CHCHD2 P14L, found in amyotrophic lateral sclerosis, exhibits cytoplasmic mislocalization and alters Ca2+ homeostasis.

CHCHD2 and CHCHD10, linked to Parkinson's disease and amyotrophic lateral sclerosis-frontotemporal dementia (ALS), respectively, are mitochondrial intermembrane proteins that form a heterodimer. This study aimed to investigate the impact of the CHCHD2 P14L variant, implicated in ALS, on mitochondrial function and its subsequent effects on cellular homeostasis. The missense variant of CHCHD2, P14L, found in a cohort of patients with ALS, mislocalized CHCHD2 to the cytoplasm, leaving CHCHD10 in the mitochondria. Drosophila lacking the CHCHD2 ortholog exhibited mitochondrial degeneration. In contrast, human CHCHD2 P14L, but not wild-type human CHCHD2, failed to suppress this degeneration, suggesting that P14L is a pathogenic variant. The mitochondrial Ca2+ buffering capacity was reduced in Drosophila neurons expressing human CHCHD2 P14L. The altered Ca2+-buffering phenotype was also observed in cultured human neuroblastoma SH-SY5Y cells expressing CHCHD2 P14L. In these cells, transient elevation of cytoplasmic Ca2+ facilitated the activation of calpain and caspase-3, accompanied by the processing and insolubilization of TDP-43. These observations suggest that CHCHD2 P14L causes abnormal Ca2+ dynamics and TDP-43 aggregation, reflecting the pathophysiology of ALS.

The SYNGAP1 3'UTR Variant in ALS Patients Causes Aberrant SYNGAP1 Splicing and Dendritic Spine Loss by Recruiting HNRNPK.

Fused in sarcoma (FUS) is a pathogenic RNA-binding protein in amyotrophic lateral sclerosis (ALS). We previously reported that FUS stabilizes Synaptic Ras-GTPase activating protein 1 (Syngap1) mRNA at its 3' untranslated region (UTR) and maintains spine maturation. To elucidate the pathologic roles of this mechanism in ALS patients, we identified the SYNGAP1 3'UTR variant rs149438267 in seven (four males and three females) out of 807 ALS patients at the FUS binding site from a multicenter cohort in Japan. Human-induced pluripotent stem cell (hiPSC)-derived motor neurons with the SYNGAP1 variant showed aberrant splicing, increased isoform α1 levels, and decreased isoform γ levels, which caused dendritic spine loss. Moreover, the SYNGAP1 variant excessively recruited FUS and heterogeneous nuclear ribonucleoprotein K (HNRNPK), and antisense oligonucleotides (ASOs) blocking HNRNPK altered aberrant splicing and ameliorated dendritic spine loss. These data suggest that excessive recruitment of RNA-binding proteins, especially HNRNPK, as well as changes in SYNGAP1 isoforms, are crucial for spine formation in motor neurons.SIGNIFICANCE STATEMENT It is not yet known which RNAs cause the pathogenesis of amyotrophic lateral sclerosis (ALS). We previously reported that Fused in sarcoma (FUS), a pathogenic RNA-binding protein in ALS, stabilizes synaptic Ras-GTPase activating protein 1 (Syngap1) mRNA at its 3' untranslated region (UTR) and maintains dendritic spine maturation. To elucidate whether this mechanism is crucial for ALS, we identified the SYNGAP1 3'UTR variant rs149438267 at the FUS binding site. Human-induced pluripotent stem cell (hiPSC)-derived motor neurons with the SYNGAP1 variant showed aberrant splicing, which caused dendritic spine loss along with excessive recruitment of FUS and heterogeneous nuclear ribonucleoprotein K (HNRNPK). Our findings that dendritic spine loss is because of excess recruitment of RNA-binding proteins provide a basis for the future exploration of ALS-related RNA-binding proteins.

Long-term Outcomes of Hypofractionated Stereotactic Radiotherapy for the Treatment of Perioptic Nonfunctioning Pituitary Adenomas.

The efficacy of stereotactic radiotherapy (SRT) has been well established for postoperative residual and recurrent nonfunctioning pituitary adenomas (NFPAs). However, the risk of visual impairment due to SRT for lesions adjacent to the optic pathways remains a topic of debate. Herein, we evaluated the long-term clinical outcomes of hypofractionated stereotactic radiotherapy (HFSRT) for perioptic NFPAs. From December 2002 to November 2015, 32 patients (18 males and 14 females; median age 63 years; range, 36-83 years) with residual or recurrent NFPAs abutting or displacing the optic nerve and/or chiasm (ONC) were treated with HFSRT. The median marginal dose was 31.3 Gy (range, 17.2-39.6) in 8 fractions (range, 6-15). Magnetic resonance imaging (MRI) and visual and hormonal examinations were performed before and after HFSRT. The median follow-up period was 99.5 months (range, 9-191). According to MRI findings at the last follow-up, the tumor size had decreased in 28 (88%) of 32 patients, was unchanged in 3 (9%), and had increased in 1 (3%). The successful tumor size control rate was 97%. Visual functions remained unchanged in 19 (60%) out of 32 patients, improved in 11 (34%), and deteriorated in 2 (6%). Two patients had deteriorated visual functions; no complications occurred because of the HFSRT. One patient developed hypopituitarism that required hormone replacement therapy. The result of this long-term follow-up study suggests that HFSRT is safe and effective for the treatment of NFPAs occurring adjacent to the ONC.

Differentiating between Primary Central Nervous System Lymphoma and Glioblastoma: The Diagnostic Value of Combining 18F-fluorodeoxyglucose Positron Emission Tomography with Arterial Spin Labeling.

Using conventional magnetic resonance imaging (MRI) methods, the differentiation of primary central nervous system lymphoma (PCNSL) and glioblastoma (GBM) is often difficult due to overlapping imaging characteristics. This study aimed to evaluate the diagnostic value of combining 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) with arterial spin labeling (ASL) for differentiating PCNSL from GBM. In all, 20 patients with PCNSL and 55 with GBM were retrospectively examined. From the FDG-PET data, the maximum standardized uptake values (SUVmax) and the ratio of tumor to normal contralateral gray matter (T/N_SUVmax) were calculated. From the ASL data, the T/N ratio of the maximum tumor blood flow (relative TBFmax: rTBFmax) was obtained. Diagnostic performance of each parameter was analyzed using univariate and multivariate logistic regression analyses and receiver-operating characteristic (ROC) curve analyses. A generalized linear model was applied for comparing the performance of FDG-PET and ASL individually, and in combination. In univariate analysis, SUVmax and T/N_SUVmax were statistically higher in patients with PCNSL and rTBFmax was higher in patients with GBM. In the multivariate analysis, T/N_SUVmax and rTBFmax were statistically independent. The sensitivity, specificity, and area under the curve (AUC) for discriminating PCNSL from GBM were 100%, 87.3%, and 0.950 in T/N_SUVmax; 90%, 72.7%, and 0.824 in rTBFmax; and 95%, 96.4%, and 0.991 in the combined model, respectively. The combined use of T/N_SUVmax and rTBFmax may contribute to better differentiation between PCNSL and GBM.

Long-term survival of a patient with diffuse midline glioma in the pineal region: A case report and literature review.

BACKGROUND: Diffuse midline glioma (DMG) is an invasive astrocytic tumor arisen from midline structures, such as the pons and thalamus. Five cases of DMG in the pineal region have been reported, but the clinical course was poor; there was no case of survival for more than 2 years. CASE DESCRIPTION: We report the case of a 12-year-old boy with DMG in the pineal region who is living a normal daily life for more than 6 years following multimodal treatment. He complained of a headache accompanied by vomiting that had gradually worsened 1 month previously, and initial magnetic resonance imaging revealed a pineal tumor. Germinoma was initially suspected; however, a combination of chemotherapy using carboplatin and etoposide was ineffective. The first surgery was performed through the left occipital transtentorial approach (OTA); the diagnosis was DMG. After 60 Gy radiotherapy concomitant with temozolomide (TMZ), the tumor enlarged. Second surgery was performed through bilateral OTAs, and 90% of the tumor was removed. In addition, stereotactic radiotherapy (30 Gy, six fractions) was administered, and the local equivalent dose in 2 Gy/fraction reached 97.5 Gy. Maintenance chemotherapy using TMZ and bevacizumab was continued for 2 years. After finishing chemotherapy, the enhancing lesion enlarged again, and bevacizumab monotherapy was effective. Now, at 6 years after diagnosis, the patient leads an ordinary life as a student. CONCLUSION: Maximum resection and high-dose radiotherapy followed by bevacizumab may have been effective in the present case.

Transventricular Preforniceal Approach Combined with Endoscopic Transnasal Surgery for a Giant Pituitary Adenoma: A Case Report and Literature Review.

Giant pituitary adenomas carry significant surgical risks when treated with transsphenoidal approaches or the transcranial approach alone. Combined transsphenoidal and transcranial approaches have been reported; however, removing adenomas extending into the third ventricle may still be challenging. We report a case of giant pituitary adenoma expanding into the third ventricle, which was removed using a combined transventricular preforniceal approach and an endoscopic endonasal transsphenoidal surgery (ETSS). A 41-year-old man with headache, nausea, and a 1-week history of a visual field defect was transferred to our hospital. He had a disturbed left visual acuity, right homonymous hemianopia, and choked disc in both eyes. Preoperative magnetic resonance imaging revealed a giant pituitary adenoma with a maximum diameter of 55 mm extending from the intrasellar to the suprasellar region, thus occupying the entire third ventricle and causing hydrocephalus. The space between the anterior commissure and the fornix was expanded. The foramen of Monro was shifted backward due to compression by the tumor. He underwent maximum surgical resection using a combined transventricular preforniceal approach and ETSS. Considering technical demands and reliability, the intra- to suprasellar parts were removed by ETSS while the intraventricular part was removed through the preforniceal approach. The residual tumor in the right cavernous sinus and behind the anterior communicating artery was treated with stereotactic radiotherapy. One year after the operation, the patient leads an independent life. The combined technique of the preforniceal approach and ETSS provided a direct view of the entire third ventricle and hemostasis in the present case.

[Intracranial Growing Teratoma Syndrome:Case Reports and Literature Review].

BACKGROUND: Growing teratoma syndrome(GTS)is the progression of a mature teratoma during or following radiochemotherapy for germ cell tumors. We report two surgical cases of GTS. CASE 1: A 24-day-old new-born presented with vomiting and head enlargement. Blood alfa-feto protein(AFP)and beta-human chorionic gonadotropin(ß-hCG)were within or at the upper limits of the normal ranges. Magnetic Resonance Imaging(MRI)demonstrated a large mass in the posterior fossa causing the severe hydrocephalus. Tumor removal was immediately performed. Histological diagnosis given was immature teratoma. While chemotherapy effectively reduced the level of tumor makers, multiple recurrence was noticed on MRI 70 days after the surgery. GTS was suspected and total removal was performed. Histological examination revealed a mature teratoma. The patient is growing normally thereafter, 2.5 years after the onset. CASE 2: A 16-year-old male presented with binasal hemianopsia. Blood AFP and ß-hCG were within or at the upper limits of the normal ranges. MRI demonstrated an intrasellar mass protruding upward. Tumor removal was performed and histological diagnosis given was mixed germ cell tumor. While radiochemotherapy effectively normalized the tumor makers, recurrence was noticed on MRI 190 days after the surgery. Total removal was performed with the diagnosis of GTS. Histological examination revealed a mature teratoma. The patient lives a normal school life thereafter as followed up after a year after the onset. CONCLUSION: It is important to diagnose and perform the surgery early enough to enable total removal of the mass presenting as GTS because total surgical removal is the only treatment for GTS.

Endovascular Stenting Following Stereotactic Radiosurgery for Meningioma Involving the Superior Sagittal Sinus.

Objective: Surgical removal of meningiomas that have partially invaded the superior sagittal sinus (SSS) is difficult because it requires reconstruction of the SSS, which can lead to SSS occlusion and venous infarction. The present report details the case of an SSS-involved meningioma treated by stereotactic radiosurgery (SRS) and stenting. Case Presentation: A 60-year-old woman was admitted to the hospital with blurred vision and papilledema. Lumbar puncture showed markedly increased intracranial pressure (ICP; 340 mm H2O). Gadolinium-enhanced T1-weighted imaging revealed a 1-cm meningioma located mainly in the SSS. Digital subtraction angiography revealed severe stenosis, at the posterior part of the SSS, and no collateral flow. The ICP was considered a result of the stenosis caused by the meningioma. A combined therapy comprising transarterial embolization (for tumor growth suppression), endovascular stenting of the SSS (for intracranial hypertension improvement), and SRS (for tumor control) was planned. SRS was performed first to avoid interference by the metal artifacts caused by the stent. After placement of a self-expanding stent, partial recanalization was achieved. Two months after stenting, SSS stenosis improved and MRI results showed shrinkage of the meningioma. Thirty months after the treatment, no tumor recurrence was observed. Conclusion: The treatment strategy of SRS followed by stenting was successful for a SSS-involved meningioma. ICP and a pressure gradient between the pre- and post-stenotic segments should be considered indications for stenting.

Clinical Significance of Molecular Diagnosis of Pilocytic Astrocytoma: A Case Report.

This paper reports on a case of pilocytic astrocytoma (PA), for which a diagnosis by conventional pathological diagnosis was difficult but an accurate diagnosis was possible by a new molecular diagnostic method. A 13-year-old girl whose tumor developed by a headache that gradually worsened, and a well-demarcated T2-hyperintense lesion was found in the left cerebellum by a magnetic resonance imaging while the apparent diffusion coefficient value was also high. While the finding was a typical PA, histological features of PA were not found in the surgical specimen. An initial diagnosis was anaplastic astrocytoma (AA), and the final diagnosis through a central review was diffuse astrocytoma (DA). On the other hand, using MethylationEPIC (850 K) array, an analysis by a DNA methylation-based tumor classifier tool as reported by Capper et al. showed that this case belonged to a methylation class of PA. The copy number profile calculated from the methylation array data showed hints of BRAF/KIAA1549 fusion and no other chromosomal alterations, which also supported the molecular diagnosis. The patient was treated with local radiotherapy concomitant with temozolomide based on the initial pathological diagnosis during the consultation, but maintenance temozolomide therapy was not done according to the final molecular diagnosis. The tumor showed no recurrence for 20 months. In this case, the integrated diagnostic approach based on histological and molecular findings was clinically significant to select proper adjuvant treatment. It is crucial that the usefulness and robustness of this new molecular diagnostic method be validated further.

Amyotrophic lateral sclerosis of long clinical course clinically presenting with progressive muscular atrophy.

Amyotrophic lateral sclerosis (ALS) primarily affects upper and lower motor neurons. Phosphorylated trans-activation response DNA-binding protein of 43 kDa (TDP-43) inclusion bodies are reportedly a pathological hallmark of sporadic ALS. Here, we present an atypical case of sporadic ALS that progressed very slowly, persisted for 19 years, and clinically appeared to only affect the lower motor neurons; however, upper motor neuron degeneration was detected at autopsy. Furthermore, no inclusion bodies positive for phosphorylated TDP-43, ubiquitin, fused in sarcoma, or superoxide dismutase-1 were detected in the central nervous system. We performed exome-sequencing data analysis but found no genetic disorders. This was therefore an unusual case of lower motor neuron-predominant ALS without TDP-43 pathology or known gene-disease associations. We also reviewed autopsied ALS cases that progressed slowly and had no phosphorylated TDP-43 or ubiquitin-positive inclusions and present the clinicopathological features of such cases. Based on these results, there may be a sporadic ALS subgroup that progresses slowly and shows no accumulation of phosphorylated TDP-43.

Acute onset of autoimmune hepatitis with sinusoidal and central vein endotheliitis, and marked involvement of activated dendritic cells: A case report.

RATIONALE: Autoimmune hepatitis (AIH) is characterised by interface hepatitis. However, some acute cases exhibit atypical centrilobular necrosis with mild portal inflammation. Detailed histological and ultrastructural analyses of acute AIH are limited. PATIENT CONCERNS: A 44-year-old female was admitted to our hospital with jaundice, general fatigue and liver dysfunction. Her transaminase levels were elevated, her immunoglobulin G level was 1735 mg/dL and her anti-nuclear titres were ×80. DIAGNOSIS: AIH was diagnosed, and histochemical examination of a liver biopsy showed the presence of atypical histological features of prominent centrilobular necrosis and central vein and hepatic sinusoidal endotheliitis. Electron microscopy showed that dendritic cells (DCs) and lymphocytes were attached to disrupted liver sinusoidal endothelial cells (LSECs) in hepatic sinusoids and that DCs attached to LSECs via pseudopods in the central vein. INTERVENTIONS AND OUTCOMES: The patient was started on 40 mg/day prednisolone to control the hepatic inflammation. Her aspartate and alanine aminotransferase levels started declining after prednisolone was initiated. Three weeks later, these levels had normalised. The dosage of prednisolone was gradually decreased as liver function improved. The patient remains under observation and continues to receive 2.5 mg prednisolone. LESSONS: An important marker of acute AIH may be the presence of activated DCs in the hepatic sinusoids and central vein.

Autotaxin and vascular endothelial growth factor receptor-2 and -3 are related to vascular development during the progression of chronic viral hepatitis C.

Vascular endothelial growth factor (VEGF) and autotaxin (ATX) play important roles in embryonic vasculogenesis and cancer progression. This study examines whether these two angiogenic factors cooperate in the mechanism that regulates vascular development during the progression of chronic viral hepatitis C (CVH-C) (Inuyama classification, F1-F4). First, surgical wedge biopsy specimens and needle biopsy specimens were obtained. Immunohistochemical staining for ATX and vascular endothelial growth factor receptor was assessed in serial sections. Immunoelectron microscopy was conducted with a perfusion-fixation method. In normal control liver tissue specimens, ATX was expressed at low levels within the branches of the hepatic artery and hepatic sinusoids. In F1 CVH-C liver tissue specimens, ATX was expressed within the branches of the hepatic artery. Additionally, VEGFR-2 was expressed within the branches of the hepatic artery and capillaries. In F3-F4 CVH-C liver tissue specimens, positive staining for ATX and VEGFR-2 or VEGFR-3 was detected in the branches of the hepatic artery or microlymphatic vessels. ATX-1 reaction products were specifically expressed on the plasma membrane of some microvascular endothelial cells (ECs) in the proliferative capillary artery. VEGFR-2 was expressed on caveolae in ECs and vascular smooth muscle cells. VEGFR-3 immunogold particles were also observed in lymphatic ECs. These results suggest functional interactions among ATX, VEGFR-2, and VEGFR-3 in the modulation of hemovascular and lymphovascular cell activation during vascular development.

A sensitive and efficient procedure for the high-throughput determination of nine urinary metabolites of pyrethroids by GC-MS/MS and its application in a sample of Japanese children.

Four pyrethroids (PYRs), metofluthrin, profluthrin, tefluthrin, and transfluthrin, which were newly developed and have relatively high vapor activity at ambient temperature, are now playing a key role in safely controlling insects in our daily lives. We developed a sensitive and high-throughput determination method for urinary metabolites derived from the newly developed PYR, e.g., 2,3,5,6-tetrafluoro-1,4-benzenedimethanol (HOCH2-FB-Al), 2,3,5,6-tetrafluorobenzyl alcohol (FB-Al), and other PYR metabolites such as trans-chrysanthemumdicarboxylic acid (trans-CDCA) and 3-phenoxybenzoic acid (3PBA). After high temperature acid hydrolysis of 2 mL urine sample in 24-deep well plate, the PYR metabolites were extracted by semi-automated liquid-liquid extraction with tert-butyl methyl ether. N,O-Bis (trimethylsilyl) trifluoroacetamide containing 1% trimethylchlorosilane or 1,1,1,3,3,3-hexafluoroisopropanol were used for the derivatization of PYR metabolites, and the derivatized metabolites were analyzed separately by GC-MS/MS equipped with dual injector system (DB-5MS and mid- to high-polarity phase Rtx-65 columns). The derivatization and evaporation conditions were mainly optimized for improving sensitivity and reproducibility. The mean within-run day precisions were less than 18.4% (relative standard deviation, %RSD) with low detection limits ranging from 0.01 µg/L for HOCH2-FB-Al to 0.06 µg/L for trans-CDCA. This method was successfully applied to urine samples obtained from 50 3-year-old children with high detection frequencies (e.g., 82% for HOCH2-FB-Al and 84% for FB-Al). This method may be a pivotal tool for developing risk assessment from PYR exposure in the general population.

Serum matrix metalloproteinase-1 level represents disease activity as opposed to fibrosis in patients with histologically proven nonalcoholic steatohepatitis.

BACKGROUND/AIMS: Nonalcoholic steatohepatitis (NASH) is prevalent in both economically developed and developing countries. Twenty percent of NASH progresses to cirrhosis with/without hepatocellular carcinoma, and there is an urgent need to find biomarkers for early diagnosis and monitoring progression of the disease. Using immunohistochemical and immunoelectron microscopic examination we previously reported that expression of matrix metalloproteinase-1 (MMP-1) increased in monocytes, Kupffer cells and hepatic stellate cells in early stage NASH. The present study investigated whether serum MMP-1 levels reflect disease activity and pharmaceutical effects in NASH patients. METHODS: We measured the serum levels of MMPs, tissue inhibitors of metalloproteinases (TIMPs), and several cytokines/chemokines in patients with histologically proven early and advanced stages of NASH and compared them with those in healthy controls. RESULTS: Serum MMP-1 levels in stage 1 fibrosis, but not in the more advanced fibrosis stages, were significantly higher than in healthy controls (P=0.019). There was no correlation between serum MMP-1 level and fibrosis stage. Serum MMP- 1 levels in NASH patients represented disease activity estimated by serum aminotransferase values during the follow-up period. In contrast, MMP-2, MMP-9 and TIMPs did not change with disease activity. Consistent with the finding that MMP-1 is expressed predominantly in monocytes and Kupffer cells, serum levels of monocyte chemotactic protein-1 and granulocyte-colony stimulating factor were significantly increased in NASH with stage 1 fibrosis. CONCLUSIONS: These results suggest that serum MMP-1 levels represent disease activity and may serve as a potential biomarker for monitoring the progression of NASH.

The Apelin Receptor APJ in Hematopoietic Stem Cells/Progenitor Cells in the Early Stage of Non-Alcoholic Steatohepatitis.

BACKGROUND: Non-alcoholic steatohepatitis (NASH) is characterized by hepatic steatosis and inflammation with or without fibrosis. The apelin receptor (APJ) is related to angiotensin-like-receptor 1 (AGTRL1). The present study aimed to evaluate APJ as an indicator of the pathophysiology of early-stage NASH. METHODS: APJ expression was evaluated in six tissue samples with histologically proven early-stage NASH using immunohistochemistry (IHC) and immunoelectron microscopy (IEM). RESULTS: On IHC, in control liver tissue, APJ was mainly localized in the aortic artery, although APJ was detected only slightly in the sinusoids. In early NASH liver tissue, on IEM, APJ was observed mainly at the sites of sinusoidal lining cells around the central vein and periportal regions, and at arterial capillaries in the portal tract. With regard to endothelial cells (ECs), one sample showed a hematopoietic stem cell (HSC)/progenitor cell (HPC) partially wrapped with an EC. CONCLUSION: HSCs/HPCs expressing APJ may contribute to the angiogenesis of liver tissue in early-stage NASH.

Opening the ventricle during surgery diminishes survival among patients with newly diagnosed glioblastoma treated with carmustine wafers: a multi-center retrospective study.

Carmustine wafers (CW) were approved in Japan for newly diagnosed and recurrent malignant gliomas during 2013. The ventricle is often opened during surgery to achieve maximum resection. While not generally recommended in such situations, CW might be safely achieved by occluding an opened ventricle using gelform or collagen sheets. However, whether CW implantation actually confers a survival benefit for patients who undergo surgery with an open ventricle to treat glioblastoma remains unclear. Clinical, imaging, and survival data were collected in this multicenter retrospective study of 122 consecutive patients with newly diagnosed glioblastoma to determine adverse events and efficacy. Overall, 54 adverse events of all grades developed in 35 (28.6%) patients, with the most common being new seizures (16%). Adverse events did not significantly differ between patients with opened and closed ventricles during surgery. The 10- and 21.7-month, median, progression-free (PFS) and overall survival (OS), respectively did not significantly differ according to resection rates. However, median PFS and OS were significantly longer among patients with closed, than open ventricles (12.8 vs. 7.4 months; p = 0.0039 and 26.9 vs. 18.6 months; p = 0.011, respectively). Implanting CW into the resection cavity during concomitant radiochemotherapy with temozolomide seems to yield better survival rates without increased adverse events. Occlusion of the ventricular opening during surgery might be safe for CW implantation, but less so for treating patients with newly diagnosed glioblastoma.

Significance of Cholinergic and Peptidergic Nerves in Stress-Induced Ulcer and MALT Lymphoma Formation.

Backgound: The role of enteric nerves has previously been demonstrated in the formation of several gastric diseases. In the present review, the significance of the cholinergic nerves in stress-induced ulcer formation as well as the importance of substance P in the formation of gastric MALT lymphoma is discussed. METHODS: The stress-induced ulcer was induced by the plaster bandage methods in rats. The gastric MALT lymphoma was formed by the peroral infection of gastric mucosal homogenate of the infected mouse in C57BL/6 mice. For the stress-induced ulcer, the distribution of the cholinergic nerves and muscarinic acetylcholine receptors was investigated by acetylcholinesterase histochemistry and autoradiography of water soluble compounds using 3H-quinuclidinyl benzilate was performed. To the MALT lymphoma study, the distribution of the substance P and effect of substance P antagonist, spantide II, was investigated by immunohistochemical studies. RESULTS: The stress induced ulcer formation was shown to be related to the hyperactivity of the cholinergic nerves. The gastric MALT lymphoma was shown to be related to the increased localization of substance P. CONCLUSION: Stress-induced ulceration as a model of hyperactivity of the cholinergic nerves was proved to be a useful approach, while substance P and its role in MALT lymphoma formation may serve as a tool to clarify the neuroimmune modulation of chronic infectious diseases.

Over-the-counter Drug Induced Autoimmune Hepatitis.

A 64-year-old man seeking treatment for a common cold was admitted to our hospital due to symptoms of general fatigue and liver dysfunction. A thorough history review revealed that the patient had recently started taking an over-the-counter (OTC) drug. Drug-induced lymphocyte stimulation tests were positive. Serum markers for autoimmune hepatitis (AIH) were particularly elevated. Liver biopsy revealed spotty necrosis and ceroid-pigmented Kupffer cells and piecemeal necrosis with multiple plasma cells. He responded to corticosteroids, thus suggesting the presence of an immune-mediated component associated with the liver injury. Liver injury after using OTCs should be included in the differential diagnosis for chronic hepatitis with features of AIH.

Next-generation sequencing of 28 ALS-related genes in a Japanese ALS cohort.

We investigated the frequency and contribution of variants of the 28 known amyotrophic lateral sclerosis (ALS)-related genes in Japanese ALS patients. We designed a multiplex, polymerase chain reaction-based primer panel to amplify the coding regions of the 28 ALS-related genes and sequenced DNA samples from 257 Japanese ALS patients using an Ion Torrent PGM sequencer. We also performed exome sequencing and identified variants of the 28 genes in an additional 251 ALS patients using an Illumina HiSeq 2000 platform. We identified the known ALS pathogenic variants and predicted the functional properties of novel nonsynonymous variants in silico. These variants were confirmed by Sanger sequencing. Known pathogenic variants were identified in 19 (48.7%) of the 39 familial ALS patients and 14 (3.0%) of the 469 sporadic ALS patients. Thirty-two sporadic ALS patients (6.8%) harbored 1 or 2 novel nonsynonymous variants of ALS-related genes that might be deleterious. This study reports the first extensive genetic screening of Japanese ALS patients. These findings are useful for developing genetic screening and counseling strategies for such patients.