Urinary Immunoglobulin G Is a Novel Biomarker for Atherosclerotic Burden in Mild Acute Ischemic Stroke Patients.

AIMS: Urinary immunoglobulin G (IgG) may be a stronger marker of atherosclerosis than microalbuminuria are because urinary IgG reflects proteinuria level and size-selectivity loss. Microalbuminuria-not urinary IgG-is associated with mild acute ischemic stroke (MAIS). METHODS: Using the Jikei University School of Medicine Stroke Registry, we selected and screened patients with symptomatic acute ischemic stroke (onset-to-door time ≤ 24 h). The exclusion criteria were (1) on-admission NIHSS scores ＞10, (2) a modified Rankin Scale (mRS) score ≥ 2 prior to stroke onset, (3) incomplete data (no urinalysis ≤ 3 days after admission or no mRS score at 90 days from stroke onset), and (4) an active malignancy. Patients at 90 days post-discharge were divided into those with favorable mRS scores of 0-1 and those with unfavorable mRS scores of 2-6. Clinical backgrounds were compared for (1) patients with positive and negative urinary IgG results, and (2) patients with favorable and unfavorable outcomes. RESULTS: Of our study's 210 patients (164=male, median age=68, median eGFR=53.2 ml/min/1.73 m2), 30 (14%) presented with positive urinary IgG, which was associated with cardiovascular risk factors. Higher BNP, higher D-dimer, lower eGFR, and higher CAVI were associated with higher positive urinary IgG. The favorable group, comprising 155 (74%) patients, had higher negative urinary IgG than the unfavorable group (89% vs 76%, P=0.026). No statistical difference emerged regarding microalbuminuria (29% vs 29%, P=1.000). CONCLUSION: In MAIS, urinary IgG was associated with both the presence of atherosclerosis and an unfavorable outcome at 90 days after stroke onset.

FABP3 in the Anterior Cingulate Cortex Modulates the Methylation Status of the Glutamic Acid Decarboxylase67 Promoter Region.

Polyunsaturated fatty acids (PUFAs) are essential for brain development and function. Increasing evidence has shown that an imbalance of PUFAs is associated with various human psychiatric disorders, including autism and schizophrenia. Fatty acid-binding proteins (FABPs), cellular chaperones of PUFAs, are involved in PUFA intracellular trafficking, signal transduction, and gene transcription. In this study, we show that FABP3 is strongly expressed in the GABAergic inhibitory interneurons of the male mouse anterior cingulate cortex (ACC), which is a component of the limbic cortex and is important for the coordination of cognitive and emotional behaviors. Interestingly, Fabp3 KO male mice show an increase in the expression of the gene encoding the GABA-synthesizing enzyme glutamic acid decarboxylase 67 (Gad67) in the ACC. In the ACC of Fabp3 KO mice, Gad67 promoter methylation and the binding of methyl-CpG binding protein 2 (MeCP2) and histone deacetylase 1 (HDAC1) to the Gad67 promoter are significantly decreased compared with those in WT mice. The abnormal cognitive and emotional behaviors of Fabp3 KO mice are restored by methionine administration. Notably, methionine administration normalizes Gad67 promoter methylation and its mRNA expression in the ACC of Fabp3 KO mice. These findings demonstrate that FABP3 is involved in the control of DNA methylation of the Gad67 promoter and activation of GABAergic neurons in the ACC, thus suggesting the importance of PUFA homeostasis in the ACC for cognitive and emotional behaviors.SIGNIFICANCE STATEMENT The ACC is important for emotional and cognitive processing. However, the mechanisms underlying its involvement in the control of behavioral responses are largely unknown. We show the following new observations: (1) FABP3, a PUFA cellular chaperone, is exclusively expressed in GABAergic interneurons in the ACC; (2) an increase in Gad67 expression is detected in the ACC of Fabp3 KO mice; (3) the Gad67 promoter is hypomethylated and the binding of transcriptional repressor complexes is decreased in the ACC of Fabp3 KO mice; and (4) elevated Gad67 expression and abnormal behaviors seen in Fabp3 KO mice are mostly recovered by methionine treatment. These suggest that FABP3 regulates GABA synthesis through transcriptional regulation of Gad67 in the ACC.

Hybrid laparoscopic complete untinatectomy of pancreas by Shuriken shaped umbilicoplasty with sliding windows method.

In this study, we demonstrated the complete resection of untinate process that was performed by the hybrid laparoscopic surgery using our original new technique of Shuriken shaped umbilicoplasty with sliding window`s method. A 70-year-old weman was hospitalized for surgery of intraductal papillary mucinous neoplasm located in the uncinate process of pancreas. Under general anesthesia, a Shuriken shaped umbilical skin incision was made by 7 cm in horizontal and 4cm longitudinal width with 3cm round skin incision. The intermediate skin between outside and inside skin incision was removed. Subcutaneous tissue around the umbilicus and the upper abdominal subcutaneous region was dissected, and the 8cm of upper abdominal minilaparotomy was performed. The complete resection of untinate process was performed by hybrid laparoscopic procedure with the hand-assisted or the laparo-assisted manner. The umbilicoplasty of only 3cm round skin wound was made by the reefing of subcutaneous suture with 5-0 absorbable suture. The patient suffered from pancreas leakage from pancreas stump, however it was recovered spontaneously. Our new procedure could be used for PD, DP, and Major hepatectomy with the hybrid laparoscopic procedure. It might be considered that our method is good for both cosmetic and safety benefits in HPB surgery.

Effects of hypothermia on ex vivo microglial production of pro- and anti-inflammatory cytokines and nitric oxide in hypoxic-ischemic brain-injured mice.

INTRODUCTION: Activated microglia produce neurotoxic factors, including pro-inflammatory cytokines and nitric oxide (NO), in response to neuronal destruction. Therapeutic suppression of microglial release of these factors by various approaches including hypothermia is considered to be neuroprotective after severe brain damage. We examined the effects of hypothermic culture on the production of pro- and anti-inflammatory cytokines and NO in ex vivo microglia that were derived from mice with hypoxic-ischemic (HI) brain injury, through the stimulation of toll-like receptors (TLRs) that play significant roles in the pathological processes underlying a sterile central nervous system injury. MATERIAL AND METHODS: Two-day-old mice underwent the right common carotid artery ligation followed by 6% oxygen for 30 min, and thereafter were placed at 37°C for 24 h, after which microglia were isolated and then cultured with TLR2 and TLR4 agonists at 33°C and 37°C. Cytokine and NO levels in culture supernatants were measured. RESULTS: Compared with 37°C, hypothermia (33°C) reduced the production of tumour necrosis factor-alpha (TNF-α: a pro-inflammatory cytokine) at 6 h and interleukin-10 (IL-10: an anti-inflammatory cytokine) and NO at 48 h. CONCLUSIONS: In TLR-activated microglia that were derived from mice with HI brain injury, hypothermia reduced the production of TNF-α, IL-10, and NO temporally, a clinically relevant finding suggesting that neuroprotection conferred by therapeutic hypothermia is related to attenuation of early-phase and late-phase inflammatory factors as well as that of late-phase anti-inflammatory factor(s) released from microglia.

A single nucleotide polymorphism in fibronectin 1 determines tumor shape in colorectal cancer.

Depressed and flat surface lesions are not easy to identify with routine colonoscopies during screening for colorectal cancer (CRC). Identifying clinically relevant genes that influence tumor shape could be useful when screening for the presence of depressed lesions. Total RNA was extracted from tumor cells collected by laser microdissection from the primary lesions of 146 CRC cases. Microarray analysis was performed to identify genes that were differentially expressed between depressed and elevated tumors. Single nucleotide polymorphism (SNP) analysis of genomic DNA from the peripheral blood of 67 CRC patients was then used to associate polymorphisms with the occurrence of depressed tumors. Microarray analysis revealed significantly higher expression of the fibronectin 1 (FN1) gene in 129 depressed-type tumors and lesions compared to 17 elevated-type tumors. FN1-abundant CRC tumors were large with a significantly higher incidence of lymphatic permeation. SNP analysis indicated that 44 tumors with a GG genotype at SNP rs6707530 showed significantly higher FN1 expression than did 23 tumors with GT/TT genotypes (p<0.05). The product of the FN1 gene (located at 2q34) is involved in cell adhesion, migration and metastasis in mesenchymal tumors. Abundant expression of FN1 may allow cancer cells to invade deeper layers, which would eventually define tumor shape. Identification of this SNP in blood samples may facilitate disease diagnosis and allow prediction of the presence of depressed tumors in the colorectal epithelium before a colon fiberscope examination.

[A case of severe enteritis induced by adjuvant chemotherapy for colon cancer].

A 77-year-old man underwent surgery for sigmoid colon cancer. He was diagnosed with Stage IIIa colon cancer; there- fore, we initiated oral administration of adjuvant chemotherapy comprising uracil/tegafur(UFT)plus Leucovorin(LV). However, chemotherapy was stopped after 21 days because of fatigue and diarrhea. He recovered after 3 weeks, and we administered the same regimen with a dose reduction. However, he again experienced fatigue and diarrhea after 20 days; therefore, chemotherapy was discontinued. Subsequently, he was hospitalized 8 times for conditions such as diarrhea, hypoalbuminemia, and fever. Computed tomography revealed thickening of the transverse colonic wall and colonoscopy revealed colitis, which we believe was induced by UFT plus LV. Twelve months after the last chemotherapy session, he was diagnosed with Clostridium difficile colitis. Therefore, we initiated the oral administration of vancomycin, which resulted in rapid recovery from colitis. However, he developed liver metastasis and died 29 months after the initiation of chemotherapy. We believe that this severe case of intractable colitis was caused by UFT plus LV. Therefore, we report this case with a review of the literature on enteritis induced by fluorouracil-based anticancer agents in Japan.

Cortical region-specific engraftment of embryonic stem cell-derived neural progenitor cells restores axonal sprouting to a subcortical target and achieves motor functional recovery in a mouse model of neonatal hypoxic-ischemic brain injury.

Hypoxic-ischemic encephalopathy (HIE) at birth could cause cerebral palsy (CP), mental retardation, and epilepsy, which last throughout the individual's lifetime. However, few restorative treatments for ischemic tissue are currently available. Cell replacement therapy offers the potential to rescue brain damage caused by HI and to restore motor function. In the present study, we evaluated the ability of embryonic stem cell-derived neural progenitor cells (ES-NPCs) to become cortical deep layer neurons, to restore the neural network, and to repair brain damage in an HIE mouse model. ES cells stably expressing the reporter gene GFP are induced to a neural precursor state by stromal cell co-culture. Forty-hours after the induction of HIE, animals were grafted with ES-NPCs targeting the deep layer of the motor cortex in the ischemic brain. Motor function was evaluated 3 weeks after transplantation. Immunohistochemistry and neuroanatomical tracing with GFP were used to analyze neuronal differentiation and axonal sprouting. ES-NPCs could differentiate to cortical neurons with pyramidal morphology and expressed the deep layer-specific marker, Ctip2. The graft showed good survival and an appropriate innervation pattern via axonal sprouting from engrafted cells in the ischemic brain. The motor functions of the transplanted HIE mice also improved significantly compared to the sham-transplanted group. These findings suggest that cortical region specific engraftment of preconditioned cortical precursor cells could support motor functional recovery in the HIE model. It is not clear whether this is a direct effect of the engrafted cells or due to neurotrophic factors produced by these cells. These results suggest that cortical region-specific NPC engraftment is a promising therapeutic approach for brain repair.

Depressed-Type Colonic Lesions and "De Novo" Cancer in Familial Adenomatous Polyposis: A Colonoscopist's Viewpoint.

Familial adenomatous polyposis (FAP) is the most common inherited polyposis syndrome. Almost all patients with FAP will develop colorectal cancer if their FAP is not identified and treated at an early stage. Although there are many reports about polypoid lesions and colorectal cancers in FAP patients, little information is available concerning depressed lesions in FAP patients. Several reports suggested that depressed-type lesions are characteristic of FAP and important in the light of their rapid growth and high malignancy. Here, we describe the occurrence of depressed-type lesions in FAP patients treated at our institution. Between April 2001 and March 2010, eight of 18 FAP patients had colorectal cancers. Depressed-type colorectal cancer was found in three patients. It should be kept in mind that depressed-type lesions occur even in FAP.

Clinicopathological characteristics and optimal management for esophagogastric junctional cancer; a single center retrospective cohort study.

BACKGROUND: Esophagogastric junctional (EGJ) cancer occurs in the mucosa near the esophagogastric junction, and has characteristics of both esophageal and gastric malignancies; its optimal treatment strategy is controversial. METHODS: We conducted a single-center retrospective cohort study of the patients who underwent curative surgery with lymphadenectomy for EGJ cancer. Tumor specimens were categorized by histology and location into four types-centered in the esophagus < 5 cm from EGJ (type E), which were subtyped as (i) squamous-cell carcinoma (SQ) or (ii) adenocarcinoma (AD); (iii) any histological tumor centered in the stomach < 5 cm from EGJ, with EGJ invasion (type Ge); (iv) any histological tumor centered in the stomach < 5 cm from EGJ, without EGJ invasion (type G)-and classified by TNM system; these were compared to patients' clinicopathological characteristics and survival outcomes. RESULTS: A total of 92 EGJ cancer patients were studied. Median follow-up of surviving patients was 35.5 months. Tumors were categorized as 12 type E (SQ), 6 type E (AD), 27 type Ge and 47 type G; of these 7 (58.3%), 3 (50%), 19 (70.4%) and 14 (29.8%) and 23 patients, respectively, had lymph node metastases. No patients with type E (AD) and Ge tumors had cervical lymph node metastasis; those with type G tumors had no nodal metastasis at cervical and mediastinal lymph nodes. Multivariate analysis showed that type E (AD) tumor was an independent prognostic factor. CONCLUSIONS: We should distinguish type Ge tumor from type E (AD) tumor because of the clinicopathological and prognostic differentiation. Extended gastrectomy with or without lower esophagectomy according to tumor location and lower mediastinal and abdominal lymphadenectomy are recommended for EGJ cancer. TRIAL REGISTRATION: University Hospital Medical Information Network in Japan, UMIN000008596.

Neuroprotective effects of focal brain cooling on photochemically-induced cerebral infarction in rats: analysis from a neurophysiological perspective.

Although systemic hypothermia provides favorable outcomes in stroke patients, it has only been adopted in a limited number of patients because of fatal complications. To resolve these issues, focal brain cooling (FBC) has recently drawn attention as a less-invasive treatment for brain injuries. Therefore, we investigated whether FBC has a favorable effect on focal cerebral ischemia (FCI). Male-adult-Wistar rats were used. Under general anesthesia, a small burr hole was made and FCI was induced in the primary sensorimotor area (SI-MI) using photothrombosis. An additional craniotomy was made over the SI-MI and FBC was performed at a temperature of 15°C for 5h. Electrocorticograms (ECoG) were recorded on the border cortex of the ischemic focus. Thereafter, rats were sacrificed and the infarct area was measured. In another experiment, rats were allowed to recover for 5 days after cooling and neurobehavioral function was evaluated. FBC suppressed all ECoG frequency bands during and after cooling (p<0.05), except for the delta frequency band in the precooling versus rewarming periods. The injured areas in the cooling and non-cooling groups were 0.99±0.30 and 1.71±0.54 mm(2), respectively (p<0.03). The grip strength at 2 days after surgery was preserved in the cooling group (p<0.05). We report the novel finding that epileptiform discharges were suppressed in the ischemic border, the infarct area was reduced and neurobehaviour was preserved by FBC. These results indicate that FBC is neuroprotective in the ischemic brain and has demonstrated therapeutic potential for cerebral infarction.

[A case of metastatic colon cancer treated with oxaliplatin combination chemotherapy].

A 77-year-old male had been operated for ascending colon cancer with liver metastases. After hepatic artery injection therapy and CPT-11 plus 5'-DFUR combination therapy, oxaliplatin-based systemic chemotherapy was performed. Consequently, the tumor size was controlled for about 10 months. During the chemotherapy, we observed grade 3 neurological toxicity, but not grade 3-4 blood toxicity. Thus, the QOL of the patient was properly maintained. We conclude that the oxaliplatin-based chemotherapy may be useful for patients suffering 5-FU and CPT-11 resistant metastatic colorectal cancer in Japan.

[A case report of hepatocellular carcinoma (Vp4)--an attempt to reduce residual tumor thrombus using combination therapy (hepatic arterial infusion, hepatic arterial embolization and radiation)].

A 57-year-old man was found to have elevated levels of HCC markers during an observation of chronic hepatitis C. Diffused hepatoma was involved in the posterior lobe, and tumor thrombus extended into the main portal vein (Vp4). Posterior segmentectomy and tumor thrombectomy were performed. But, CT scan 45 days after the operation showed an enhancement at the residual tumor thrombus in the posterior branch. The patient received a hepatic arterial infusion of 5-FU, followed by hepatic arterial embolization. Then, we chose radiation therapy to the tumor thrombus. The most recent CT showed no enhancement at the reduced tumor thrombus. There have been almost no reports of treatment for residual portal thrombus. Careful observations are necessary in such patients.

[Efficacy of the combination therapy in early stage of recurrent cholangio celluler carcinoma (CCC)].

We report a case of cholangio celluler carcinoma (CCC) with a good quality of life, in spite of the recurrence of peritoneum and portal hepatic lymph nodes (PHLN), due to the combination therapy that consisted of hepatic arterial infusion, systemic chemotherapy, radiation therapy and an insertion of a metallic stent into the bile duct. The patient was a 61-year-old man. Left hepatectomy was done due to multiple CCC. For the purpose of preventing the recurrence of CCC in residual liver, we performed an arterial infusion therapy. Ten months later, metastases to peritoneum and portal hepatic lymph nodes were found, so the resection of the peritoneum was performed, and cells in ascites were defined to be positive with cytology. After 2 years from the first operation, the size of portal hepatic lymph nodes had grown and both the billilbin and tumor marker levels had increased, so we started systemic chemotherapy, radiation therapy and insertion of a metallic stent into the bile duct. The tumor marker level decreased in a short time. Consequently, we inserted a metallic stent into the bile duct and radiation therapy was performed. Until the patient's death due to peritonitis carcinomatosa, the recurrence in residual liver occurred only once in three years after the first operation, and portal hepatic lymph nodes did not grow for two years after the recurrence.

[A case of unresectable cholangiocellular carcinoma treated with surgery followed by combination chemotherapy].

The patient was a 44-year-old man, who was investigated for lateral abdominal pain and liver dysfunction, and subsequently referred to our department with a diagnosis of unresectable intrahepatic cholangiocellular carcinoma (CCC). Radiological examinations revealed the huge mass in the right lobe of the liver with intrahepatic metastasis in the left lobe. The main tumor was surgically removed, but the metastases were not removed. A month after the operation, a subcutaneous implant reservoir was indwelled for repeated transcatheter hepatic arterial chemo infusion therapy (5-fluorouracil 500 mg/day continuous infusion, day 1-5, and CDDP 10 mg/day, day 1) from the right femoral artery. After 15 courses of home anti-cancer chemotherapy, abdominal CT revealed that the size of intrahepatic metastasis in the left lobe of the liver had not shown growth, whereas other metastitic sites popped up in the caudate lobe, which were free of chemical agent flow. There was no major complication related to the chemotherapy throughout the post-treatment course. Although he maintained a good level of QOL, he refused further chemotherapy due to depression. He died of liver failure 7 months after the operation. In conclusion, volume reduction surgery followed by transcatheter hepatic arterial chemo infusion might be promising as an effective therapy for non resectable CCC.

[A patient with gastric cancer complicated with severe DIC and multiple bone metastasis showing a high response to combination of TS-1 and CDDP].

We report a 48-year-old male with gastric cancer who was suffering from acute onset of DIC due to multiple bone metastases. Treatment with TS-1 + CDDP was started with the following regimen: daily oral administration of 80 mg/m2 TS-1 for 21 days, followed by a 14-day rest and CDDP 60 mg/m2 infusion on day 8. The DIC was suddenly resolved and bone metastases were well controlled after the chemotherapy combined with anticoagulant therapy and bisphosphonate. The combination of TS-1 and CDDP can be applied for the management of DIC caused by multiple bone metastases.

Pseudomyxoma peritonei of appendiceal cancer with metastasis to the stomach: report of a case.

Appendiceal cancer associated with pseudomyxoma peritonei is a relatively low-grade malignancy rarely associated with extraperitoneal metastasis. We report herein the case of a 71-year-old man in whom a metastasis was found in the stomach 2 years after he underwent surgery for pseudomyxoma peritonei of appendiceal cancer. He was referred to our hospital after presenting with anorexia and vomiting. Gastrofiberscopy, abdominal computed tomography, and ultrasound examination all revealed a mass 4 x 4cm in size, containing a small ulcer, in the antrum of the greater curvature of the stomach. The histopathological diagnosis made from a biopsy of the tumor was mucinous cystadenocarcinoma. A distal partial gastrectomy was performed and the resected specimens from the appendiceal cancer resected 2 years earlier showed the same histological pattern as that of the gastric lesion. To the best of our knowledge, this is only the second report of pseudomyxoma peritonei secondary to mucinous cystadenocarcinoma of the appendix that metastasized to the stomach.