Autoimmune Polyglandular Syndrome Type 3 Complicated with IgG4-related Disease.

A 52-year-old Japanese woman developed type 1 diabetes mellitus (type 1 DM) at 41 years old. She became complicated with Hashimoto's disease and showed swelling of both submandibular glands, which was diagnosed as IgG4-related disease (IgG4-RD). This is a rare case of a Japanese patient with autoimmune polyglandular syndrome type 3A (APS-3A) coexisting with autoimmune thyroid disease (AITD) and type 1 DM complicated by IgG4-RD. Bilateral submandibular gland resection was successfully performed without steroid therapy. We discuss the possibility that the immunological pathogenic mechanisms of APS-3A and IgG4-RD are related.

Cerebrospinal fluid rhinorrhea with meningoencephalocele related to Sternberg's canal: A report of two cases.

Background: Cerebrospinal fluid (CSF) rhinorrhea with meningoencephalocele (MEC) associated with Sternberg's canal is rare. We treated two such cases. Case Description: A 41-year-old man and a 35-year-old woman presented with CSF rhinorrhea and mild headache worsening with standing posture. Head computed tomography showed a defect close to the foramen rotundum in the lateral wall of the left sphenoid sinus in both cases. Head magnetic resonance (MR) imaging and MR cisternography revealed that brain parenchyma had herniated into the lateral sphenoid sinus through the defect of the middle cranial fossa. The intradural and extradural spaces and bone defect were sealed with fascia and fat through both intradural and extradural approaches. The MEC was cut away to prevent infection. CSF rhinorrhea completely stopped after the surgery. Conclusion: Our cases were characterized by empty sella, thinning of the dorsum sellae, and large arteriovenous malformations that suggest chronic intracranial hypertension. The possibility of Sternberg's canal in patients with CSF rhinorrhea with chronic intracranial hypertension should be considered. The cranial approach has the advantages of lower infection risk and the ability to close the defect with multilayer plasty under direct vision. The transcranial approach is still safe if performed by a skillful neurosurgeon.

Late orbital metastasis from colon cancer complicated by multiple tumors in the breast, lung, liver, and spine.

A 69-year-old woman sustained progressive proptosis for 2 months. The patient had undergone surgery for resection of colon cancer 10 years prior, which was considered to have been completely cured 5 years prior. She was also aware of a hard mass in her left breast, but it had been left untreated. Furthermore, she experienced back pain for a month. Blood examination revealed an elevated level of serum carcinoembryonic antigen, at 17.4 ng/mL (< 5). Computed tomography (CT) revealed a tumor occupying the superolateral part of the right orbit, with intratumoral calcifications and destructive changes in the lateral orbital wall. On magnetic resonance imaging, it appeared as a heterogeneously enhancing, extraconal tumor, 44 mm × 31 mm in maximal dimension, extending into the middle fossa and the adjacent subcutaneous region. Fluorodeoxyglucose positron emission tomography/CT revealed abnormal accumulation in the left breast, T12 vertebra, liver, and lung, in addition to the orbital tumor. The patient underwent total tumor resection through a lateral orbitotomy. Histological examination of the tumor was highly suggestive of a metastatic colon cancer. Late metastasis should be assumed as a differential diagnosis that can be determined only through histological verification.

An infantile case of posterior fossa arachnoid cyst presenting with marked engorgement of contralateral supraorbital vein.

A 6-month-old, previously healthy boy presented with poor feeding and vomiting for 2 weeks. At presentation, his left supraorbital vein was found to engorge considerably. A cranial computed tomography (CT) scan revealed a large cyst in the posterior fossa with a prominent left superior ophthalmic vein (SOV). Magnetic resonance imaging delineated the well-demarcated cyst markedly compressing the right cerebellar hemisphere. The patient underwent microscopic fenestration of the cyst wall through lateral suboccipital craniotomy. The cyst wall, comprising multi-layered, opacified membranes, was extensively resected and communicated with the prepontine cistern. The histological appearance of the cyst wall was consistent with an arachnoid cyst. Engorgement of the left supraorbital vein resolved immediately after surgery. A postoperative CT scan did not identify the SOV in the left orbit. In the present case, engorgement of the supraorbital vein might reflect the increased venous pressure of the SOV caused by compression of the contralateral cerebellar hemisphere.

An unprecedented case of penetrating head trauma caused by shoji (a Japanese-style paper sliding door).

Penetrating head trauma (PHT) includes any traumatic injury where an object pierces the skull and breaches the dural membrane surrounding the brain. PHTs are less prevalent than blunt head injuries. However, they often have more complex damage, worse prognosis, and higher rates of morbidity and mortality. An 83-year-old man fell at his home and hit his head on the right side toward a shoji (a Japanese-style paper sliding door). He reported to the emergency room the following day with his family. He had a small wound before the right ear, which was sutured in the emergency room. A CT scan demonstrated tiny pieces of bone fragments inside the brain, as well as right temporal subcortical hemorrhage and pneumocephalus. He was admitted to the hospital and received intensive prophylaxis with antibiotics. He developed life-threatening skin disease and subsequent acute kidney disease requiring hemodialysis. He fully recovered from his life-threatening condition. Here, we report an unprecedented case of a penetrating head injury of an older adult caused by a shoji.

Infantile acute subdural hemorrhage probably caused by injury to the diploic channels.

A 6-month-old, previously healthy boy hit the right frontal region of his head against the corner of a plastic toy box. At presentation, a small area with scalp discoloration was noted in the right frontal region. Head computed tomography at the level of discoloration revealed an intracranial hematoma, 5 mm in maximal thickness, below the coronal suture. In addition, there were bony bridges connecting the frontal and parietal bones. Furthermore, a linear crack was found in the diploe of the frontal bone in contact with the coronal suture. Cerebral MRI confirmed linear hyperintensity between the inner tables. We assumed that a kind of ping-pong ball fracture was caused by the head blow, centering on the coronal suture, resulting in rupture of contacting diploic channels and tear of the dura mater, and forming a subdural hematoma. Acute subdural hemorrhage may be caused by an insignificant blow to the coronal suture in infantile patients with underdeveloped cranial bones and sutures, accompanied by subtle external findings.

Supratentorial extraventricular ependymoma presenting calvarial erosion: A report of 3 cases.

Calvarial erosion is an infrequent manifestation associated with oligodendrogliomas, astrocytomas, dysembryoplastic neuroepithelial tumors, astroblastomas, glioblastomas, and meningiomas. Anaplastic ependymoma (AE), a rare malignant form of ependymoma, commonly results in poor prognosis. During the last 12 years, six patients were diagnosed with supratentorial ependymomas. All of them were AEs with extraventricular location identified in the right parietal, left parietal, and left frontal lobes, respectively. Three of them, 7-, 15, and 17-year-old male patients, presented focal calvarial erosion with smooth contour. Calvarial erosion may be a diagnostic hallmark of supratentorial AEs.

Quadrigeminal cistern arachnoid cyst as a probable cause of hemifacial spasm.

Arachnoid cysts arising in the quadrigeminal cistern (ACQCs) are uncommon. A 68-year-old woman presented with an unsteady gait, facial spasm, and cerebellar ataxia. Non-contrast head computed tomography showed a cystic mass centered in the quadrigeminal cistern accompanying ventriculomegaly. On MRI, the cyst appeared hypointense on T1- and hyperintense on T2-weighted sequence. There was no restricted diffusion on diffusion-weighted imaging. The cerebral aqueduct was obstructed and the prepontine cistern was narrowed. The left vertebral artery (VA) coursed adjacent to the facial nerve at its origin. The patient underwent neuroendoscopic fenestration of the posterior wall of the third ventricle and ventral wall of the ACQC. Postoperatively, the patient's symptoms resolved. MRI showed a considerable reduction in the ACQC and expansion of the prepontine cistern, whereas the relationship between the left VA and the proximal segment of the facial nerve did not change. We assumed that the pre-existing close relationship between the VA and facial nerve might have been aggravated by the anterior displacement of the brainstem, thus causing the facial spasm.

Activation of heat shock response improves biomarkers of NAFLD in patients with metabolic diseases.

Nonalcoholic fatty liver disease (NAFLD) is often accompanied by metabolic disorders such as metabolic syndrome and type 2 diabetes (T2DM). Heat shock response (HSR) is one of the most important homeostatic abilities but is deteriorated by chronic metabolic insults. Heat shock (HS) with an appropriate mild electrical stimulation (MES) activates HSR and improves metabolic abnormalities including insulin resistance, hyperglycemia and inflammation in metabolic disorders. To analyze the effects of HS + MES treatment on NAFLD biomarkers, three cohorts including healthy men (two times/week, n = 10), patients with metabolic syndrome (four times/week, n = 40), and patients with T2DM (n = 100; four times/week (n = 40) and two, four, seven times/week (n = 20 each)) treated with HS + MES were retrospectively analyzed. The healthy subjects showed no significant alterations in NAFLD biomarkers after the treatment. In patients with metabolic syndrome, many of the NAFLD steatosis markers, including fatty liver index, NAFLD-liver fat score, liver/spleen ratio and hepatic steatosis index and NAFLD fibrosis marker, aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio, were improved upon the treatment. In patients with T2DM, all investigated NAFLD steatosis markers were improved and NAFLD fibrosis markers such as the AST/ALT ratio, fibrosis-4 index and NAFLD-fibrosis score were improved upon the treatment. Thus, HS + MES, a physical intervention, may become a novel treatment strategy for NAFLD as well as metabolic disorders.

Dural arteriovenous fistula with crista galli erosion in a patient with suspected sinusitis.

Dural arteriovenous fistula (dAVF) of the anterior cranial fossa is an aggressive entity with a high risk of intracranial hemorrhage. A 38-year-old woman presented to our institution with nasal obstruction and discharge. Computed tomography (CT) scans performed for suspected sinusitis revealed erosion of the crista galli predominantly on the left side. The frontal and ethmoidal sinuses adjacent to the crista galli were clear and did not communicate with the crista galli. Contrast computed tomography scans revealed ectatic vessels adjacent to the crista galli, coursing on the cortical surface. Cerebral angiography identified an anterior fossa dAVF supplied by the bilateral anterior and posterior ethmoidal arteries and drained by the dilated cortical veins. Based on these findings, we assumed that long-term compression by the pulsatile draining veins caused the erosion. The patient underwent successful microsurgical disconnection procedure of the dAVF with an uneventful postoperative course. We concluded that external erosion of the crista galli could be a sign of aggressive dAVF and requires careful examination.

Impact of hepatic HSP72 on insulin signaling.

Heat shock protein 72 (HSP72) is a major inducible molecule in the heat shock response that enhances intracellular stress tolerance. Decreased expression of HSP72 is observed in type 2 diabetes, which may contribute to the development of insulin resistance and chronic inflammation. We used HSP72 knockout (HSP72-KO) mice to investigate the impact of HSP72 on glucose metabolism and endoplasmic reticulum (ER) stress, particularly in the liver. Under a high-fat diet (HFD) condition, HSP72-KO mice showed glucose intolerance, insulin resistance, impaired insulin secretion, and enhanced hepatic gluconeogenic activity. Furthermore, activity of the c-Jun NH2-terminal kinase (JNK) was increased and insulin signaling suppressed in the liver. Liver-specific expression of HSP72 by lentivirus (lenti) in HFD-fed HSP72-KO mice ameliorated insulin resistance and hepatic gluconeogenic activity. Furthermore, increased adipocyte size and hepatic steatosis induced by the HFD were suppressed in HSP72-KO lenti-HSP72 mice. Increased JNK activity and ER stress upon HFD were suppressed in the liver as well as the white adipose tissue of HSP72-KO lenti-HSP72 mice. Thus, HSP72 KO caused a deterioration in glucose metabolism, hepatic gluconeogenic activity, and ß-cell function. Moreover, liver-specific recovery of HSP72 restored glucose homeostasis. Therefore, hepatic HSP72 may play a critical role in the pathogenesis of type 2 diabetes.

Identification of microRNA that represses IRS-1 expression in liver.

MicroRNAs (miRNAs) are short, non-coding RNAs that post-transcriptionally regulate gene expression and have been shown to participate in almost every cellular process. Several miRNAs have recently been implicated in glucose metabolism, but the roles of miRNAs in insulin-resistant conditions, such as obesity or type 2 diabetes, are largely unknown. Herein, we focused on miR-222, the expression of which was increased in the livers of high fat/high sucrose diet-fed mice injected with gold thioglucose (G+HFHSD). Overexpression of miR-222 in primary mouse hepatocytes attenuated Akt phosphorylation induced by insulin, indicating that miR-222 negatively regulates insulin signaling. As per in silico analysis, miR-222 potentially binds to the 3' untranslated region (3' UTR) of the IRS-1 gene, a key insulin signaling molecule. In fact, IRS-1 protein expression was decreased in the livers of G+HFHSD-fed mice. We further confirmed a direct interaction between miR-222 and the 3' UTR of IRS-1 via luciferase assays. Our findings suggest that up-regulation of miR-222 followed by reduction in IRS-1 expression may be a viable mechanism of insulin resistance in the liver.

Acetate alters expression of genes involved in beige adipogenesis in 3T3-L1 cells and obese KK-Ay mice.

The induction of beige adipogenesis within white adipose tissue, known as "browning", has received attention as a novel potential anti-obesity strategy. The expression of some characteristic genes including PR domain containing 16 is induced during the browning process. Although acetate has been reported to suppress weight gain in both rodents and humans, its potential effects on beige adipogenesis in white adipose tissue have not been fully characterized. We examined the effects of acetate treatment on 3T3-L1 cells and in obese diabetic KK-Ay mice. The mRNA expression levels of genes involved in beige adipocyte differentiation and genes selectively expressed in beige adipocytes were significantly elevated in both 3T3-L1 cells incubated with 1.0 mM acetate and the visceral white adipose tissue from mice treated with 0.6% acetate for 16 weeks. In KK-Ay mice, acetate reduced the food efficiency ratio and increased the whole-body oxygen consumption rate. Additionally, reduction of adipocyte size and uncoupling protein 1-positive adipocytes and interstitial areas with multilocular adipocytes appeared in the visceral white adipose tissue of acetate-treated mice, suggesting that acetate induced initial changes of "browning". In conclusion, acetate alters the expression of genes involved in beige adipogenesis and might represent a potential therapeutic agent to combat obesity.

Regulation of TNFα converting enzyme activity in visceral adipose tissue of obese mice.

Tumor necrosis factor α (TNFα) is a pro-inflammatory cytokine and one of the major mediators of obesity-induced insulin resistance. TNFα is generated through TNFα converting enzyme (TACE)-mediated cleavage of the transmembrane precursor pro-TNFα. Inhibition of TACE resulted in the improvement in glucose and insulin levels in diabetic animals, suggesting a crucial role of TACE activity in glucose metabolism. However, the regulation of TACE activity in insulin-sensitive tissues has not been fully determined. This study aimed to investigate the impact of TACE in insulin-sensitive tissues in the early stage of the development of obesity. C57BL6 mice were fed standard chow (B6-SC) or high-fat/high-sucrose diet (B6-HF/HS). KK-Ay mice were fed SC ad libitum (Ay-AL) or fed reduced amounts of SC (caloric restriction (CR); Ay-CR). As control for Ay-AL, KK mice fed SC ad libitum (KK-AL) were used. TACE activity in visceral adipose tissue (VAT), but not in liver or skeletal muscle, was significantly elevated in B6-HF/HS and Ay-AL compared with B6-SC and KK-AL, respectively. Phosphorylation of JNK and p38MAPK, but not ERK, in VATs from B6-HF/HS and Ay-AL was also significantly elevated. Ay-CR showed significantly lower TACE, JNK and p38MAPK activities in VAT and serum TNFα level compared with those of Ay-AL. In contrast, intraperitoneal injection of TNFα activated TACE, JNK and p38MAPK activities in VAT in KK mice. In conclusion, during the development of obesity, TACE activity is elevated only in VAT, and CR effectively reduced TACE activity and TACE-mediated pro-TNFα shedding in VAT.

Plasma renin activity and aldosterone concentration are not altered by the novel calcium channel antagonist, azelnidipine, in hypertensive patients.

OBJECTIVE: In hypertensive patients, primary aldosteronism (PA) is the most prevalent type of secondary hypertension, and screening for PA has become very important. Calcium channel blockers (CCB) are widely used to treat hypertension, but most CCBs stimulate plasma renin activity (PRA) and increase plasma aldosterone concentration (PAC), both of which are used in the screening for PA. The aim of this study was to determine whether the newly introduced CCB, azelnidipine, affects PRA and PAC. METHODS: 40 hypertensive patients were treated with 16 mg of azelnidipine for 4 weeks. RESULTS: Azelnidipine treatment in drug-naïve (DN) cases significantly decreased systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR). PRA and PAC in the DN group on azelnidipine treatment were indistinguishable from those in the DN group before treatment. Compared with other CCB treatments such as amlodipine, manidipine and slow-release nifedipine, azelnidipine showed comparable or significant reductions in SBP, DBP and HR. In patients who were switched from other CCBs to azelnidipine, PRA and PAC were decreased, except for PAC on amlodipine treatment. Since the PRA reduction rate exceeded that of PAC, the aldosterone/renin ratio (ARR) was significantly increased in those on azelnidipine treatment who had been switched from manidipine or nifedipine treatment, suggesting the restoration of possibly underestimated ARR values. CONCLUSION: These data indicate that azelnidipine does not affect PRA or PAC, suggesting that azelnidipine could be a useful antihypertensive CCB while undergoing PA screening.

A case of ectopic adrenocorticotropic hormone-producing pancreatic neuroendocrine tumor with multiple liver metastases.

Ectopic adrenocorticotropic hormone (ACTH) production by the pancreatic neuroendocrine tumor (p-NET) is relatively rare, and patients with this tumor show poor prognosis. In this study, we present the case of a 64-year-old woman who presented with ectopic ACTH syndrome due to p-NET with multiple liver metastases. Computed tomography revealed that she had multiple masses in the liver and a solid mass in the head of the pancreas. Endocrinological examinations revealed markedly elevated plasma ACTH (735.0 pg/mL) and cortisol (34.7 microg/dL) levels associated with hypokalemia (2.7 mEq/L), diabetes and typical Cushingoid features. Histological examinations by needle biopsy of liver tumors in S5 and S8 indicated metastatic ACTH-producing NET, which was also confirmed by venous sampling. The metastatic live tumor was somatostatin receptor (SSTR)-2a- and SSTR-5-positive as revealed by immunohistochemical staining, and reverse transcription polymerase chain reaction revealed divergent expression patterns of SSTRs, pro-opiomelanocortin, and gastrin mRNA. To avoid complications of hypercortisolemia, metyrapone was first administered to reduce the cortisol levels. After near-normalization of cortisol levels, transarterial chemoembolization and somatostatin analogue treatment were performed. The combination of these treatments effectively decreased ACTH and cortisol levels and also ameliorated hyperglycemia. We have achieved controlled hormone secretion and prevented tumor growth in this patient for more than 20 months, suggesting that highly individualized treatment for NET should be undertaken because of its divergent and heterogeneous characteristics.

Resonance energy transfer from dibucaine to acriflavine in polystyrene latex dispersions.

Resonance energy transfer from dibucaine (DC) to acriflavine (AF) has been investigated both in homogeneous aqueous solutions and in polystyrene latex dispersions. The energy transfer reaction is observed by monitoring fluorescence quenching of DC as well as sensitized emission of AF. It is found that the energy transfer from DC to AF is remarkably enhanced on going from the aqueous homogeneous solution to the latex dispersion. This is mainly attributed to the fact that both the donor and acceptor are effectively adsorbed onto the latex particles, as evidenced by the measurement of adsorption isotherms. From the adsorption experiments, it is also elucidated that electrostatic interaction is significant at low DC concentration, while hydrophobic interaction dominates at the higher concentration especially at higher pH.