. She also had low triiodothyronine syndrome and central hypothyroidism. Treatment involved adrenalectomy followed by 30 mg/day of hydrocortisone. Inappropriate secretion of thyroid-stimulating hormone occurred postoperatively. She developed Graves' disease nine months postoperatively and was treated with methimazole. Excess glucocorticoids followed by their withdrawal may influence the hypothalamic-pituitary-thyroid axis and immune system. Therefore, a careful evaluation of the thyroid function and antibodies is important after surgery for Cushing's syndrome.

Role of a new bioassay for thyroid-stimulating antibodies (aequorin TSAb) in Graves' ophthalmopathy.

Graves' ophthalmopathy (GO) is characterized by an autoimmune reaction against thyrotropin (TSH) receptors and is diagnosed by TSH receptor antibody (TRAb). A novel assay for thyroid-stimulating antibody (TSAb) was recently introduced using a frozen Chinese hamster ovary cell line expressing TSH receptors, cyclic adenosine monophosphate (cAMP)-gated calcium channel, and aequorin (aequorin TSAb). The aim of this study was to evaluate the role of aequorin TSAb in GO. We studied 136 Japanese patients with GO (22 euthyroid and 8 hypothyroid GO patients) at our hospital. TRAbs were estimated by first generation TRAb (TRAb 1st), second generation TRAb (hTRAb 2nd), conventional porcine TSAb, and the new aequorin TSAb assays. Aequorin TSAb, porcine TSAb, TRAb 1st, and hTRAb 2nd were positive in 125/136 (92%), 110/136 (81%), 81/130 (62%), and 93/114 (82%) patients, respectively. In patients with hyperthyroid GO, they were positive in 98/106 (98%), 96/106 (91%), 78/101 (77%), and 84/93 (90%) patients, respectively. In patients with euthyroid GO, they were positive in 19/22 (86%), 9/22 (41%), 1/21 (5%), and 6/17 (35%) patients, respectively. Aequorin TSAb levels were significantly related to TRAb 1st (r = 0.4172, p < 0.0001), hTRAb 2nd (r = 0.2592, p < 0.0001), and porcine TSAb (r = 0.4665, p < 0.0001). Clinical activity score (CAS) was significantly greater in patients with high titers of aequorin TSAb than in those with low titers. Aequorin TSAb levels were significantly related to the signal intensity ratio of the enlarged eye muscle and proptosis evaluated by MRI before steroid pulse therapy. Aequorin TSAb assay was more sensitive than the conventional assays, especially in euthyroid GO.

[Clinical examination of cases of radiation proctitis after intensity-modulated radiation therapy for prostate cancer].

In our series of 366 patients who received intensity-modulated radiation therapy (IMRT) for prostate cancer, radiation proctitis developed in 24 patients. We examined the endoscopic evidence and clinical characteristics of radiation proctitis in these patients. The onset time was 2-29 months after treatment, with bloody bowel discharge being the most common symptom (22 cases). Colonoscopy revealed that the lesions tended to be concentrated on the rectal right anterior wall. Severity, according to the Tada classification, was 0b or Ia in 70.8% of all cases. The incidence of radiation proctitis decreased, and the clinical and endoscopic findings showed only mild radiation proctitis after IMRT.

Liver Dysfunction Associated with Intravenous Methylprednisolone Pulse Therapy in Patients with Graves' Orbitopathy.

Intravenous methylprednisolone (IVMP) pulse therapy is the first-line treatment for the active phase of moderate to severe Graves' orbitopathy (GO). However, acute and severe liver damage has been reported during and after IVMP therapy. In this retrospective study, we investigated risk factors for liver dysfunction during and after IVMP therapy based on 175 Japanese patients with moderate to severe GO and treated at our center between 2003 and 2011. The results showed that seven patients developed severe liver dysfunction with elevated serum alanine aminotransferase (ALT > 300 U/L). Mild (40-100 U/L) and moderate (100-300 U/L) increases of ALT occurred in 62 patients (35%) and 10 patients (6%), respectively. Liver dysfunction was more frequently observed in males, in patients receiving high-dose methylprednisolone, and patients aged over 50 years. Preexistent viral hepatitis was significantly associated with liver dysfunction (65% in patients positive for hepatitis B core antibody and patients positive for hepatitis C virus antibodies). Our study confirmed the association of liver dysfunction with IVMP during and after treatment. It suggests that, in patients with GO, evaluation of preexisting risk factors-including viral hepatitis-and careful weekly monitoring of liver function during IVMP therapy and monthly thereafter for 12 months are warranted.

Graves' ophthalmopathy: epidemiology and natural history.

Graves' ophthalmopathy (GO) is an autoimmune disorder of the orbit that is clinically relevant in 25-50% of patients with Graves' disease and 2% of patients with chronic thyroiditis. The age-adjusted annual incidence of clinically relevant GO is 16 per 100,000 population in women and 2.9 in men. At the onset of ophthalmopathy, 80-90% of patients have hyperthyroidism, with the rest having euthyroidism or hypothyroidism. The natural history of GO consists of two phases: an active inflammatory phase and a static phase. Anti-inflammatory therapy is indicated for the first phase of GO. Approximately 5% of patients experience late reactivation of GO. Asians appear to have less severe manifestations, with milder orbital edema, proptosis and muscle restriction. Genetic, anatomic and environmental factors influence the development of GO. Aging, thyroid dysfunction, thyroid stimulating hormone (TSH) receptor antibodies, smoking and radioiodine treatment for hyperthyroidism also influence the development and course of GO.

Hypophosphatemic osteomalacia due to drug-induced Fanconi's syndrome associated with adefovir dipivoxil treatment for hepatitis B.

We herein present the case of a 58-year-old Japanese man with Fanconi's syndrome with a 13-month history of bone pain in his ribs, hips, knees and ankles. He had been receiving low-dose adefovir dipivoxil (ADV) for the treatment of lamivudine-resistant chronic hepatitis B virus infection for eight years and subsequently developed severe hypophosphatemia and proximal renal tubule dysfunction. Magnetic resonance imaging showed multiple insufficiency fractures in the ribs, ileum, tibia and calcaneus. Whole-body bone scintigraphy demonstrated increased uptake in those areas. Following dose reduction of ADV and the administration of treatment with calcitriol and phosphates, the patient's serum phosphate level increased and his clinical symptoms improved. Physicians prescribing ADV should carefully monitor the renal function and serum phosphate level.

Case of cytomegalovirus-associated direct anti-globulin test-negative autoimmune hemolytic anemia.

A 1-year-old boy developed autoimmune hemolytic anemia after a negative direct anti-globulin test. The concentration of erythrocyte membrane-associated immunoglobulin G, determined using an immunoradiometric assay, correlated with disease activity. He was positive for cytomegalovirus (CMV) both serologically and by quantitative real-time polymerase chain reaction, indicating that his autoimmune hemolytic anemia was directly caused by CMV infection. Since anti-CMV immunoglobulin G was not absorbed by the patient's erythrocytes, cross-reaction between erythrocyte antigens and CMV was not likely a causative factor for hemolysis.

[Management of Graves' ophthalmopathy by using orbital magnetic resonance imaging].

Orbital magnetic resonance imaging (MRI) can visualize the inflamed lesions of Graves' ophthalmopathy(GO). Parasagittal, transverse and coronal sections of T1-weighted, T2-weighted and short inversion time inversion recovery(STIR) images correlate clinical manifestations with the location of the inflamed lesions. In addition, the measurement of T2 relaxation time or signal intensity ratio of the enlarged muscles in T2-weighted fat suppression images or STIR images provide a precise quantitative evaluation of disease activity and may predict the outcome of immunosuppressive therapy for GO. Thus, MRI is useful for decision-making regarding immunosuppressive therapy and prompt surgery for GO. Therefore, we recommend MRI as a useful tool for the management of GO in specialized clinics.

Japanese Guidelines for the Management of Respiratory Infectious Diseases in Children 2007 with focus on pneumonia.

Members of the Japanese Society of Pediatric Pulmonology and the Japanese Society for Pediatric Infectious Diseases developed the Guidelines for the Management of Respiratory Infectious Diseases in Children with the objective of facilitating the appropriate diagnosis and treatment of childhood respiratory infections. To date, a first edition (2004) and a revised edition (2007) have been issued. Many problems complicate the diagnosis of the pathogens responsible for bronchopulmonary infections in children. The Guidelines were the first pediatric guidelines in the world to recommend treatment with antimicrobials suited to causative pathogens as identified from cultures of sputum and other clinical specimens collected from infection sites and satisfying assessment criteria. The major causative microorganisms for pneumonia in infants and children were revealed to be Streptococcus pneumoniae, Haemophilus influenzae and Mycoplasma pneumoniae. This manuscript describes the Guidelines for the Management of Respiratory Infectious Diseases in Children in Japan 2007, with a focus on pneumonia.

Only two-week smoking cessation improves platelet aggregability and intraplatelet redox imbalance of long-term smokers.

OBJECTIVES: We investigated whether and how soon smoking cessation ameliorates the smoking-induced intracellular oxidative stress and platelet aggregability in long-term smokers. BACKGROUND: Smoking is a major risk factor of atherothrombosis. Smoking cessation reduces cardiac events. However, the underlying mechanisms of the beneficial effects remain to be elucidated. METHODS: Twenty-seven male long-term smokers were divided into two groups. Group A (n = 14) quit smoking for four weeks whereas group B (n = 13) resumed smoking two weeks after quitting. Smoking status was monitored by measurement of urinary cotinine. Using gel-filtered platelets, agonist (adenosine diphosphate and collagen)-induced platelet aggregation, platelet-derived nitric oxide (PDNO), intraplatelet nitrotyrosine production, intraplatelet levels of the reduced form of glutathione (GSH) and its oxidized form (GSSG), and urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) and urinary 8-iso-prostaglandin F(2alpha) (8-iso-PGF(2alpha)), as markers of systemic oxidative stress, were measured. The baseline measurements were similar between the two groups. RESULTS: Smoking cessation quickly reduced agonist-induced platelet aggregations, intraplatelet nitrotyrosine level, and urinary productions of 8-OHdG and 8-iso-PGF(2alpha) by two weeks in both groups. In group A, they were maintained at the low levels until four weeks, whereas they were reversed by resmoking in group B; PDNO release and intraplatelet GSH/GSSG ratio were time-dependently increased by smoking cessation but reversed by resmoking. CONCLUSIONS: The present findings are the first demonstration that only two weeks of smoking cessation can ameliorate the enhanced platelet aggregability and intraplatelet redox imbalance in long-term smokers, possibly by decreasing oxidative stress. Our findings may strengthen the motivation for smokers to quit smoking.

Relation of plasma folate and methylenetetrahydrofolate reductase C677T polymorphism to colorectal adenomas.

BACKGROUND: Folate intake may be related to decreased risk of colorectal cancer and adenomas. Methylenetetrahydrofolate reductase (MTHFR) is a key regulatory enzyme in folate metabolism. We examined the relation between plasma folate status and colorectal adenomas with reference to effect modification by the genetic polymorphism (C677T) of MTHFR. METHODS: Study subjects were middle-aged Japanese men: 177 cases of colorectal adenomas and 192 controls with normal total colonoscopy. Statistical adjustment was made for hospital, rank in the Self Defense Forces, alcohol use, smoking, and body mass index. RESULTS: Plasma folate levels were slightly lower in adenoma cases than in controls. Adjusted odds ratio (OR) for high (>5.50 ng/ml) versus low plasma folate levels was 0.72 (95% CI: 0.46-1.14). As compared with subjects with the CC or CT genotype having low plasma folate levels, those with the TT genotype showed a decreased risk of colorectal adenomas when they had high levels of plasma folate (adjusted OR = 0.58, 95% CI: 0.21-1.61), and an increased risk when they had low folate levels (adjusted OR = 2.13, 95% CI: 0.82-5.54). There was no clear relation between plasma folate and colorectal adenomas among those with the CC or CT genotype. CONCLUSIONS: The findings suggest an interaction between folate and the MTHFR genotype on colorectal adenomas.

Glucose intolerance and serum aminotransferase activities in Japanese men.

BACKGROUND/AIMS: Elevated activities of serum aminotransferase are commonly observed in patients with diabetes mellitus. Few studies have addressed the relation between glucose intolerance and serum activities of aminotransferase in free-living populations. METHODS: Using a 75 g oral glucose tolerance test, we examined the association of impaired fasting glycemia (IFG), impaired glucose tolerance (IGT), and type 2 diabetes mellitus with serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyltransferase (GGT) among 4621 men aged 49-59 years of the Japan Self-Defense Forces. Statistical adjustment was made for body mass index, waist-hip ratio, and other possible confounding factors. RESULTS: Proportions of an elevated ALT (>50 IU/l) in men with normal glucose tolerance, IFG, IGT, and newly diagnosed diabetes mellitus were 3.5%, 9.5%, 7.7%, and 18.0%, respectively. Adjusted odds ratios of an elevated ALT for IFG, IGT, and newly diagnosed diabetes mellitus were 2.2 (95% confidence interval 1.1-4.3), 1.7 (1.2-2.4), and 4.4 (3.0-6.6), respectively. IGT and diabetes mellitus were also significantly positively associated with elevated AST (>40 IU/l) and GGT (>50 IU/l). CONCLUSIONS: Glucose intolerance is associated with elevated serum aminotransferase independent of obesity, but even a mildly elevated ALT is relatively uncommon in free-living men with glucose intolerance.

Insulin-like growth factor (IGF)-I, IGF-binding protein-3 and colorectal adenomas in Japanese men.

Several epidemiological studies have found that high levels of plasma insulin-like growth factor (IGF)-I and low levels of IGF-binding protein (IGFBP)-3 are related to an increased risk of colorectal cancer or late-stage adenomas. We examined the relation of body mass index, fasting and 2-h postload plasma glucose levels and plasma concentrations of IGF-I and IGFBP-3 to colorectal adenomas in middle-aged Japanese men. The study subjects comprised 157 cases of histologically diagnosed colorectal adenomas and 311 controls with normal colonoscopy or non-polyp benign lesions in a consecutive series of 803 men receiving a preretirement health examination at two hospitals of the Self Defense Forces (SDF). After adjustment for rank in the SDF, hospital, smoking and IGFBP-3, a statistically nonsignificant modest increase in the prevalence odds of colorectal adenomas was observed for the highest versus the lowest quartile level of IGF-I. The increase was slightly greater with further adjustment for 2-h glucose concentrations (adjusted odds ratio 1.8, 95% confidence interval 1.0-4.5, trend P=0.06). Men with high levels of IGFBP-3 showed only a minimal decrease in risk after adjustment for IGF-I. The association with IGF-I was less evident for advanced adenomas (>5 mm in size or tubulovillous/villous). Fasting and 2-h glucose and body mass index were more strongly positively associated with colorectal adenomas than IGF-I, especially with advanced adenomas, independently of IGF-I and IGFBP-3. The findings suggest that plasma IGF-I and IGFBP-3 may be involved in colorectal tumorigenesis regardless of the stage in growth of adenoma, but not as a mediator for the effects of being overweight or of hyperglycemia.

Anthropometric and behavioral correlates of insulin-like growth factor I and insulin-like growth factor binding protein 3 in middle-aged Japanese men.

High levels of plasma insulin-like growth factor I (IGF-I) and low levels of insulin-like growth factor binding protein 3 (IGFBP-3) have been related to increased risk of several cancers. Little is known about the behavioral determinants of these biologic markers. The authors examined the relation of anthropometric and behavioral factors to plasma concentrations of IGF-I and IGFBP-3 in a cross-sectional study of 616 Japanese men aged 45-55 years in 1995-1996. In univariate analyses, body mass index was strongly, positively associated with both IGF-I and IGFBP-3. The waist/hip ratio was also linearly related to IGF-I and IGFBP-3 up to the third quartile level. Height was weakly, positively associated with IGF-I and IGFBP-3. Smoking was inversely associated with IGF-I and IGFBP-3. Alcohol use was associated inversely with IGF-I and positively with IGFBP-3. Neither IGF-I nor IGFBP-3 was related to physical activity. Results of the multivariate analysis were essentially the same as those of the univariate analyses. The findings regarding body mass index are in contrast to those of previous studies showing null or inverse associations, and they suggest that the relation of body mass index to IGF-I or IGFBP-3 may vary among populations. The study also indicates that smoking and alcohol use might affect plasma IGF-I and IGFBP-3.

Core aldehydes of alkyl glycerophosphocholines in atheroma induce platelet aggregation and inhibit endothelium-dependent arterial relaxation.

Plaque disruption with superimposed thrombosis is considered to be responsible for precipitating acute coronary syndrome. We identified sn-1-alkyl- and sn-1-acyl-type glycerophosphocholine (GroPCho) core aldehydes from human atheromas and demonstrated their activities on platelets and arteries. The naturally occurring core aldehydes were identified and quantified in relation to synthetic standards by high performance liquid chromatography with on-line electrospray mass spectrometry. 1-O-Hexadecyl-2-(5-oxovaleroyl)-sn-GroPCho (C(5) alkyl GroPCho core aldehyde), occurring in atheroma at less than 0.1% of total phosphatide, induced aggregation of washed rabbit platelets (50% effective dose was approximately 50 nM). Aggregations induced by C(5) alkyl GroPCho core aldehydes were completely inhibited by two different platelet-activating factor receptor antagonists. 1-Palmitoyl-2-(5-oxovaleroyl)-sn-GroPCho (C(5) acyl GroPCho core aldehyde) induced platelet shape change, but not aggregation. By contrast, 10 microM C(5) alkyl and C(5) acyl GroPCho core aldehydes both inhibited endothelium-dependent relaxation of rabbit artery by 50% (endothelium-independent relaxation was not affected). The present demonstration of platelet aggregation by physiologically relevant concentrations of alkyl GroPCho core aldehydes suggests that alkyl GroPCho core aldehyde generated in atheroma could be involved in precipitating acute coronary events, in which thrombus formation following lipid-rich plaque disruption plays an important role.

Relation of impaired glucose tolerance and diabetes mellitus to colorectal adenomas in Japan.

OBJECTIVE: Because a link between hyperinsulinemia and colorectal carcinogenesis has been hypothesized, we explored the relation between glucose tolerance status and colorectal adenomas. METHODS: We conducted a case-control study of 560 cases of histologically confirmed colorectal adenomas and 829 controls of normal total colonoscopy in Japanese middle-aged men. Subjects were classified into normal, impaired fasting glucose (IFG), impaired glucose tolerance (IGT), newly diagnosed type 2 diabetes mellitus (DM), and known DM based on fasting blood glucose, 75 g glucose tolerance test, and medical history. Odds ratios (ORs) and 95% confidence intervals (CIs) were obtained from logistic regression analysis with subjects with normal glucose tolerance and IFG as a referent group. RESULTS: IGT, new type 2 DM, and known DM were each associated with a modest increase in the risk of colorectal adenomas after adjustment for possible confounding factors. An increased risk of large, but not small, adenomas was observed among men with IGT and new type 2 DM. An increased risk associated with new type 2 DM was observed for proximal adenomas only. CONCLUSIONS: Not only type 2 DM but also IGT is associated with increased risk of colorectal adenomas. Hyperinsulinemia may be involved in colorectal carcinogenesis.