Therapeutic time window for the effects of erythropoietin on astrogliosis and neurite outgrowth in an in vitro model of spinal cord injury

Hong, Hea Nam,Shim, Ju Hee,Won, You Jin,Yoo, Jong Yoon,Hwang, Chang Ho Williams & Wilkins Co 2018 Medicine Vol.97 No.9

<P>Background:The objective of this study was to investigate the underlying molecular mechanisms and the therapeutic time window for preventing astrogliosis with erythropoietin (EPO) treatment after in vitro modeled spinal cord injury (SCI).Methods:Cultured rat spinal cord astrocytes were treated with kainate and scratching to generate an in vitro model of SCI. EPO (100U/mL or 300U/mL) was added immediately or 2, 4, or 8 hours after injury. Some cultures were also treated with AG490, an inhibitor of the EPO-EPO receptor (EpoR) pathway mediator Janus kinase 2 (JAK2). To evaluate neurite extension, rat embryonic spinal cord neurons were seeded onto astrocyte cultures and treated with EPO immediately after injury in the presence or absence of anti-EpoR antibody.Results:EPO treatment at up to 8 hours after injury reduced the expression of axonal growth inhibiting molecules (glial fibrillary acidic protein, vimentin, and chondroitin sulfate proteoglycan), cytoskeletal regulatory proteins (Rho-associated protein kinase and ephephrin A4), and proinflammatory cytokines (tumor necrosis factor-alpha, transforming growth factor-beta, and phosphorylated-Smad3) in a dosedependent manner (P<.001). Most effects peaked with EPO treatment 2-4hours after injury. Additionally, EPO treatment up to 4 hours after injury promoted expression of the EpoR (>2-fold) and JAK2 (>3-fold) in a dose-dependent manner (P<.001), whereas co-treatment with AG490 precluded these effects (P<.001). EPO treatment up to 4hours after injury also enhanced axonal b-III tubulin-immunoreactivity (>12-fold), and this effect was precluded by co-treatment with an anti-EpoR antibody (P<.001).Conclusions:EPO treatment within 8 hours after injury reduced astrogliosis, and EPO treatment within 4 hours promoted neurite outgrowth. EPO therapy immediately after spinal cord injury may regulate glia to generate an environment permissive of axonal regeneration.</P>

Assessment of cytomegalovirus and cell-mediated immunity for predicting outcomes in non-HIV-infected patients with <i>Pneumocystis jirovecii</i> pneumonia

Kim, Taeeun,Park, Se Yoon,Lee, Hyun-Jung,Kim, Sun-Mi,Sung, Heungsup,Chong, Yong Pil,Lee, Sang-Oh,Choi, Sang-Ho,Kim, Yang Soo,Woo, Jun Hee,Kim, Sung-Han Williams & Wilkins Co 2017 Medicine Vol.96 No.30

<▼1><P>Supplemental Digital Content is available in the text</P></▼1><▼2><P><B>Abstract</B></P><P>The clinical importance of pulmonary cytomegalovirus (CMV) co-infection in patients with <I>Pneumocystis jirovecii</I> pneumonia (PCP) is uncertain. We therefore determined the association of CMV infection with outcomes in non-HIV-infected patients with PCP by assessing CMV viral load and CMV-specific T-cell response.</P><P>We prospectively enrolled all non-HIV-infected patients with confirmed PCP, over a 2-year period. Real-time polymerase chain reaction from bronchoalveolar lavage was performed to measure CMV viral load, and CMV enzyme-linked immunospot assays of peripheral blood were used to measure CMV-specific T-cell responses. The primary outcome was 30-day mortality.</P><P>A total of 76 patients were finally analyzed. The mortality in patients with high BAL CMV viral load (>2.52 log copies/mL, 6/32 [18%]) showed a nonsignificant trend to be higher than in those with low CMV viral load (2/44 [5%], <I>P</I> = .13). However, the mortality in patients with low CMV-specific T-cell responses (<5 spots/2.0 × 10<SUP>5</SUP> PBMC, 6/29 [21%]) was significantly higher than in patients with high CMV-specific T-cell response (2/47 [4%], <I>P</I> = .048). Moreover, the 2 strata with high CMV viral load and low CMV-specific T-cell responses (4/14 [29%]) and low CMV viral load and low CMV-specific T-cell responses (2/15 [13%]) had poorer outcomes than the 2 strata with high CMV viral load and high CMV-specific T-cell responses (2/18 [11%]) and low CMV viral load and high CMV-specific T-cell responses (0/29 [0%]).</P><P>These data suggest that the CMV replication and impaired CMV-specific T-cell responses adversely affect the outcomes in non-HIV-infected patients with PCP.</P></▼2>

Upregulation of Vanilloid Receptor-1 in Functional Dyspepsia With or Without Helicobacter pylori Infection

Choi, Yoon Jin,Kim, Nayoung,Kim, Jinjoo,Lee, Dong Ho,Park, Ji Hyun,Jung, Hyun Chae Williams & Wilkins Co 2016 Medicine Vol.95 No.19

<P>The etiological basis of functional dyspepsia (FD) is incompletely understood. The aim of this study was to evaluate the involvement of nociceptor-related genes and Helicobacter pylori (HP) in the pathogenesis of FD. The expression of nociceptor-related genes was measured in gastric cell lines that were co-cultured with HP. FD patients (n=117) and controls (n=55) were enrolled from a tertiary hospital gastroenterology clinic. Expression of the genes nerve growth factor (NGF), glial cell line-derived neurotrophic factor (GDNF), and transient receptor potential cation channel subfamily V member 1 (TRPV1) in the gastric mucosa were detected by reverse transcription polymerase chain reaction (RT-PCR), and immunohistochemical staining of TRPV1 was analyzed. These measurements were repeated after 1 year. TRPV1, GDNF, and NGF expression was elevated in gastric cell lines co-cultured with HP. TRPV1 immunostaining was stronger in HP-positive than HP-negative subjects. The FD group showed higher expression levels of TRPV1, GDNF, and NGF and increased TRPV1 immunostaining compared with those of the control group (all P<0.05). Among 61 subjects who were followed up at 1 year, controls with successful HP eradication and patients whose symptoms had improved both showed significant reductions in the expression of TRPV1 and NGF (all P<0.05) compared with controls without HP eradication and patients whose symptoms had not improved, respectively. The expression of NGF, GDNF, and TRPV1 may be associated with the pathogenesis of FD. Since HP infection may induce the increased expression of these genes, anti-HP therapy could be beneficial for HP-positive patients with FD.</P>

Clinicopathological features of diabetic and nondiabetic renal diseases in type 2 diabetic patients with nephrotic-range proteinuria

Lee, Yu Ho,Kim, Ki-Pyo,Kim, Yang Gyun,Moon, Ju-Young,Jung, Su Woong,Park, Eunji,Kim, Jin Sug,Jeong, Kyung-Hwan,Lee, Tae Won,Ihm, Chun-Gyoo,Jo, Young-Il,Choi, Hoon-Young,Park, Hyeong-Cheon,Lee, So-Youn Williams & Wilkins Co 2017 Medicine Vol.96 No.36

<▼1><P>Supplemental Digital Content is available in the text</P></▼1><▼2><P><B>Abstract</B></P><P>Heavy proteinuria with or without features of nephrotic syndrome is associated with many primary and systemic diseases. For diabetic patients, distinguishing nondiabetic renal disease (NDRD) from diabetic nephropathy (DN) is important in choosing treatment modalities and determining renal prognosis. However, clinical relevance of heavy proteinuria is inconsistent with clinical DN assessments. This study investigated the clinicopathological features and renal outcomes of DN and NDRD in type 2 diabetic patients with nephrotic-range proteinuria.</P><P>We enrolled 220 cases of type 2 diabetic patients who underwent renal biopsy. They were grouped according to the presence of nephritic-range proteinuria and pathological features. Baseline characteristics, laboratory findings, types of pathological diagnosis, and renal outcomes were analyzed in patients with heavy proteinuria.</P><P>Upon kidney biopsy, 129 patients (58.6%) showed nephritic-range proteinuria. Patients with heavy proteinuria (an average urine protein-to-creatinine ratio of 10,008 ± 7307 mg/gCr) showed lower serum albumin levels and higher total cholesterol levels, but did not show any difference in age, duration of diabetes, renal function, or the presence of retinopathy compared with those with mild-to-moderate proteinuria (an average urine protein-to-creatinine ratio of 1581 ± 979 mg/gCr). Renal biopsy revealed that the prevalence of NDRD was 37.2% in patients with heavy proteinuria, which was significantly lower than that in patients with mild-to-moderate proteinuria (63.7%). The most common pathological types of NDRD were membranous nephropathy (41.7%), IgA nephropathy (14.6%), and minimal change disease (10.4%). NDRD patients showed lower prevalence of diabetic retinopathy and better kidney function irrespective of proteinuria. Immunosuppressive treatment was administered more frequently in patients with heavy proteinuria (56.3%) compared with patients with mild-to-moderate proteinuria (20%) because of the pathological differences according to the amount of proteinuria. Renal outcomes were significantly worse in patients with DN than in patients with NDRD.</P><P>DN patients with heavy proteinuria exhibited different prevalence of NDRD and worse prognosis. Renal biopsy in type 2 diabetic patients should be more extensively considered to accurately diagnose NDRD, guide further management, and predict renal outcomes, especially in patients with nephrotic-range proteinuria.</P></▼2>

Arthroscopic Resection of a Tenosynovial Giant Cell Tumor in the Wrist : A Case Report

Lee, Young-Keun,Han, Youngshin,Lee, Malrey Williams & Wilkins Co 2015 Medicine Vol.94 No.42

<P><B>Abstract</B></P><P>The treatment for giant cell tumors of the tendon sheath is surgical therapy, but surgical recurrence rates were reported to be as high as 50% in some cases. Therefore, complete radical excision of the lesion is the treatment of choice. If the tumor originates from the joint, it is important to perform capsulotomy. Here, the authors report the first case of successful treatment of a localized intra-articular giant cell tumor in the wrist by arthroscopic resection.</P><P>A 28-year-old right-handed woman visited the clinic because of left wrist ulnar-side pain, which had been aggravated during the previous 15 days. Vague ulnar-side wrist pain had begun 2 years ago. When the authors examined the patient, the wrist showed mild swelling on the volo-ulnar aspect and the distal radioulnar joint, as well as volar joint line tenderness. She showed a positive result on the ulnocarpal stress test and displayed limited range of motion. Magnetic resonance imaging revealed an intra-articular mass with synovitis in the ulnocarpal joint. Wrist arthroscopy was performed using standard portals under regional anesthesia. The arthroscopic findings revealed a large, well-encapsulated, yellow lobulated soft-tissue mass that was attached to the volar side of the ulnocarpal ligament and connected to the extra-articular side. The mass was completely excised piece by piece with a grasping forceps. Histopathologic examination revealed that the lesion was an intra-articular localized form of a tenosynovial giant cell tumor.</P><P>At 24-month follow-up, the patient was completely asymptomatic and had full range of motion in her left wrist, and no recurrence was found in magnetic resonance imaging follow-up evaluations.</P><P>The authors suggest that the arthroscopic excision of intra-articular giant cell tumors, as in this case, may be an alternative method to open excisions, with many advantages.</P>

Coadministration of a Na+-H+ exchange inhibitor and sodium bicarbonate for the treatment of asphyxia-induced cardiac arrest in piglets.

Lin, Xinchun,Kraut, Jeffrey A,Wu, Dongmei Williams & Wilkins Co.[etc.] 2014 Pediatric research Vol.76 No.2

<P>The present study tested the hypothesis that addition of an inhibitor of Na(+)/H(+) exchanger (NHE1) to sodium bicarbonate might improve the response to base therapy from prolonged asphyxial cardiac arrest in piglets.</P>

Which Biomarker is the Best for Predicting Mortality in Incident Peritoneal Dialysis Patients: NT-ProBNP, Cardiac TnT, or hsCRP? : A Prospective Observational Study

Oh, Hyung Jung,Lee, Mi Jung,Kwon, Young Eun,Park, Kyoung Sook,Park, Jung Tak,Han, Seung Hyeok,Yoo, Tae-Hyun,Kim, Yong-Lim,Kim, Yon Su,Yang, Chul Woo,Kim, Nam-Ho,Kang, Shin-Wook Williams & Wilkins Co 2015 Medicine Vol.94 No.44

<P><B>Abstract</B></P><P>Although numerous previous studies have explored various biomarkers for their ability to predict mortality in end-stage renal disease (ESRD) patients, these studies have been limited by retrospective analyses, mostly prevalent dialysis patients, and the measurement of only 1 or 2 biomarkers. This prospective study was aimed to evaluate the association between 3 biomarkers and mortality in incident 335 ESRD patients starting continuous ambulatory peritoneal dialysis (CAPD) in Korea. According to the baseline NT-proBNP, cTnT, and hsCRP levels, the patients were stratified into tertiles, and cardiovascular (CV) and all-cause mortalities were compared. Additionally, time-dependent ROC curves were constructed, and the net reclassification index (NRI) and integrated discrimination improvement (IDI) of the models with various biomarkers were calculated. We found the upper tertile of NT-proBNP was significantly associated with increased risk of both CV and all-cause mortalities. However, the upper tertile of hsCRP was significantly related only to the high risk of all-cause mortality even after adjustment for age, sex, and white blood cell counts. Moreover, NT-proBNP had the highest predictive power for CV mortality, whereas hsCRP was the best prognostic marker for all-cause mortality among these biomarkers. In conclusions, NT-proBNP is a more significant prognostic factor for CV mortality than cTnT and hsCRP, whereas hsCRP is a more significant predictor than NT-proBNP and cTnT for all-cause mortality in incident peritoneal dialysis patients.</P>

Factors Associated With Outcomes in Endoscopic Submucosal Dissection of Gastric Cardia Tumors : A Retrospective Observational Study

Jang, Yae Su,Lee, Bong Eun,Kim, Gwang Ha,Park, Do Youn,Jeon, Hye Kyung,Baek, Dong Hoon,Kim, Dong Uk,Song, Geun Am Williams & Wilkins Co 2015 Medicine Vol.94 No.31

<P><B>Abstract</B></P><P>Tumors of the gastric cardia are among the most technically difficult lesions to remove by endoscopic submucosal dissection (ESD). This study aimed to evaluate the therapeutic outcomes of ESD in gastric cardia tumors according to clinicopathologic characteristics, and to assess the predictive factors for incomplete resection.</P><P>We conducted a retrospective observational study of 82 patients with adenomas and early cancers of the gastric cardia who underwent ESD between January 2006 and December 2013 at the Pusan National University Hospital. Therapeutic outcomes of ESD and procedure-related complications were analyzed.</P><P>En bloc resection, complete resection, and curative resection rates were 87%, 79%, and 66%, respectively. Deep submucosal invasion was the most common cause of noncurative resection in the cases in which complete resection was achieved. On multivariate analyses, hemispheric distribution (anterior hemisphere; odds ratio [OR] 4.808) and depth of tumor invasion (submucosal cancer; OR 22.056) were independent factors associated with incomplete resection. The rates of procedure-related bleeding, perforation, and stenosis were 6%, 1%, and 0%, respectively; none of the complications required surgical intervention.</P><P>In conclusion, ESD is a safe, effective, and feasible treatment for gastric cardia tumors. However, the complete resection rate decreases for tumors that are located in the anterior hemisphere or have deep submucosal invasion.</P>

Molecular Etiology of Hereditary Single-Side Deafness : Its Association With Pigmentary Disorders and Waardenburg Syndrome

Kim, Shin Hye,Kim, Ah Reum,Choi, Hyun Seok,Kim, Min Young,Chun, Eun Hi,Oh, Seung-Ha,Choi, Byung Yoon Williams & Wilkins Co 2015 Medicine Vol.94 No.43

<P><B>Abstract</B></P><P>Unilateral sensorineural hearing loss (USNHL)/single-side deafness (SSD) is a frequently encountered disability in children. The etiology of a substantial portion of USNHL/SSD still remains unknown, and genetic causes have not been clearly elucidated. In this study, the authors evaluated the heritability of USNHL/SSD.</P><P>The authors sequentially recruited 50 unrelated children with SSD. For an etiologic diagnosis, we performed a rigorous review on the phenotypes of family members of all children and conducted, if necessary, molecular genetic tests including targeted exome sequencing of 129 deafness genes.</P><P>Among the 50 SSD children cohort, the authors identify 4 (8%) unrelated SSD probands from 4 families (SH136, SB173, SB177, and SB199) with another hearing impaired family members. Notably, all 4 probands in our cohort with a familial history of SSD also have pigmentary abnormalities such as brown freckles or premature gray hair within first degree relatives, which may indicate that genes whose products are involved with pigmentary disorder could be candidates for heritable SSD. Indeed, SH136 and SB199 turned out to segregate a mutation in <I>MITF</I> and <I>PAX3</I>, respectively, leading to a molecular diagnosis of Waardenburg syndrome (WS).</P><P>We report, for the first time in the literature, a significant heritability of pediatric SSD. There is a strong association between the heritability of USNHL/SSD and the pigmentary abnormality, shedding a new light on the understanding of the molecular basis of heritable USNHL/SSD. In case of children with congenital SSD, it would be mandatory to rigorously screen pigmentary abnormalities. WS should also be included in the differential diagnosis of children with USNHL/SSD, especially in a familial form.</P>

GLI1 Transcription Factor Affects Tumor Aggressiveness in Patients With Papillary Thyroid Cancers

Lee, Jandee,Jeong, Seonhyang,Lee, Cho Rok,Ku, Cheol Ryong,Kang, Sang-Wook,Jeong, Jong Ju,Nam, Kee-Hyun,Shin, Dong Yeob,Chung, Woong Youn,Lee, Eun Jig,Jo, Young Suk Williams & Wilkins Co 2015 Medicine Vol.94 No.25

<▼1><P>Supplemental Digital Content is available in the text</P></▼1><▼2><P><B>Abstract</B></P><P>A significant proportion of patients with papillary thyroid cancer (PTC) present with extrathyroidal extension (ETE) and lymph node metastasis (LNM). However, the molecular mechanism of tumor invasiveness in PTC remains to be elucidated.</P><P>The aim of this study is to understand the role of Hedgehog (Hh) signaling in tumor aggressiveness in patients with PTC.</P><P>Subjects were patients who underwent thyroidectomy from 2012 to 2013 in a single institution. Frozen or paraffin-embedded tumor tissues with contralateral-matched normal thyroid tissues were collected. Hh signaling activity was analyzed by quantitative RT-PCR (qRT-PCR) and immunohistochemical (IHC) staining. Datasets from Gene Expression Omnibus (GEO) (National Center for Biotechnology Information) were subjected to Gene Set Enrichment Analysis (GSEA). BRAFT1799A and telomerase reverse transcriptase promoter mutation C228T were analyzed by direct sequencing.</P><P>Among 137 patients with PTC, glioma-associated oncogene homolog 1 (<I>GLI1</I>) group III (patients in whom the ratio of <I>GLI1</I> messenger ribonucleic acid (mRNA) level in tumor tissue to <I>GLI1</I> mRNA level in matched normal tissue was in the upper third of the subject population) had elevated risk for ETE (odds ratio [OR] 4.381, 95% confidence interval [CI] 1.414–13.569, <I>P</I> = 0.01) and LNM (OR 5.627, 95% CI 1.674–18.913, <I>P</I> = 0.005). Glioma-associated oncogene homolog 2 (<I>GLI2</I>) group III also had elevated risk for ETE (OR 4.152, 95% CI 1.292–13.342, <I>P</I> = 0.017) and LNM (OR 3.924, 95% CI 1.097–14.042, <I>P</I> = 0.036). GSEA suggested that higher <I>GLI1</I> expression is associated with expression of the <I>KEGG</I> gene set related to axon guidance (<I>P</I> = 0.031, false discovery rate < 0.05), as verified by qRT-PCR and IHC staining in our subjects.</P><P><I>GLI1</I> and <I>GLI2</I> expressions were clearly related to aggressive clinicopathological features and aberrant activation of GLI1 involved in the axon guidance pathway. These results may contribute to development of new prognostic markers, as well as novel therapeutic targets.</P></▼2>