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Myositis-specific autoantibody is associated with the clinical phenotype and prognosis of dermatomyositis. Anti-melanoma differentiation-associated gene 5 (MDA5) and anti-aminoacyl-tRNA synthetase (ARS) antibodies are generally mutually exclusive. We herein present an extremely rare case of dermatomyositis which showed double positivity for anti-MDA5 and anti-ARS antibodies. There have been very few reported cases of double positive anti-MDA5, anti-ARS antibodies. In such cases, the clinical characteristics of each autoantibody can coexist. Thus, we should pay attention to the rapidly progressing features of anti-MDA5 as well as the chronic relapsing features of anti-ARS for the better management of this rare condition.

Liver kinase B1 (LKB1) is a serine/threonine protein kinase that acts as a key tumor suppressor protein by activating its downstream kinases, such as AMP-activated protein kinase (AMPK). However, the regulatory actions of LKB1 and AMPK on DNA damage response (DDR) remain to be explored. In this study, we investigated the function of LKB1 in DDR induced by cisplatin, a representative DNA-damaging agent, and found that LKB1 stabilizes and activates p53 through the c-Jun N-terminal kinase (JNK) pathway, which promotes cisplatin-induced apoptosis in human fibrosarcoma cell line HT1080. On the other hand, we found that AMPKα1 and α2 double knockout (DKO) cells showed enhanced stabilization of p53 and increased susceptibility to apoptosis induced by cisplatin, suggesting that AMPK negatively regulates cisplatin-induced apoptosis. Moreover, the additional stabilization of p53 and subsequent apoptosis in AMPK DKO cells were clearly canceled by the treatment with the antioxidants, raising the possibility that AMPK suppresses the p53 activation mediated by oxidative stress. Thus, our findings unexpectedly demonstrate the reciprocal regulation of p53 by LKB1 and AMPK in DDR, which provides insights into the molecular mechanisms of DDR.

Acute encephalitis is an extremely rare condition in primary Sjogren's syndrome (pSS), and its characteristics and prognosis remain unclear. Here we report the case of pSS presented with acute encephalitis. She was admitted to our hospital for acute disturbance of consciousness. Acute encephalitis was diagnosed based on the results for cerebrospinal fluid test (the increase of leukocyte counts, protein, and interleukin-6 level), magnetic resonance imaging (a high signal intensity of the white matter around lateral ventricle on T2 FLAIR images), and single photon emission computed tomography with 99mTc (hypoperfusion in the bilateral cerebrum with frontal lobe predominance). The infectious etiologies and underlying malignancies were excluded. Serum anti-SSA/Ro antibody was positive with extremely high titer, whereas anti-dsDNA, anti-Sm, anti-ribosomal P, anti-RNP, and anti-phospholipid antibodies were all negative. Anti-NAE, anti-NMDAR, and anti-ribosomal P antibodies in cerebrospinal fluid were absent. The biopsy specimen of her labial salivary gland revealed a focal lymphocytic sialadenitis with a score of grade 4 in Greenspan grade. She also developed diffuse alveolar hemorrhage during the clinical course. She was diagnosed with pSS complicated with acute encephalitis followed by diffuse alveolar hemorrhage and successfully treated with pulse steroids, high dose of prednisolone and intravenous cyclophosphamide. Our present case and literature review suggest that acute encephalitis associated with pSS can be treatable with the immunosuppressive therapy, and thus, early recognition and treatment initiation are important for this life-threatening condition. Thus, pSS should be included in the differential diagnosis of unexplained encephalitis. Notably, our case characteristically showed diffuse alveolar hemorrhage, adding the new insight in the pathogenesis of acute encephalitis associated with pSS that capillaritis might be the underlying cause of this condition. (272 words).

Receptor-interacting protein kinase 1 (RIPK1) is a key component of the tumor necrosis factor (TNF) receptor signaling complex that regulates both pro- and anti-apoptotic signaling. The reciprocal functions of RIPK1 in TNF signaling are determined by the state of the posttranslational modifications (PTMs) of RIPK1. However, the underlying mechanisms associated with the PTMs of RIPK1 are unclear. In this study, we found that RING finger protein 4 (RNF4), a RING finger E3 ubiquitin ligase, is required for the RIPK1 autophosphorylation and subsequent cell death. It has been reported that RNF4 negatively regulates TNF-α-induced activation of the nuclear factor-κB (NF-κB) through downregulation of transforming growth factor β-activated kinase 1 (TAK1) activity, indicating the possibility that RNF4-mediated TAK1 suppression results in enhanced sensitivity to cell death. However, interestingly, RNF4 was needed to induce RIPK1-mediated cell death even in the absence of TAK1, suggesting that RNF4 can promote RIPK1-mediated cell death without suppressing the TAK1 activity. Thus, these observations reveal the existence of a novel mechanism whereby RNF4 promotes the autophosphorylation of RIPK1, which provides a novel insight into the molecular basis for the PTMs of RIPK1.

Synthetic excitatory synaptic organizer The human brain contains trillions of synapses within a vast network of neurons. Synapse remodeling is essential to ensure the efficient reception and integration of external stimuli and to store and retrieve information. Building and remodeling of synapses occurs throughout life under the control of synaptic organizer proteins. Errors in this process can lead to neuropsychiatric or neurological disorders. Suzuki et al. combined structural elements of natural synaptic organizers to develop an artificial version called CPTX, which has different binding properties (see the Perspective by Salinas). CPTX could act as a molecular bridge to reconnect neurons and restore excitatory synaptic function in animal models of cerebellar ataxia, familial Alzheimer's disease, and spinal cord injury. The findings illustrate how structure-guided approaches can help to repair neuronal circuits. Science , this issue p. eabb4853 ; see also p. 1052

Tumor necrosis factor receptor-associated factor 2 (TRAF2) is an essential component of tumor necrosis factor-α (TNF-α) signaling that regulates nuclear factor-κB (NF-κB) and c-Jun N-terminal kinase (JNK) pathways, and compelling evidence has demonstrated that TRAF2 suppresses TNF-α-induced cytotoxicity. On the other hand, it has been reported that oxidative stress-induced cytotoxicity is potentiated by TRAF2, indicating that TRAF2 both positively and negatively regulates stress-induced cytotoxicity in a context-specific manner. However, the causal role of TRAF2 in DNA damage response (DDR) remains to be explored. In this study, we assessed the function of TRAF2 in DDR induced by cisplatin, a representative DNA-damaging agent, and found that TRAF2 exerts pro-apoptotic activity through p53-dependent mechanisms at least in human fibrosarcoma cell line HT1080. TRAF2 deficient cells exhibit significant resistance to cell death induced by cisplatin, accompanied by the reduction of both p53 protein level and caspase-3 activation. Moreover, cisplatin-induced JNK activation was attenuated in TRAF2-deficient cells, and pharmacological inhibition of JNK signaling suppressed p53 stabilization. These results suggest that TRAF2 promotes p53-dependent apoptosis by activating the JNK signaling cascade in HT1080 cells. Thus, our data demonstrate a novel function of TRAF2 in cisplatin-induced DDR as a pro-apoptotic protein.

In this study, a spectroscopic method is applied to measure two-dimensional (2D) distributions of flame temperatures during regenerative combustion of natural gas with highly preheated air in a test furnace of industrial size. By using a CCD camera fitted with an optical bandpass filter, the 2D distributions of the continuum emission from soot particles in premix and diffusion flames are measured at two different wavelengths. Subsequently, the temperature is determined on the basis of the two-color 2D thermometry, in which the ratio of the 2D emission intensity distributions is converted into the 2D temperature distribution with much higher spatial resolution in comparison with those obtainable by thermocouples. The emission profiles of NO radiation also were measured and the results are discussed in conjunction with difference in the temperature profiles of the flames.

Polymyalgia rheumatica (PMR) and exacerbated pulmonary fibrosis presented concurrently in a 69-year-old woman with a 5-year history of idiopathic interstitial pneumonia. The radiographic and histological examinations suggested usual interstitial pneumonia (UIP) as a more likely diagnosis. Corticosteroid therapy resulted in relief of the patient's muscle symptoms and improvement in the functional and radiographical signs of the pulmonary fibrosis. The final diagnosis was pulmonary fibrosis associated with PMR, because PMR is believed to be one of the causes contributing to interstitial lung diseases.

We present a rare case of a 66-year-old woman with the syndrome of inappropriate antidiuresis (SIAD) accompanied by an empty sella whose symptoms were seen twice in the eight years after the administration of non-steroidal anti-inflammatory drugs (NSAID) or prochlorperazine. No diuresis or suppression of the plasma level of vasopressin (AVP) was observed after water loading upon cessation of the causative agents. Suppression of the renin-aldosterone system and a low plasma level of atrial natriuretic peptide (ANP) were observed during natriuresis. The plasma levels of AVP were increased after water loadings. Restriction of water intake ameliorated the symptoms and reduced hyponatremia. These findings suggest that NSAID or prochlorperazine caused overt SIAD twice in eight years. The water loading test itself stimulated the release of AVP and a suppression of the renin-aldosterone system played a more important role in natriuresis than ANP in this case.

A 59-year-old woman with primary hyperparathyroidism was found to have a parathyroid adenoma behind the left clavicle. Preoperatively, it appeared as a hypoechoic mass on ultrasonography, as a hot nodule on thallium scintigraphy, and as a high signal on T2-weighted magnetic resonance imaging. Histological, immunohistochemical and ultrastructural studies of the surgically resected tumor revealed a parathyroid adenoma composed mainly of oxyphil cells with production of a parathyroid hormone. Moreover, a multilocular lesion of lymphangiectasia was contained. Hypercalcemia was alleviated postoperatively. These observations corroborated a functioning parathyroid oxyphil cell adenoma. This is the first case report of functioning oxyphil cell adenoma of the parathyroid gland with lymphangiectasia in Japan.

Noninvasive diagnostic procedures for the preoperative localization of parathyroid tumors were performed on a 59-year-old woman with hypercalcemia. In this case, sonography and computed tomographic scanning could not pinpoint the location of the tumor. Thallium-201 and technetium-99m subtraction scintigraphy was also inconclusive in the precise localization of the tumor, but it did define the location retrospectively. However, magnetic resonance imaging (MRI) clearly demonstrated the parathyroid tumor as a high signal on T2-weighted image in the left upper part of the superior mediastinum. The intrathymic parathyroid oxyphil adenoma was resected. Therefore, MRI was considered an effective tool for the localization of parathyroid adenoma, particularly mediastinal parathyroid adenoma.

A 41-year-old woman was found to have had spontaneous submucosal dissection of the esophagus by esophagoscopy. Food ingestion was postulated to have been an initiating factor in this instance. Conservative therapy was sufficient in this case. Patients who complain of sore throat with retrosternal pain and an obstructed sensation on swallowing or mild hematemesis should be examined by esophagoscopy for evidence of this disorder.(Internal Medicine 32: 795-797, 1993)

In order to identify non-endocrine laboratory tests of diagnostic value in Cushing's syndrome, we measured platelet counts and serum myogenic and hepatic enzyme levels in 10 patients with Cushing's syndrome and compared the findings with those of 15 obese patients without Cushing's syndrome. Patients with Cushing's syndrome had increased numbers of platelets, moderately elevated serum lactic dehydrogenase and gamma-glutamyltranspeptidase levels, and significantly lower creatine phosphokinase and choline esterase activities compared with those of obese control patients. We concluded that when several of these abnormal values were seen in obese patients the levels of suspicion for Cushing's syndrome should be high.

In order to clarify the conversion of thyroxine (T4) to triiodothyronine (T3) or to reverse T3 (rT3), serum concentrations of T4, T3, rT3, thyrotropin (TSH), thyroxine-binding globulin (TBG) and values of T3 uptake (T3 U) were measured in 61 hyperthyroid and 31 hypothyroid patients, 8 patients with subacute thyroiditis, and 40 normal subjects. Then, free T4 index (FT4I), T3/T4, rT3/T4, and rT3/T3 ratio were calculated. The rT3/T3 ratio was high in the hyperthyroid patients and low in the hypothyroid patients compared with that in the normal subjects. The ratio was positively related to serum T4, T3, rT3 levels, and FT4I in the patients and normal subjects. The regression equation was represented by rT3/T3 = 0.015[T4] + 0.083. No influences of serum TBG and age on the rT3/T3 ratio were observed. Our results indicated that thyroid hormones themselves could regulate the conversion of T4 to T3 or rT3 by activating 5-monodeiodinase in hyperthyroidism and by activating 5'-monodeiodinase and suppressing 5-monodeiodinase in hypothyroidism. Serum rT3 level was a more sensitive parameter than serum T4 or T3 for evaluating thyroid dysfunction. During the treatment with methimazole (MMI) or L-thyroxine and the natural course of subacute thyroiditis, serum T4 levels and rT3/T3 ratios changed parallel to the regression line. However, once adverse effects of MMI occurred, those changed out of the line. From these results, we concluded that the relationship between serum T4 level and rT3/T3 ratio should be examined for adequate information concerning the peripheral conversion of thyroid hormones under various thyroid diseases.

We report a patient with pseudohypoparathyroidism (PHP) in whom parathyroid hormone (PTH) infusion failed to produce an increase in urinary adenosine 3', 5' monophosphate (cAMP) excretion in spite of the positive urinary phosphate excretion. The dbcAMP infusion test showed almost the same increase in phosphate as in the E-H test, although high urinary cAMP excretion was detected. Furthermore, a PTH infusion test in combination with calcium antagonist (diltiazem) administration markedly increased phosphate excretion, whereas the response of urinary cAMP excretion also remained negative. After treatment with 1 alpha(OH)D3, phosphaturic response increased by at least 14.3 mg/2 h compared with that in the pretreatment period. Therefore, intra and extra cellular calcium seem to affect the phosphaturic response induced by PTH.

A 29-year-old female who had undergone resection of an abdominal paraaortic pheochromocytoma weighing 33 g at the age of 20 had had severe headaches, hypertension and hyperhidrosis 3 years prior to the surgery. Postoperatively, her symptoms completely disappeared and urinary catecholamines were normalized. She was well and had married and had had 2 children. She was admitted to our hospital on August 22, 1982, for further evaluation of hypertension (154/100), which had been diagnosed 2 months previously. Endocrinological studies confirming the presence of a pheochromocytoma were as follows: 1) Plasma noradrenaline level was significantly elevated to 1750 pg/ml. 2) Urinary catecholamine and their metabolites (Metanephrines and VMA) were markedly elevated. Her blood pressure was borderline hypertension and its diurnal rhythm was lost. Her blood pressure decreased to normal values after the oral administration of labetalol (100 mg). Plasma noradrenaline level was still high at 180 minutes after the oral administration of clonidine (150 micrograms). Hypertensive response to insulin-induced hypoglycemia (regular insulin 0.1 u/kg i.v.) was observed, but blood pressure returned to normal after the infusion of glucose alone. Hypertensive response to both metoclopramide (5 mg i.v.) and sulpiride (50 mg per os) was observed accompanying the significant elevation of plasma noradrenaline. Computed tomography and ultrasonography revealed a tumor localized between the aorta and the vena cava inferior. Selective venous sampling also revealed an intrathoracic pheochromocytoma. On October 8, 1982, a 28 g mass was removed from the mediastinum just above the diaphragma. Histologically, it was typical of a pheochromocytoma. Electron microscopy showed large polygonal cells with numerous large secretory granules characteristic of noradrenaline-granules. Postoperative blood pressure was normal, but repeated measurements of plasma and urinary catecholamines were still slightly high. We, therefore, followed her case carefully at our out-patient clinic. In order to clarify the mechanism of catecholamine release by metoclopramide and sulpiride, tissue cultures of removed pheochromocytoma with and without these drugs were carried out. The in vitro studies revealed that metoclopramide released noradrenaline eight-fold and sulpiride 13-fold as compared with noradrenaline in a control medium. We concluded that both drugs stimulated catecholamine secretion directly from the tumor and thus, careless administration of these drugs should be avoided when pheochromocytoma was suspected, large or small. Finally, the rate of tumor growth seemed to be very slow because it took 9 years to ach

26才の主婦で,妊娠35週目より発作性頭痛,高血圧(210/120mmHg),浮腫および蛋白尿を来し,妊娠中毒症を疑われ産婦人科に入院した.第37週で2800gの男児を自然分娩し,その直後に痙〓発作と著明な血圧上昇(240/120)を来し,以後も血圧の動揺がはげしく,褐色細胞腫を疑われて当科へ転じた.血中・尿中カテコールアミン(CA)の著増と,下大静脈血CA, CTスキャン,超音波エコーなどより,右副腎褐色細胞腫と診断し,手術により腫瘍を摘出,術後,血中・尿中CAや血圧は正常化した.なお本例では,入院時に甲状腺腫,甲状腺ホルモン高値および血小板数増加を認めたが,甲状腺ホルモンはその後,正常化し,妊娠・分娩に伴う変化と考えた.一方,血小板数増加は術後正常化し,褐色細胞腫,特にCAの関与が推測された.文献上,本邦での妊娠に伴う褐色細胞腫は,本例を含めて計23例で,症状出現は妊娠後期に多く,妊娠中毒症とされた例が約半数に及んでいる.高血圧は78%が発作型で,母児の死亡は,記載のあるものでそれぞれ14%と30%であつた.以上,妊婦の褐色細胞腫はかなり特徴的であると考えた.

In order to clarify an alteration in thyroid functions in patients with chronic liver diseases, serum total and free thyroxine (T4, FT4), total and free triiodothyronine (T3, FT3), total reverse T3 (rT3), thyrotropin (TSH), thyroxine-binding globulin (TBG) concentrations, and T3 uptake (T3U) were measured by radioimmunoassays in 53 patients with chronic hepatitis (CH), 24 patients with compensated liver cirrhosis (LC), 17 patients with hepatocellular carcinoma associated with LC (HCC), and 40 normal subjects. Serum T4, T3, and rT3 in CH, and serum rT3 in HCC were significantly increased, while serum T4 in LC and serum T3 in HCC were significantly decreased. Serum TBG was increased and T3U was decreased in these patients. Serum TBG in CH and LC correlated positively with transaminase, and inversely with prothrombin time. FT4 and T4/TBG ratios in CH and LC and FT3 and T3/TBG ratios in LC and HCC were significantly decreased. Although T4/TBG ratios in HCC and T3/TBG ratios in CH were significantly decreased, FT4 in HCC and FT3 in CH were not decreased. The ratio of rT3/T3 in CH and LC correlated with various liver function tests. FT3 in LC and HCC correlated inversely with BSP (45') and positively with KICG. No differences in serum TSH values were found between chronic liver diseases and normal subjects. From these results, it was concluded that the thyroid functions in patients with chronic liver diseases were affected by the decrease in serum thyroxine, elevated serum TBG, the degree of which is in proportion to that of the liver cell damage, and impaired peripheral conversion of T4 to T3, the degree of which is in proportion to that of the hepatic dysfunction.

A 54-year-old woman who had proteinuria due to stage II membranous nephropathy is reported. She was treated with indomethacin for proteinuria and developed drug-induced hepatitis four months later. Liver dysfunction gradually recovered, but hormonal studies revealed abrupt fall of T3 and T4 and concomitant elevation of TSH levels within a month. Pathological findings of thyroid specimen and positive antithyroglobulin and antimicrosomal antibodies were compatible to chronic thyroiditis. In the second renal biopsy, glomerular deposits of thyroglobulin, thyroid microsomal antigens and IgG were demonstrated by immunofluorescence. Therefore, membranous nephropathy in this patient is presumed to be caused by immune complexes mediated by thyroid constituents. We believe that this is a precious case because continuous changes in T3, T4 and TSH were followed in a course of chronic thyroiditis, especially in the stage of progress to hypothyroidism, and the chronic thyroiditis was shown to be involved in the membranous nephropathy.

Twenty-seven patients with primary hypothyroidism were studied to evaluate the relationship between hepatic function and thyroid hormone deficiency in this disorder. In hypothyroidism, hypergammaglobulinemia was found in 71%, elevated glutamic oxaloacetic transaminase (GOT) in 48%, high lactic dehydrogenase (LDH) in 58%, hypercholesteremia in 52% and low elimination rate constant of indocyanin green (KICG) in 44%. In each criterion of liver function, these patients were divided into two groups, normal level and abnormal level group, respectively. T3 and T4 in patients with abnormal levels of GOT, glutamic pyruvic transaminase (GPT), gamma-glutamyl transpeptidase (gamma-GTP), leucine aminopeptidase (LAP), alkaline phosphatase (ALP) and 45 minutes retention rate of bromsulphalein (BSP) were not different from those in the normal level group. However, T3 and T4 in patients with abnormal levels of LDH, cholesterol, cholinesterase (ChE) and KICG were lower than those in the normal level group. The abnormal KICG group had a statistically higher cardio-thoracic ratio (CTR) than the normal group (65.7 +/- 18.8% vs 50.4 +/- 8.3%, p less than 0.05). In patients with pericardial effusion, CTR was 65.9 +/- 14.6%, while that in patients without pericardial effusion was 49.9 +/- 7.5% (p less than 0.05). These abnormalities of liver function were normalized in all cases after hormone replacement therapy. Liver biopsy in three cases disclosed normal liver in two cases and mild infiltration of monocyte into Glisson's capsule in one case.(ABSTRACT TRUNCATED AT 250 WORDS)

Seventy-five elderly patients with atrial fibrillation (41 males and 34 females with a mean age of 75.6 years) were studied to evaluate the incidence of masked thyroid dysfunction. A thyrotropin (TSH)-releasing-hormone (TRH) test (intravenous injection of 250 micrograms of synthetic TRH) was performed in the patients and 30 age matched controls without atrial fibrillation. In the controls, no abnormal TRH stimulated TSH response was observed. In the patients with atrial fibrillation, no response of TSH to TRH (hyperthyroidism) was found in 5 cases (6.6%), while hyperresponse of TSH to TRH (hypothyroidism) was found in 6 cases (8.0%). Thyroid dysfunction (hyper or hypothyroidism) was more frequently observed in the patients than in the controls (p less than 0.05). Two of 5 hyperthyroid patients had normal thyroid hormone levels. All patients with hyperthyroidism were treated with antithyroid drugs or 131I. Unfortunately, atrial fibrillation persisted in all but 1 case. It is concluded that the TRH test is a useful screening test for detecting those patients with abnormal thyroid function among elderly patients with atrial fibrillation, and that hypothyroidism should be considered as a cause of atrial fibrillation in the elderly.

A patient with Cushing's disease was described who showed non-suppressibilities of plasma ACTH, serum cortisol, and urinary 17-hydroxycorticosteroid (17-OHCS) with a standard dexamethasone suppression test. Serum cortisol was not suppressed even after a larger dose of oral and intravenous dexamethasone (up to 33mg). An intravenous injection of cortisol also failed to suppress the plasma ACTH level. Repeated dexamethasone suppression tests gave similar results. Since the patient had no adrenal tumor but a submucosal tumor of the stomach, ectopic ACTH syndrome was suspected. However, removal of the gastric tumor resulted in no improvement of hypercortisolism. Selective sampling from the petrosal vein showed a higher ACTH concentration than that in the peripheral vein. In addition, the salivary cortisol concentration after 8mg of dexamethasone administration was seen to decrease to 24.7% of the basal level, which was greater than that of serum cortisol and urinary 17-OHCS (65.4 and 78.0%, respectively). She underwent Hardy's operation, and adenomatous tissue 2mm in diameter was found and curetted out. However, hypercortisolism recurred after the transient remission. Additional treatments with medical adrenalectomy, pituitary irradiation, and administration of reserpine were carried out. After that, her clinical course was uneventful. We concluded that the determination of salivary cortisol was a reliable tool for evaluation of the response in dexamethasone non-suppressible Cushing's disease.