Mice with deficiency in Pcdh15, a gene associated with bipolar disorders, exhibit significantly elevated diurnal amplitudes of locomotion and body temperature.

Genetic factors significantly affect the pathogenesis of psychiatric disorders. However, the specific pathogenic mechanisms underlying these effects are not fully understood. Recent extensive genomic studies have implicated the protocadherin-related 15 (PCDH15) gene in the onset of psychiatric disorders, such as bipolar disorder (BD). To further investigate the pathogenesis of these psychiatric disorders, we developed a mouse model lacking Pcdh15. Notably, although PCDH15 is primarily identified as the causative gene of Usher syndrome, which presents with visual and auditory impairments, our mice with Pcdh15 homozygous deletion (Pcdh15-null) did not exhibit observable structural abnormalities in either the retina or the inner ear. The Pcdh15-null mice showed very high levels of spontaneous motor activity which was too disturbed to perform standard behavioral testing. However, the Pcdh15 heterozygous deletion mice (Pcdh15-het) exhibited enhanced spontaneous locomotor activity, reduced prepulse inhibition, and diminished cliff avoidance behavior. These observations agreed with the symptoms observed in patients with various psychiatric disorders and several mouse models of psychiatric diseases. Specifically, the hyperactivity may mirror the manic episodes in BD. To obtain a more physiological, long-term quantification of the hyperactive phenotype, we implanted nano tag® sensor chips in the animals, to enable the continuous monitoring of both activity and body temperature. During the light-off period, Pcdh15-null exhibited elevated activity and body temperature compared with wild-type (WT) mice. However, we observed a decreased body temperature during the light-on period. Comprehensive brain activity was visualized using c-Fos mapping, which was assessed during the activity and temperature peak and trough. There was a stark contrast between the distribution of c-Fos expression in Pcdh15-null and WT brains during both the light-on and light-off periods. These results provide valuable insights into the neural basis of the behavioral and thermal characteristics of Pcdh15-deletion mice. Therefore, Pcdh15-deletion mice can be a novel model for BD with mania and other psychiatric disorders, with a strong genetic component that satisfies both construct and surface validity.

Mizoribine halts kidney fibrosis in childhood IgA nephropathy: association with modulation of M2-type macrophages.

BACKGROUND: The immunosuppressant mizoribine (Miz) can reduce progression of childhood IgA nephropathy (IgAN). This study examined whether Miz affects CD163+ M2-type macrophages which are associated with kidney fibrosis in childhood IgAN. METHODS: A retrospective cohort of 90 children with IgAN were divided into groups treated with prednisolone (PSL) alone (P group; n = 42) or PSL plus Miz (PM group; n = 48) for a 2-year period. Normal human monocyte-derived macrophages were stimulated with dexamethasone (Dex), or Dex plus Miz, and analyzed by DNA microarray. RESULTS: Clinical and histological findings at first biopsy were equivalent between patients entering the P and PM groups. Both treatments improved proteinuria and haematuria, and maintained normal kidney function over the 2-year course. The P group exhibited increased mesangial matrix expansion, increased glomerular segmental or global sclerosis, and increased interstitial fibrosis at 2-year biopsy; however, the PM group showed no progression of kidney fibrosis. These protective effects were associated with reduced numbers of glomerular and interstitial CD163+ macrophages in the PM versus P group. In cultured human macrophages, Dex induced upregulation of cytokines and growth factors, which was prevented by Miz. Miz also inhibited Dex-induced expression of CD300E, an activating receptor which can prevent monocyte apoptosis. CD300e expression by CD163+ macrophages was evident in the P group, which was reduced by Miz treatment. CONCLUSION: Miz halted the progression of kidney fibrosis in PSL-treated pediatric IgAN. This was associated with reduced CD163+ and CD163+CD300e+ macrophage populations, plus in vitro findings that Miz can suppress steroid-induced macrophage expression of pro-fibrotic molecules. A higher resolution version of the Graphical abstract is available as Supplementary information.

Chronic kidney disease is a key predictive factor for potential myocardial ischaemia and poor prognosis in asymptomatic patients with diabetes mellitus.

Some asymptomatic patients with diabetes mellitus (DM) have critical coronary artery disease (CAD), although the guidelines do not recommend aggressive screening for CAD in asymptomatic patients. Chronic kidney disease (CKD) is among the serious co-morbidities of severe systemic atherosclerosis. Thus, CKD may be associated with potential myocardial ischaemia. Therefore, the present study aimed to determine the impact of CKD on the incidence of silent myocardial ischaemia (SMI) and the long-term outcomes in asymptomatic patients with DM. This study investigated 461 consecutive patients with DM. All patients who were asymptomatic and self-sufficient in daily life underwent the ergometer exercise (ERG) test. Coronary angiography was performed if the stress test was positive, or if the patient did not achieve 90% of the target heart rate. The primary end point included major adverse cardiac and cerebrovascular events (MACCE) including death, non-fatal myocardial infarction and stroke. The median follow-up duration after study enrolment was 35 months for the entire cohort of 461 patients. Eighty-one patients were diagnosed with SMI. The estimated glomerular filtration rate was significantly lower in the SMI group (70.5 ± 23.8 vs. 81.8 ± 30.0 mL/min/1.73 m2, P < 0.001). SMI occurred more frequently in patients with advanced CKD [27/103, (26.2%) in stages 3-5], whereas only 5/68 (7.3%) patients without CKD, 13/81 (16.0%) patients with stage 1 CKD and 36/209, (17.2%) in stage 2, had SMI. The Kaplan-Meier curves revealed that, patients with SMI had poor clinical outcomes (log-rank: P = 0.016). The incidence of MACCE (log-rank: P = 0.009) was higher in patients with severe CKD > stage 3a in the SMI subgroup. Urinary albumin (mg/gCr) was associated with MACCE in the SMI subgroup [HR 3.37, 95%CI (1.170-9.521), P = 0.025] after adjusting for age, sex, and conventional risk factors. SMI was more prevalent in patients with CKD and the incidence was proportional to the CKD stage in asymptomatic patients with DM. Those Patients with CKD and SMI exhibited poor clinical outcomes. CKD may be a key factor for the identification and management of SMI in asymptomatic patients with DM in routine clinical practice.Trial Registration: UMIN000038340.

Multiple large cell neuroendocrine carcinomas in the rectum and descending colon presented with liver metastasis: A case report.

Colorectal large cell neuroendocrine carcinoma (LCNEC) is rare and multiple LCNECs have not been previously reported. We encountered a case of multiple LCNECs in the rectum and the descending colon. A 66-year-old man presented with anal pain. Colonoscopy showed an ulcerated infiltrating tumor in the rectum, and 0.5 cm of erosion in the descending colon. A biopsy revealed LCNEC in both regions. Abdominal computed tomography revealed irregularly enhanced wall thickening at the rectum and hepatic metastases. Due to the diagnosis of LCNEC, laparoscopic abdominoperineal resection of the rectum was performed. Histopathological examination showed a poorly differentiated, LCNEC in both regions. Immunohistochemical examination demonstrated that the tumor cells were positive for chromogranin and synaptophysin. LCNEC was confirmed, and systemic chemotherapy with cisplatin/irinotecan was initiated. To our knowledge, this is the first case report that describes multiple LCNECs in the rectum and descending colon.

Treatment patterns in pancreatic cancer patients based on a hospital claims database in Japan.

BACKGROUND: Pancreatic cancer treatment is evolving, but few studies have examined a nationwide trend in the treatment patterns. The purpose of this study was to clarify real-world treatment patterns for pancreatic cancer in Japan. METHODS: This retrospective study examined the treatment patterns among 68 479 patients, who had pancreatic cancer diagnosis in Medical Data Vision claims database from 2010 to 2018. We extracted relevant data on treatment options, including chemotherapy, surgery and their combination. For patients who had undergone chemotherapy, we sought to analyse the use of different chemotherapy regimens. In addition, we examined the trend in treatment patterns by age group (<59, 60-69, 70-79, ≥80). RESULTS: The trend in treatment options of pancreatic cancer remained stable from 2010 to 2018, with chemotherapy being the most common therapeutic option and surgery performed in approximately half that of chemotherapy. On the other hand, the use of chemotherapy regimen had changed during the same period. Although gemcitabine was the most commonly administrated single-agent regimen in 2010, gemcitabine + nab-paclitaxel was the most frequently used therapeutic agent in 2018. In the older age groups (age ≥80), the majority of patients was untreated (supposedly received supportive care), and the use of conventional regimens such as gemcitabine or S-1 was common among those undergoing chemotherapy. CONCLUSIONS: Although chemotherapy has been the main treatment option for pancreatic cancer, the regimens of choice have increased significantly during the last decade. With accumulating evidence on combination chemotherapy, treatment options may further evolve in the future.

Congenital hearing impairment associated with peripheral cochlear nerve dysmyelination in glycosylation-deficient muscular dystrophy.

Hearing loss (HL) is one of the most common sensory impairments and etiologically and genetically heterogeneous disorders in humans. Muscular dystrophies (MDs) are neuromuscular disorders characterized by progressive degeneration of skeletal muscle accompanied by non-muscular symptoms. Aberrant glycosylation of α-dystroglycan causes at least eighteen subtypes of MD, now categorized as MD-dystroglycanopathy (MD-DG), with a wide spectrum of non-muscular symptoms. Despite a growing number of MD-DG subtypes and increasing evidence regarding their molecular pathogeneses, no comprehensive study has investigated sensorineural HL (SNHL) in MD-DG. Here, we found that two mouse models of MD-DG, Largemyd/myd and POMGnT1-KO mice, exhibited congenital, non-progressive, and mild-to-moderate SNHL in auditory brainstem response (ABR) accompanied by extended latency of wave I. Profoundly abnormal myelination was found at the peripheral segment of the cochlear nerve, which is rich in the glycosylated α-dystroglycan-laminin complex and demarcated by "the glial dome." In addition, patients with Fukuyama congenital MD, a type of MD-DG, also had latent SNHL with extended latency of wave I in ABR. Collectively, these findings indicate that hearing impairment associated with impaired Schwann cell-mediated myelination at the peripheral segment of the cochlear nerve is a notable symptom of MD-DG.

Robotic transanal minimally invasive surgery (TAMIS) with the newest robotic surgical platform: a multi-institutional North American experience.

BACKGROUND: Transanal minimally invasive surgery (TAMIS) offers intra-luminal full-thickness excision of rectal neoplasia. Robotic TAMIS (RT) allows for greater versatility in motion while operating in the limited space of the rectum. We present our experience with this technique in practice using the DaVinci Xi™ platform. METHOD: This is a multi-institutional retrospective analysis for patient undergoing Robotic TAMIS for resection of rectal lesions at two tertiary referral hospitals in the United States. Morbidity, mortality, anatomic measurement, and final pathology were analyzed. RESULTS: Thirty-four patients planned for Robotic TAMIS were identified. Average follow-up was 188 days. The average BMI was 29.5 ± 5.9. All patients had an American Society of Anesthesiologist (ASA) Class of 2 or greater and 21 (62%) were ASA 3 or greater. Rectal lesions located from 2 to 15 cm from the dentate line were successfully resected. Lesions up to 4.5 cm in the longest dimension were successfully resected. The average operative time was 100 ± 70 min, which correlated to a robotic console time of 76 ± 67 min. Patients were placed in Lithotomy in 32 (94%) cases and were prone in only 2 (6%) cases. There were no intraoperative complications or conversions to another technique. The only postoperative complication was a medically managed Clostridium difficile infection in 1 patient. Three patients were upstaged to T2 on final pathology and underwent successful formal resections. BMI was a statistically significant predictor of a longer operation. CONCLUSIONS: With increased reach and operative range of motion, Robotic TAMIS is a safe and effective method for excising low-risk rectal neoplasia with a wide range of anatomical measurements. Higher BMI is a significant predictor of a longer and likely more challenging operation.

Multiplex Neural Circuit Tracing With G-Deleted Rabies Viral Vectors.

Neural circuits interconnect to organize large-scale networks that generate perception, cognition, memory, and behavior. Information in the nervous system is processed both through parallel, independent circuits and through intermixing circuits. Analyzing the interaction between circuits is particularly indispensable for elucidating how the brain functions. Monosynaptic circuit tracing with glycoprotein (G) gene-deleted rabies viral vectors (RVΔG) comprises a powerful approach for studying the structure and function of neural circuits. Pseudotyping of RVΔG with the foreign envelope EnvA permits expression of transgenes such as fluorescent proteins, genetically-encoded sensors, or optogenetic tools in cells expressing TVA, a cognate receptor for EnvA. Trans-complementation with rabies virus glycoproteins (RV-G) enables trans-synaptic labeling of input neurons directly connected to the starter neurons expressing both TVA and RV-G. However, it remains challenging to simultaneously map neuronal connections from multiple cell populations and their interactions between intermixing circuits solely with the EnvA/TVA-mediated RV tracing system in a single animal. To overcome this limitation, here, we multiplexed RVΔG circuit tracing by optimizing distinct viral envelopes (oEnvX) and their corresponding receptors (oTVX). Based on the EnvB/TVB and EnvE/DR46-TVB systems derived from the avian sarcoma leukosis virus (ASLV), we developed optimized TVB receptors with lower or higher affinity (oTVB-L or oTVB-H) and the chimeric envelope oEnvB, as well as an optimized TVE receptor with higher affinity (oTVE-H) and its chimeric envelope oEnvE. We demonstrated independence of RVΔG infection between the oEnvA/oTVA, oEnvB/oTVB, and oEnvE/oTVE systems and in vivo proof-of-concept for multiplex circuit tracing from two distinct classes of layer 5 neurons targeting either other cortical or subcortical areas. We also successfully labeled common input of the lateral geniculate nucleus to both cortico-cortical layer 5 neurons and inhibitory neurons of the mouse V1 with multiplex RVΔG tracing. These oEnvA/oTVA, oEnvB/oTVB, and oEnvE/oTVE systems allow for differential labeling of distinct circuits to uncover the mechanisms underlying parallel processing through independent circuits and integrated processing through interaction between circuits in the brain.

An ERAS protocol for bariatric surgery: is it safe to discharge on post-operative day 1?

BACKGROUND: Laparoscopic sleeve gastrectomy is the most commonly performed bariatric surgery in the world. Enhanced recovery after surgery (ERAS) protocols have been shown to reduce complications and decrease length of stay for various types of surgeries. In this study, we propose an ERAS protocol for laparoscopic sleeve gastrectomy and compare the clinical outcomes with patients who received standard care. METHODS: We performed a single-institution retrospective analysis in patients who underwent laparoscopic sleeve gastrectomy from February 2015 to December 2017. Patients were stratified into standard care and ERAS protocol groups. The ERAS protocol consisted of goal-directed patient education, specific pre- and post-op multi-modal medication regimen, early ambulation, and early oral intake. Patients were discharged on their first post-operative day if they met appropriate post-surgical milestones. The primary outcomes were length of stay, 7- and 30-day readmission rates, and complication rates. Secondary outcomes included anti-emetic and pain medication utilization, post-operative emesis episodes per day, post-operative pain scores, and mortality. RESULTS: We included 214 consecutive patients who underwent sleeve gastrectomy, 130 were in the ERAS group and 84 were in the standard care group. Median hospital stay was significantly shorter in the ERAS group compared to the standard care group (1 vs. 2 days; p < 0.001). There were no differences in 7- or 30-day readmission rates (1.5 vs. 1.2%; p = 0.838, 2.3 vs. 2.4%; p = 0.966) or post-operative complications (6.2 vs. 3.6%; p = 0.410). The ERAS group also had decreased median intra-operative opioid consumption and self-reported pain scores on post-operative day 1 (27.5 MME vs. 27.4 MME; p = 0.044, 3.3 vs. 3.9; p = 0.046). Mortality rate was 0% overall. CONCLUSION: A cost-effective ERAS protocol for laparoscopic sleeve gastrectomy results in shorter length of stay, without increase in peri-operative morbidity or readmission rates.

Pregabalin as an analgesic option for patients undergoing thoracotomy: cost analysis of pregabalin versus epidural analgesia for post-thoracotomy pain relief.

BACKGROUND: Our previous randomized controlled trial (RCT) to evaluate the effects of pregabalin on acute post-thoracotomy pain compared with epidural analgesia showed that pregabalin is a safe and effective treatment and that it may be an alternative to epidural analgesia for acute post-thoracotomy pain. In this analysis, to additionally analyze the economic aspects of pregabalin in patients undergoing thoracotomy, we compared the medical costs between pregabalin and epidural analgesia as an analgesic technique for post-thoracotomy pain. METHODS: Costs for patients undergoing thoracotomy and receiving either pregabalin or epidural analgesia for post-thoracotomy pain relief in the previous RCT were retrospectively collected from health insurance claims data. The following five cost categories were compared between the groups: (I) surgery costs; (II) costs for surgical materials and medications; (III) costs for anesthetic management; (IV) total hospitalization costs; and (V) costs for outpatient pain-relief medications (from hospital discharge to 6 months after thoracotomy). RESULTS: We analyzed data from 90 patients (45 patients for each group). Median costs for surgical materials and medications and those for anesthetic management were significantly lower in the pregabalin group than in the epidural analgesia group [(Japanese yen) ¥69,720 vs. ¥77,180, P=0.017; ¥161,000 vs. ¥195,500, P<0.001, respectively]. However, total hospitalization costs and costs for outpatient pain-relief medications were similar between the groups. Pregabalin was prescribed to more patients in the pregabalin group than those in the epidural analgesia group as outpatient treatment (75.0% vs. 37.5%), but median prescribed doses were much smaller in the pregabalin group. CONCLUSIONS: Although the use of pregabalin did not result in lower total hospitalization costs, it may reduce fee-for-service surgery- and anesthesia-related costs. The economic benefits of pregabalin may reinforce its usefulness as an alternative to epidural analgesia, especially for patients who are unsuitable for epidural analgesia.

How bariatric surgery affects liver volume and fat density in NAFLD patients.

INTRODUCTION: Nonalcoholic fatty liver disease (NAFLD) is an epidemic in the obese population. Bariatric surgery is known to reverse multiple metabolic complications of obesity such as diabetes, dyslipidemia, and NAFLD, but the timing of liver changes has not been well described. MATERIALS AND METHODS: This was an IRB-approved, two-institutional prospective study. Bariatric patients received MRIs at baseline and after a pre-operative liquid diet. Liver biopsies were performed during surgery and if NAFLD positive, the patients received MRIs at 1, 3, and 6 months. Liver volumes and proton-density fat fraction (PDFF) were calculated from offline MRI images. Primary outcomes were changes in weight, body mass index (BMI), percent excess weight loss (EWL%), liver volume, and PDFF. Resolution of steatosis, as defined as PDFF < 6.4% based on previously published cutoffs, was assessed. Secondarily, outcomes were compared between patients who underwent laparoscopic sleeve gastrectomy (LSG) versus laparoscopic Roux-en-Y gastric bypass (LRYGB). RESULTS: From October 2010 to June 2015, 124 patients were recruited. 49 patients (39.5%) completed all five scans. EWL% at 6 months was 55.6 ± 19.0%. BMI decreased from 45.3 ± 5.9 to 34.4 ± 5.1 kg/m2 and mean liver volume decreased from 2464.6 ± 619.4 to 1874.3 ± 387.8 cm3 with a volume change of 21.4 ± 11.4%. PDFF decreased from 16.6 ± 7.8 to 4.4 ± 3.4%. At 6 months, 83.7% patients had resolution of steatosis. Liver volume plateaued at 1 month, but PDFF and BMI continued to decrease. There were no statistically significant differences in liver volume or PDFF reduction from baseline to 6 months between the LSG versus LRYGB subgroups. CONCLUSION: Patients with NAFLD undergoing bariatric surgery can expect significant decreases in liver volume and hepatic steatosis at 6 months, with 83.7% of patients achieving resolution of steatosis. Liver volume reduction plateaus 1-month post-bariatric surgery, but PDFF continues to decrease. LSG and LRYGB did not differ in efficacy for inducing regression of hepatosteatosis.

Effect of ninjin'yoeito and ginseng extracts on oxaliplatin-induced neuropathies in mice.

Oxaliplatin (L-OHP) is a platinum-based anticancer agent used to treat various types of cancer. It frequently causes acute and chronic peripheral neuropathies, such as cold allodynia and mechanical hyperalgesia. Ninjin'yoeito (NYT) is a formula used in traditional Japanese Kampo medicine to improve recovery from diseases and other medical disorders. We previously reported that treatment with a boiling-water extract of NYT prevented L-OHP-induced damage to neurite-like outgrowths from differentiated PC12 cells. The objectives of the present study were to evaluate the in vivo effects of NYT on L-OHP-induced neuropathic pain in mice and identify the active ingredients in NYT. Treatment with NYT extract significantly ameliorated both cold allodynia and mechanical hyperalgesia induced by L-OHP. While L-OHP treatment suppressed neurite outgrowths from primary dorsal root ganglion cells in vitro, NYT extract blocked this suppression in a concentration-dependent manner. Among the herbal components of NYT, the extract of ginseng (Panax ginseng roots) showed a protective effect against neurite damage induced by L-OHP, and one of its active ingredients was identified as ginsenoside Rg3. Ginseng extract partially relieved L-OHP-induced neuropathic pain in mice. Our results suggest that NYT could be an attractive agent for treating L-OHP-induced neuropathic pain, and that the active ingredient of NYT may be ginseng.

Complications of robotic foregut surgery: risks and advantages.

INTRODUCTION: Laparoscopic foregut surgeries are highly complex procedures that carry a high potential for morbidity and mortality should complications should occur. The robotic-assisted platform offers improved visualization of anatomy, optimal fine motor control, and a higher degree of instrumentation range of motion, which may potentially lead to better outcomes. This paper reviews the risks and benefits of the robotic platform in foregut procedures. EVIDENCE ACQUISITION: A web-based literature search was performed, in August 2016 using Pubmed, EMBASE, and Google Scholar from cited English publications from 1996 to 2016. We included randomized control trials, non-randomized comparison studies, and cohort studies in robotic foregut surgery. Abstracts, letters, editorials, expert opinions, review papers, and meta-analyses with no original statistical analyses were not included. EVIDENCE SYNTHESIS: A total of 619 articles were identified of which 98 articles met the inclusion criteria. The studies were divided into areas of benign and malignant foregut procedures that utilized robotic assistance. Intraoperative complications related to both the surgery itself as well as robotic hardware malfunction, short-term and long-term clinical outcomes were extracted. CONCLUSIONS: Intraoperative and postoperative complications of robotic assistance during foregut surgery are comparable or superior to those of traditional laparoscopic techniques. Our review suggests improved outcomes in Heller myotomies, gastrectomies, and esophagectomies.

Laparoscopic modified Sugarbaker parastomal hernia repair with 2-point anchoring and zigzag tacking of Parietex™ Parastomal Mesh technique.

BACKGROUND: The ideal mesh and mesh fixation technique for laparoscopic Sugarbaker (SB) parastomal hernia repair have not yet been identified. METHODS: Sixteen patients with parastomal hernia who underwent laparoscopic modified SB repair (LSB) between June 2012 and October 2015 were retrospectively analyzed. LSB was performed using a developed standardized 2-point anchoring and zigzag tacking of Parietex™ Parastomal Mesh (PCO-PM) technique. RESULTS: Out of 16 cases, 14 were primary and 2 recurrent hernias; 13 were para-end colostomy and 3 were para-ileal conduit (PIC) hernias. The median longitudinal and transverse diameters of the hernia orifice were 5 cm (2.5-7 cm) and 4.2 cm (2-6 cm), respectively. Five cases had a concomitant midline incisional hernia, which was simultaneously repaired. In all cases, the mesh was placed without deflection. The median operation time was 193 (75-386) min. Perioperative complications occurred in two cases (13 %) with PIC, one intra-operatively and the other postoperatively. The intra-operative complication was enterotomy close to the ureteroenteric anastomosis of the ileal conduit; it was repaired through a mini-laparotomy. LSB was accomplished without any subsequent postoperative complications. The postoperative complication was ureteral obstruction that required creation of nephrostomy. Mini-laparotomy was necessary in those two cases (13 %) because of intra-operative enterotomy and severe intra-abdominal adhesions. The median postoperative length of stay was 9 (5-14) days. No recurrence was observed with a median follow-up of 14.5 (2-41) months. CONCLUSIONS: Our LSB using standardized mesh fixation technique is safe and feasible, and the PCO-PM seems to be the most optimal prosthesis.

Processed aconite root and its active ingredient neoline may alleviate oxaliplatin-induced peripheral neuropathic pain.

ETHNOPHARMACOLOGICAL RELEVANCE: Processed aconite root (PA, the root of Aconitum carmichaeli, Ranunculaceae) is a crude drug used in traditional Chinese or Japanese kampo medicine to generate heat in the body and to treat pain associated with coldness. Oxaliplatin (L-OHP) is a platinum-based anticancer drug that frequently causes acute and chronic peripheral neuropathies, including cold and mechanical hyperalgesia. AIM OF THE STUDY: We investigated the effects of PA on L-OHP-induced peripheral neuropathies and identified the active ingredient within PA extract. MATERIALS AND METHODS: L-OHP was intraperitoneally injected into mice, and PA boiled water extract was orally administered. Cold and mechanical hyperalgesia were evaluated using the acetone test and the von Frey filament method, respectively. Dorsal root ganglion (DRG) neurons were isolated from normal mice and cultured with L-OHP with or without PA extract. Cell viability and neurite elongation were evaluated. RESULTS: PA extract significantly attenuated cold and mechanical hyperalgesia induced by L-OHP in mice. In cultured DRG neurons, L-OHP reduced cell viability and neurite elongation in a dose-dependent manner. Treatment with PA extract significantly alleviated the L-OHP-induced reduction of neurite elongation, while the cytotoxicity of L-OHP was not affected. Using activity-guided fractionation, we isolated neoline from PA extract as the active ingredient. Neoline significantly alleviated L-OHP-induced reduction of neurite elongation in cultured DRG neurons in a concentration-dependent manner. Moreover, subcutaneous injection of neoline attenuated cold and mechanical hyperalgesia in L-OHP-treated mice. PA extract and neoline did not show sedation and motor impairment. CONCLUSIONS: The present study indicates that PA and its active ingredient neoline are promising agents to alleviate L-OHP-induced neuropathic pain.

Initial Report of Phase II Study on Bi-weekly SOX plus Cetuximab Treatment for Wild-type K-RAS Advanced and Recurrent Colorectal Cancer.

AIM: This prospective study was designed to evaluate the tolerability and the efficacy of bi-weekly SOX (S-1 and oxaliplatin)+cetuximab as first-line chemotherapy for wild-type K-RAS metastatic colorectal cancer. PATIENTS AND METHODS: We studied patients with previously untreated, unresectable, advanced or recurrent colorectal cancer who were treated in our hospital between October 2010 and March 2013. Their performance status (PS) was 0 to 1. Cetuximab was combined with S-1 and oxaliplatin (SOX+cetuximab). S-1 was given orally at a dose of 40 mg/m(2) (40-60 mg, calculated according to body surface area) twice daily after meals for 2 weeks, followed by a 2-week rest (course 1). Oxaliplatin (85 mg/m(2)) was given on days 1 and 15 of each course. Cetuximab was administered on days 1 (400 mg/m(2)), 8 (250 mg/m(2)) and 15 (500 mg/m(2)) of course 1, followed by every 2 weeks (500 mg/m(2)) thereafter. RESULTS: The study group comprised of 18 patients. The mean age was 61 (range=32-72) years, the male:female ratio was 10:8 and the PS was 0 in 12 patients and 1 in 6 patients. The median number of administered courses was 6 (range=2-12). The treatment response was complete response (CR) in 2 and partial response (PR) in 10 (response rate=67% (12/18 patients)). The minimum number of treatment courses until a PR was 2, indicating an early response. Liver resection was performed in 4 patients (22.2%). The incidence of any adverse events (Grade 3/4) was 28% (5/18), including skin disorder (16.7%) as dry skin, cutaneous pruritus, contusion and paronychia, as well as peripheral sensory neuropathy (11.1%). The any-grade events of skin disorders and peripheral sensory neuropathy were mostly observed in all patients. These events were controllable by preventive skin care and by withdrawal and dose reduction, respectively. Death due to adverse events was not observed. Adverse events did not require the withdrawal of this regimen. CONCLUSION: Based on the 18 patients studied, combined therapy with SOX+cetuximab was free of serious adverse events and could be safely administered by reducing the dose or temporarily suspending treatment, as required. These regimens seem to be promising for conversion therapy (4 out of 18 patients) because of good outcomes and an early response.

Adjuvant chemotherapy for the perineural invasion of colorectal cancer.

BACKGROUND: To evaluate the association of perineural invasion (PNI) with outcomes in patients after colorectal resection of colorectal cancer (CRC) and to assess the effect of PNI on the response to adjuvant chemotherapy. PATIENTS AND METHODS: Data were retrospectively reviewed for 178 patients with consecutive stages I-III CRC who underwent curative surgery between January 1999 and December 2004. PNI data were examined, and the overall survival (OS) and disease-free survival rates were analyzed. RESULTS: PNI was detected in 36 of 178 patients (20%) and positively correlated with lymphatic invasion (P = 0.020), venous invasion (P = 0.037), and the incidence of metastasis or recurrence (P = 0.029). Five-year disease-free survival was 46% and 68% (P < 0.001) and the 5-y OS was 64% and 80% (P < 0.001) for patients with and without PNI, respectively. In stage III CRC, multiple regression analysis identified PNI as a strong negative prognostic factor of OS; among PNI-positive patients, median OS with adjuvant chemotherapy was almost twofold higher than that without adjuvant chemotherapy (6 versus 2.8 y; P = 0.017). CONCLUSIONS: PNI was a poor predictor of survival among patients with stage III CRC, and adjuvant chemotherapy may attenuate the adverse effects of PNI on survival.

Ninjin'yoeito and ginseng extract prevent oxaliplatin-induced neurodegeneration in PC12 cells.

Ninjin'yoeito (NYT) is a formula of Japanese traditional kampo medicine composed of 12 crude drugs, and is designed to improve the decline in constitution after recovery from disease, fatigue, anemia, anorexia, perspiration during sleep, cold limbs, slight fever, chills, persistent cough, malaise, mental disequilibrium, insomnia, and constipation. Oxaliplatin (L-OHP) is a platinum-based anticancer drug used to treat colorectal, pancreatic, and stomach cancers. However, it often causes acute and chronic peripheral neuropathies including cold allodynia and mechanical hyperalgesia. In this study, we investigated the preventive effects of NYT on neuronal degeneration caused by L-OHP using PC12 cells, which are derived from the rat adrenal medulla and differentiate into nerve-like cells after exposure to nerve growth factor. L-OHP treatment decreased the elongation of neurite-like projection outgrowths in differentiated PC12 cells. When PC12 cells were treated with NYT hot water extract, neurodegeneration caused by L-OHP was significantly prevented in a concentration-dependent manner. Among the 12 crude drugs composing NYT, the extract of Ginseng (the root of Panax ginseng) exhibited the strongest preventive effects on neurodegeneration in differentiated PC12 cells. By activity-guided fractionation, we found that the fraction containing ginsenosides displayed preventive activity and, among several ginsenosides, ginsenoside F2 exhibited significant preventive effects on L-OHP-induced decreases in neurite-like outgrowths in differentiated PC12 cells. These results suggest that NYT and ginseng are promising agents for preventing L-OHP-induced neuropathies and present ginsenoside F2 as one of the active ingredients in ginseng.

Alternatively activated macrophages in the pathogenesis of chronic kidney allograft injury.

BACKGROUND: Prevention of chronic kidney allograft injury (CAI) is a major goal in improving kidney allograft survival; however, the mechanisms of CAI are not clearly understood. The current study investigated whether alternatively activated M2-type macrophages are involved in the development of CAI. METHODS: A retrospective study examined kidney allograft protocol biopsies (at 1 h and at years 1, 5, and 10--a total of 41 biopsies) obtained from 13 children undergoing transplantation between 1991 and 2008 who were diagnosed with CAI: interstitial fibrosis and tubular atrophy (IF/TA) not otherwise specified (IF/TA-NOS). RESULTS: Immunostaining identified a significant increase in interstitial fibrosis with accumulation of CD68 + CD163+ M2-type macrophages. CD163+ cells were frequently localized to areas of interstitial fibrosis exhibiting collagen I deposition and accumulation of α-smooth muscle actin (SMA) + myofibroblasts. There was a significant correlation between interstitial CD163+ cells and the parameters of interstitial fibrosis (p < 0.0001), and kidney function (r =-0.82, p < 0.0001). The number of interstitial CD163+ cells at years 1 and 5 also correlated with parameters of interstitial fibrosis at years 5 and 10 respectively. Notably, urine CD163 levels correlated with interstitial CD163+ cells (r = 0.79, p < 0.01) and parameters of interstitial fibrosis (p < 0.0001). However, CD3+ T lymphocytic infiltration did not correlate with macrophage accumulation or fibrosis. In vitro, dexamethasone up-regulated expression of CD163 and cytokines (TGF-ß1, FGF-2, CTGF) in human monocyte-derived macrophages, indicating a pro-fibrotic phenotype. CONCLUSIONS: Our findings identify a major population of M2-type macrophages in patients with CAI, and suggest that these M2-type macrophages might promote the development of interstitial fibrosis in IF/TA-NOS.

Local excision of rectal schwannoma using transanal endoscopic microsurgery: A case report.

INTRODUCTION: Schwannoma is a neoplasm originating from the neural crest cells (schwann cells) that form nerve sheaths. These tumors are thought to be benign with little risk of malignant transformation. They rarely affect the gastrointestinal tract, and primary rectal involvement is extremely rare. Until 2013, only 11 cases of anorectal schwannoma have been reported. Optimal surgical treatment of rectal schwannoma has not been established. PRESENTATION OF CASE: We herein describe a 70-year-old woman with a submucosal tumor arising from the posterior wall of the rectum with features mimicking a gastrointestinal stromal tumor. After discussing the operative procedures and obtaining written informed consent, we attempted local excision of the tumor using a transanal endoscopic microsurgery (TEM). The tumor was proved to be S-100 positive schwannoma on immuhistochemical studies. Her postoperative course was uneventful, and there is no evidence of tumor recurrence as of 6 months after surgical excision. DISCUSSION: An extremely rare rectal schwannoma was successfully treated using a TEM without compromising anorectal function. CONCLUSION: TEM is a feasible approach for local excision of rectal tumors with low risk of malignancy.