Nephrotoxic Potential and Toxicokinetics of Melamine Combined with Cyanuric Acid in Rats

To investigate the nephrotoxic potential of melamine (MEL) and cyanuric acid (CA) in male Sprague-Dawley rats, 7-d repeated-dose studies were performed. The experimental groups of MEL100 and CA100 were orally administered with MEL and CA at 100 mg/kg/d for 7 d, respectively. In groups dosed with MEL–CA mixtures, melamine and cyanuric acid (1:1) were simultaneously administered at 4, 20, or 100 mg/kg/d for 7 d (i.e., MEL-CA4, MEL-CA20, or MEL-CA100, respectively). Body weights were not markedly affected in MEL100, CA100, and MEL-CA4 groups, but significantly reduced in MEL-CA 20 and 100 rats. Most parameters determined in sera and tissues were not markedly altered in MEL100, CA100, and MEL-CA4-treated rodents. However, BUN, creatinine, total protein, and kidney weights were significantly increased in MEL-CA20- and MEL-CA100-treated animals. Renal histopathologic findings also revealed signs of toxicity, including tubular dilatation, crystal deposition, granulomatous tubulo-interstitial inflammation, and tubular necrosis with regeneration. Data suggested that the combination of MEL and CA might be responsible for observed nephrotoxicity that was not seen following individual exposure to either MEL or CA alone. Subsequently, the concentrations of MEL and CA were determined in serum, urine, and kidney tissues by using liquid chromatography–mass spectrometry. Toxicokinetic studies indicated that MEL or CA alone might be eliminated almost completely within 24 h after dosing showing no accumulation in kidney. However, the combined MEL-CA dose produced marked accumulation of chemicals in blood and kidneys. These results suggested that combined MEL and CA might produce renal toxicity due to significant chemical accumulation in kidney accompanied by low excretion.     

An N-terminal 80 kDa recombinant fragment of human thrombospondin-2 inhibits vascular endothelial growth factor induced endothelial cell migration in vitro and tumor growth and angiogenesis in vivo

We have previously shown that stable overexpression of the thrombospondin-2 (TSP-2) gene inhibited the tumor growth and angiogenesis of human squamous cell carcinoma xenotransplants. To investigate the potential antitumoral efficacy of systemic TSP-2 therapy, we expressed a recombinant 80 kDa fragment of human TSP-2 (TSP-2/NTF), encompassing the N-terminal globular region through the three type 1 repeats, in human kidney 293 EBNA cells, using a modified pCEP4 expression vector. Daily intraperitoneal injections of TSP-2/NTF resulted in a significant inhibition of the growth of human A431 squamous cell carcinomas in vivo and in reduced tumor vascularization. To further investigate possible mechanisms of the antiangiogenic activity of TSP-2/NTF, several in vitro angiogenesis assays were performed in human dermal microvascular endothelial cells. TSP-2/NTF inhibited vascular endothelial growth factor induced migration of human dermal microvascular endothelial cells and inhibited tube formation on Matrigel in vitro. TSP-2/NTF also inhibited vascular endothelial growth factor induced angiogenesis in an in vivo Matrigel assay. Moreover, TSP-2/NTF potently induced human dermal microvascular endothelial cell apoptosis in vitro but did not affect A431 tumor cell proliferation or apoptosis. These findings identify TSP-2/NTF as a potent systemic inhibitor of tumor growth and angiogenesis, acting by direct inhibition of several endothelial cell functions involved in neovascularization.     

Growth Patterns of Signet Ring Cell Carcinoma of the Stomach for Endoscopic Resection

Background/Aims

It is difficult to precisely detect the lateral margin during endoscopic submucosal dissection (ESD) for signet ring cell carcinoma (SRC) because SRC often expands to lateral direction through the lamina propria. Thus, the aim of this study was to classify the intramucosal spreading patterns of SRC and to analyze the patients’ clinicopathological findings according to the spreading patterns.

Methods

The intramucosal spreading patterns of SRC were classified as expansive or infiltrative types. A total of 100 surgical and 42 ESD specimens were reviewed.

Results

In the surgical specimens, the proportions of expansive and infiltrative types were 44% and 56%, respectively. The infiltrative type was more commonly associated with old age, atrophy, and intestinal metaplasia in surrounding mucosa and the absence of Helicobacter pylori compared with the expansive type. In ESD specimens, the proportions of expansive and infiltrative types were each 50%. When lateral margin-positive lesions were compared with -negative lesions, larger size, residual lesion, and the lack of a neutrophil infiltration were more significantly associated with lateral margin-positive lesions. All cases with residual tumors in lateral margin-positive lesions were classified as the infiltrative type.

Conclusions

SRC surrounded with atrophy and/or intestinal metaplasia often spreads subepithelially in the margin. This finding may suggest that a larger safety margin is necessary in this type during ESD.     

Topiramate increases the risk of valproic acid–induced encephalopathy

Metabolic encephalopathy is a rare but serious complication of valproic acid (VPA) therapy that usually presents with impaired consciousness or increased seizure frequency. Although it has been suggested that topiramate (TPM) increases the risk of VPA‐induced encephalopathy, the additional risk in patients receiving TPM therapy has not been evaluated. We reviewed all adult patients who took VPA between January 2005 and February 2009 at the Seoul National University Hospital and identified patients with VPA‐induced encephalopathy based on clinical and electroencephalography (EEG) data. Information on sex, age, serum ammonia level, serum VPA level, liver function test, and EEG was collected from patient registry and medical data. We enrolled 8,372 patients who received VPA therapy and 1,236 patients who received VPA/TPM combination therapy. We identified 11 patients with VPA‐induced encephalopathy (0.13%), 7 of whom received a combination therapy of VPA and TPM. The odds ratio of VPA‐induced encephalopathy with TPM over that without TPM was 10.16. There were no significant differences in sex distribution, number of antiepileptic agents, ammonia level, VPA serum level, underlying diseases, dosage of VPA, duration of VPA treatment, treatment of encephalopathy, and outcomes between the two groups. Our study showed that the prevalence of VPA‐induced encephalopathy is approximately 0.1% among patients treated with VPA and that the risk of this condition, although still low, can increase by approximately 10 times in the presence of TPM therapy. Based on these results, we suggest that TPM should be carefully used in patients receiving VPA treatment.     

Successful Treatment of Occipital Radiating Headache Using Pulsed Radiofrequency Therapy

Rheumatoid arthritis (RA) is a chronic inflammatory disease involving multiple joints. The cervical spine is often affected, and cases involving atlantoaxial joint can lead to instability. Anterior atlantoaxial subluxation in RA patients can lead to posterior neck pain or occipital headache because of compression of the C2 ganglion or nerve. Here, we report the successful treatment of a RA patient with occipital radiating headache using pulsed radiofrequency therapy at the C2 dorsal root ganglion.     

Twin AV node and induced supraventricular tachycardia in Fontan palliation patients

INTRODUCTION: The coexistence of two distinct atrioventricular (AV) nodes has been described in congenital heart disease requiring Fontan type palliation. The purpose of this study was to evaluate the occurrence of twin AV node according to anatomical subgroups, and to determine its relation to tachycardia. METHODS: From 2001 to 2003, we performed an electrophysiologic (EP) study upon 52 consecutive patients who had undergone cardiac catheterization after Fontan completion. Atrial pacing was performed at three or more different atrial sites. RESULTS: In 10/52 patients, two different QRS complexes were recorded at different pacing sites, suggesting twin AV node (9/20 in right isomerism, 1/8 discordance AV connections, 0/24 other complex anomalies). AV reciprocating tachycardia (AVRT), presumably involving two AV nodes and a connecting sling, was induced in 6 of 10 patients who had twin AV node (4/6 used posterior AV node as an antegrade limb, 2/6 used an anterior AV node as an antegrade limb). Heterotaxy syndrome (P < 0.001) and complete AV septal defect (P = 0.002) were found to be risk factors for twin AV node. Junctional tachycardia (JT; HR > 150/min) with either VA dissociation (7/9) or second degree VA block (2/9) were induced by pacing or isoproterenol infusion in 9/52 patients. CONCLUSION: JT induction was associated with a twin AV node (P = 0.04), or a history of early postoperative junctional ectopic tachycardia (P = 0.02). A complicated AV node conduction system such as twin AV node was frequent in heterotaxy syndrome. Both AVRT and JT with VA block may be important causes of tachyarrhythmia in this patient group.     

The Effect of Denosumab and Risk Factors for Recurrence in Spinal Giant Cell Tumors: A Systematic Review and Meta-Analysis

PurposeGiant cell tumors (GCTs) are common benign primary bone tumors and are well known for their locally aggressive performance and tendency to recur. The purpose of this study was to analyze the effects of denosumab and risk factors for recurrent spinal GCTs.Materials and MethodsWe searched PubMed, EMBASE, Web of Science, and Cochrane Library databases to identify differences between individuals treated with and without denosumab and risk factors for spinal GCT recurrence. Patient data, including age, sex, tumor resection range, location, denosumab use, Campanacci grade, and radiotherapy, were documented. Comparable factors were evaluated using odds ratios (ORs) and weighted mean differences (WMDs) with 95% confidence intervals (CIs).ResultsSixteen studies were included. The overall incidence of spinal GCT recurrence was 29%. Campanacci grade III tumors showed better recurrence outcomes than grades I and II (OR, 16.36; 95% CI, 4.19–63.93; p<0.001). Gross total resection (OR, 0.09; 95% CI, 0.04–0.19; p<0.001), radiotherapy (OR, 0.27; 95% CI, 0.11–0.65; p=0.004), and the use of denosumab during subtotal resection (OR, 2.95; 95% CI, 1.07–8.17; p=0.04) were important factors for reducing recurrence.ConclusionClinicians must consider the effects of gross total resection, radiotherapy use, and denosumab use in cases of subtotal resection during spinal GCT treatment. So far, many researchers have used denosumab in spinal GCT, but none have clearly suggested an endpoint. Most studies, however, recommend using it for more than 6 months.     

Factor Structure of the Neurocognitive Tests: An Application of the Confirmative Factor Analysis in Stabilized Schizophrenia Patients

The purpose of the present study was to identify the factor structure of neurocognitive tests used on schizophrenia patients by using the confirmative factor analysis, and to assess the factor score differences of schizophrenia patients and healthy controls. Comprehensive neurocognitive tests were administered to stabilized schizophrenia patients (N=114) and healthy controls (N=120). In the results of factor analyses on patients, the multifactorial-6-factor model, which included the speed of processing, working memory, verbal learning and memory, visual learning and memory, attention/vigilance, and reasoning/problem solving as suggested by the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS), showed the better goodness of fit than any of the other models tested. And assessing the group differences of factor scores, we found the patients performed worse than the controls in all factors, but the result showed meaningful variations of impairments across the cognitive factors. Our study identifies the six major domains with multifactorial structure of cognitive abilities in schizophrenia patients and confirms the distinctive impairment patterns of each cognitive domain. These results may have utility in better understanding the pathology of schizophrenia as well as in genetic studies.