Ciliogenesis is Not Directly Regulated by LRRK2 Kinase Activity in Neurons

Mutations in the Leucine-rich repeat kinase 2 (LRRK2 ) gene are the most prevalent cause of familial Parkinson’s disease (PD). The increase in LRRK2 kinase activity observed in the pathogenic G2019S mutation is important for PD development. Several studies have reported that increased LRRK2 kinase activity and treatment with LRRK2 kinase inhibitors decreased and increased ciliogenesis, respectively, in mouse embryonic fibroblasts (MEFs) and retinal pigment epithelium (RPE) cells. In contrast, treatment of SH-SY5Y dopaminergic neuronal cells with PD-causing chemicals increased ciliogenesis. Because these reports were somewhat contradictory, we tested the effect of LRRK2 kinase activity on ciliogenesis in neurons. In SH-SY5Y cells, LRRK2 inhibitor treatment slightly increased ciliogenesis, but serum starvation showed no increase. In rat primary neurons, LRRK2 inhibitor treatment repeatedly showed no significant change. Little difference was observed between primary cortical neurons prepared from wild-type (WT) and G2019S +/- mice. However, a significant increase in ciliogenesis was observed in G2019S +/- compared to WT human fibroblasts, and this pattern was maintained in neural stem cells (NSCs) differentiated from the induced pluripotent stem cells (iPSCs) prepared from the same WT/G2019S fibroblast pair. NSCs differentiated from G2019S and its gene-corrected WT counterpart iPSCs were also used to test ciliogenesis in an isogenic background. The results showed no significant difference between WT and G2019S regardless of kinase inhibitor treatment and B27-deprivation-mimicking serum starvation. These results suggest that LRRK2 kinase activity may be not a direct regulator of ciliogenesis and ciliogenesis varies depending upon the cell type or genetic background.

Ciliogenesis is Not Directly Regulated by LRRK2 Kinase Activity in Neurons

Mutations in the Leucine-rich repeat kinase 2 (LRRK2 ) gene are the most prevalent cause of familial Parkinson’s disease (PD). The increase in LRRK2 kinase activity observed in the pathogenic G2019S mutation is important for PD development. Several studies have reported that increased LRRK2 kinase activity and treatment with LRRK2 kinase inhibitors decreased and increased ciliogenesis, respectively, in mouse embryonic fibroblasts (MEFs) and retinal pigment epithelium (RPE) cells. In contrast, treatment of SH-SY5Y dopaminergic neuronal cells with PD-causing chemicals increased ciliogenesis. Because these reports were somewhat contradictory, we tested the effect of LRRK2 kinase activity on ciliogenesis in neurons. In SH-SY5Y cells, LRRK2 inhibitor treatment slightly increased ciliogenesis, but serum starvation showed no increase. In rat primary neurons, LRRK2 inhibitor treatment repeatedly showed no significant change. Little difference was observed between primary cortical neurons prepared from wild-type (WT) and G2019S +/- mice. However, a significant increase in ciliogenesis was observed in G2019S +/- compared to WT human fibroblasts, and this pattern was maintained in neural stem cells (NSCs) differentiated from the induced pluripotent stem cells (iPSCs) prepared from the same WT/G2019S fibroblast pair. NSCs differentiated from G2019S and its gene-corrected WT counterpart iPSCs were also used to test ciliogenesis in an isogenic background. The results showed no significant difference between WT and G2019S regardless of kinase inhibitor treatment and B27-deprivation-mimicking serum starvation. These results suggest that LRRK2 kinase activity may be not a direct regulator of ciliogenesis and ciliogenesis varies depending upon the cell type or genetic background.

Toluene Inhalation Causes Early Anxiety and Delayed Depression with Regulation of Dopamine Turnover, 5-HT1A Receptor, and Adult Neurogenesis in Mice

Inhaled solvents such as toluene are of particular concern due to their abuse potential that is easily exposed to the environment. The inhalation of toluene causes various behavioral problems, but, the effect of short-term exposure of toluene on changes in emotional behaviors over time after exposure and the accompanying pathological characteristics have not been fully identified. Here, we evaluated the behavioral and neurochemical changes observed over time in mice that inhaled toluene. The mice were exposed to toluene for 30 min at a concentration of either 500 or 2,000 ppm. Toluene did not cause social or motor dysfunction in mice. However, increased anxiety-like behavior was detected in the short-term after exposure, and depression-like behavior appeared as delayed effects. The amount of striatal dopamine metabolites was significantly decreased by toluene, which continued to be seen for up to almost two weeks after inhalation. Additionally, an upregulation of serotonin 1A (5-HT1A) receptor in the hippocampus and the substantia nigra, as well as reduced immunoreactivity of neurogenesis markers in the dentate gyrus, was observed in the mice after two weeks. These results suggest that toluene inhalation, even single exposure, mimics early anxietyand delayed depression-like emotional disturbances, underpinned by pathological changes in the brain.

Retrospective study of combination chemotherapy with etoposide and ifosfamide in patients with heavily pretreated recurrent or persistent epithelial ovarian cancer

OBJECTIVE: This retrospective study is to evaluate the efficacy and toxicity of combination chemotherapy with etoposide and ifosfamide (ETI) in the management of pretreated recurrent or persistent epithelial ovarian cancer (EOC). METHODS: Patients with recurrent or persistent EOC who had measurable disease and at least one chemotherapy regimen were to receive etoposide at a dose of 100 mg/m²/day intravenous (IV) on days 1 to 3 in combination with ifosfamide 1 g/m²/day IV on days 1 to 5, every 21 days. RESULTS: From August 2008 to August 2016, 66 patients were treated with ETI regimen. Most patients were heavily pretreated prior to ETI: 53 (80.3%) patients had received 3 or more chemotherapy regimens. The response rate (RR) of ETI chemotherapy was 18.2% and median duration of response was 6.8 months (range, 0–30). Median survival of all patients was 5 months at a median follow up of 7.2 months. Platinum-free interval (PFI) more than 6 months prior to ETI has statistically significant correlation with overall survival (OS; 9.2 vs. 5.6 months; P=0.029) and RR (34.5% vs. 5.4%; P < 0.010). However, treatment free interval before ETI, number of prior chemotherapy regimen, and optimality of primary surgery did not show significant difference for RR or OS. Grade 3 or 4 hematologic toxicities were observed in 7 cases (3%) of the 232 cycles of ETI. CONCLUSION: The ETI combination regimen shows comparatively low toxicity and modest activity in heavily pretreated recurrent or persistent EOC patients with more than 6 months of PFI after last platinum treatment.

Molecular Signature for Lymphatic Invasion Associated with Survival of Epithelial Ovarian Cancer / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: We aimed to develop molecular classifier that can predict lymphatic invasion and their clinical significance in epithelial ovarian cancer (EOC) patients. MATERIALS AND METHODS: We analyzed gene expression (mRNA, methylated DNA) in data from The Cancer Genome Atlas. To identify molecular signatures for lymphatic invasion, we found differentially expressed genes. The performance of classifier was validated by receiver operating characteristics analysis, logistic regression, linear discriminant analysis (LDA), and support vector machine (SVM). We assessed prognostic role of classifier using random survival forest (RSF) model and pathway deregulation score (PDS). For external validation, we analyzed microarray data from 26 EOC samples of Samsung Medical Center and curatedOvarianData database. RESULTS: We identified 21 mRNAs, and seven methylated DNAs from primary EOC tissues that predicted lymphatic invasion and created prognostic models. The classifier predicted lymphatic invasion well, which was validated by logistic regression, LDA, and SVM algorithm (C-index of 0.90, 0.71, and 0.74 for mRNA and C-index of 0.64, 0.68, and 0.69 for DNA methylation). Using RSF model, incorporating molecular data with clinical variables improved prediction of progression-free survival compared with using only clinical variables (p < 0.001 and p=0.008). Similarly, PDS enabled us to classify patients into high-risk and low-risk group, which resulted in survival difference in mRNA profiles (log-rank p-value=0.011). In external validation, gene signature was well correlated with prediction of lymphatic invasion and patients' survival. CONCLUSION: Molecular signature model predicting lymphatic invasion was well performed and also associated with survival of EOC patients.

Predictors of Acute Postoperative Urinary Retention after Transvaginal Uterosacral Suspension Surgery

OBJECTIVES: To investigate the rate of postoperative urinary retention (POUR) and identify the risk factors for this complication in women who underwent transvaginal uterosacral suspension surgery. METHODS: A retrospective chart review was conducted for 75 women who underwent transvaginal uterosacral suspension surgery with vaginal hysterectomy, repair of cystocele, and levator myorrhaphy with/without transobturator anti-incontinence surgery. POUR was defined as a need for continuous intermittent catheterization on the third day subsequent to removal of the urethral indwelling catheter. RESULTS: Acute POUR was reported in 18 women (24.0%). Thirty-six of the 75 patients (48.0%) had undergone anti-incontinence surgery. Crude analysis revealed significant association between the following variables and the risk of POUR: hypertension, the lower average flow rate in the pressure-flow study (PFS), greater post-void residual (PVR) urine volume in PFS, and PVR >30% of the total bladder capacity (TBC) in PFS. In the logistic regression analysis, PVR >30% of the TBC in PFS was identified as the only significant predictor of POUR (odds ratio, 15.4; 95% confidence interval, 2.5–90.9; P = 0.003). CONCLUSIONS: The PVR >30% of the TBC in PFS was identified as the only predictive factor of acute POUR in women who underwent transvaginal uterosacral suspension surgery.

Acute kidney injury in childhood-onset nephrotic syndrome: Incidence and risk factors in hospitalized patients

BACKGROUND: Nephrotic syndrome (NS) is the most common glomerulopathy in children. Acute kidney injury (AKI) is a common complication of NS, caused by severe intravascular volume depletion, acute tubular necrosis, interstitial nephritis, or progression of NS. However, the incidence and risk factors of childhood-onset NS in Korea are unclear. Therefore, we studied the incidence, causes, and risk factors of AKI in hospitalized Korean patients with childhood-onset NS. METHODS: We conducted a retrospective review of patients with childhood-onset NS who were admitted to our center from January 2015 to July 2017. Patients with decreased renal function or hereditary/secondary NS, as well as those admitted for management of other conditions unrelated to NS, were excluded. RESULTS: During the study period, 65 patients with idiopathic, childhood-onset NS were hospitalized 90 times for management of NS or its complications. Of these 90 cases, 29 met the Kidney Disease Improving Global Outcomes criteria for AKI (32.2%). They developed AKI in association with infection (n = 12), NS aggravation (n = 11), dehydration (n = 3), and intravenous methylprednisolone administration (n = 3). Age ≥ 9 years at admission and combined use of cyclosporine and renin-angiotensin system inhibitors were risk factors for AKI. CONCLUSION: AKI occurred in one-third of the total hospitalizations related to childhood-onset NS, owing to infection, aggravation of NS, dehydration, and possibly high-dose methylprednisolone treatment. Age at admission and use of nephrotoxic agents were associated with AKI. As the AKI incidence is high, AKI should be considered during management of high-risk patients.

Long-term repeated rituximab treatment for childhood steroid-dependent nephrotic syndrome

BACKGROUND: Rituximab (RTX) can be used as a rescue therapy for steroid-dependent nephrotic syndrome (SDNS). However, the efficacy and safety of long-term, repeated use of RTX are not established. This study was conducted to assess the efficacy and safety of long-term, repeated RTX treatment in children. METHODS: Eighteen consecutive child patients with SDNS who were treated with three or more cycles of RTX for one year or longer were recruited, and their medical records were retrospectively reviewed. RESULTS: The patients were followed for 4.7 ± 1.9 years and received 5.2 ± 2.3 cycles of RTX over 2.8 ± 1.1 years. Approximately 70% of the additional RTX cycles were administered due to recovery of B-cells without relapse. The relapse rate decreased from 3.4 ± 2.0 per year initially to 0.4 ± 0.8 per year at the third year after RTX treatment. Approximately 10% of the RTX infusions were accompanied by mild infusion reactions. Eight patients showed sustained remission without any oral medication after the last cycle of RTX, while 10 patients had one or more episodes of relapse after the last cycle of RTX. The relapse rate in the latter group decreased from 2.8 ± 1.5 per year before RTX treatment to 1.3 ± 0.8 per year after cessation of RTX treatment. No significant differences in clinical parameters were found between the two groups. CONCLUSION: This retrospective study showed that pre-emptive and long-term, repeated RTX treatment is relatively effective and safe in children with SDNS. However, well-designed prospective studies are needed to confirm these findings.

Measurement of Fluid Status Using Bioimpedance Methods in Korean Pediatric Patients on Hemodialysis

Adequate fluid management is an important therapeutic goal of dialysis. Recently, bioelectrical impedance methods have been used to determine body fluid status, but pediatric reports are rare. To determine the accuracy of bioelectrical impedance methods in the assessment of body fluid statusof children undergoing hemodialysis (HD), 12 children on HD were studied. A multi-frequency bioimpedance analysis device (Inbody S10) and bioimpedance spectroscopy device (BCM) were used to evaluate fluid status. Fluid removal during a HD session (assessed as body-weight change, ΔBWt) was compared with the difference in total body water determined by each device (measured fluid difference, ΔMF), which showed strong correlation using either method (Pearson's coefficient, r = 0.772 with Inbody S10 vs. 0.799 with BCM). Bioimpedance measurement indicated fluid overload (FO; ΔHS greater than 7%) in 34.8% with Inbody S10 and 56.5% with BCM, and only about 60% of children with FO by bioimpedance methods showed clinical symptoms such as hypertension and edema. In some patients with larger weight gain Inbody S10-assessed overhydration (OH) was much smaller than BCM-assessed OH, suggesting that BCM is more relevant in estimating fluid accumulation amount than Inbody S10. To our knowledge, this is the first report on the use of body composition monitors to assess fluid status in Korean children receiving HD.

Nomograms Predicting Platinum Sensitivity, Progression-Free Survival, and Overall Survival Using Pretreatment Complete Blood Cell Counts in Epithelial Ovarian Cancer / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: This study was conducted to evaluate the prognostic significance of pre-treatment complete blood cell count (CBC), including white blood cell (WBC) differential, in epithelial ovarian cancer (EOC) patients with primary debulking surgery (PDS) and to develop nomograms for platinum sensitivity, progression-free survival (PFS), and overall survival (OS). MATERIALS AND METHODS: We retrospectively reviewed the records of 757 patients with EOC whose primary treatment consisted of surgical debulking and chemotherapy at Samsung Medical Center from 2002 to 2012. We subsequently created nomograms for platinum sensitivity, 3-year PFS, and 5-year OS as prediction models for prognostic variables including age, stage, grade, cancer antigen 125 level, residual disease after PDS, and pre-treatment WBC differential counts. The models were then validated by 10-fold cross-validation (CV). RESULTS: In addition to stage and residual disease after PDS, which are known predictors, lymphocyte and monocyte count were found to be significant prognostic factors for platinum-sensitivity, platelet count for PFS, and neutrophil count for OS on multivariate analysis. The area under the curves of platinum sensitivity, 3-year PFS, and 5-year OS calculated by the 10-fold CV procedure were 0.7405, 0.8159, and 0.815, respectively. CONCLUSION: Prognostic factors including pre-treatment CBC were used to develop nomograms for platinum sensitivity, 3-year PFS, and 5-year OS of patients with EOC. These nomograms can be used to better estimate individual outcomes.

Time-lapse imaging of sentinel lymph node using indocyanine green with near-infrared fluorescence imaging in early endometrial cancer / 부인종양

OBJECTIVE: Indocyanine green with near-infrared fluorescence imaging (NIR-ICG) is a new tracer modality in the limelight used for lymphatic mapping. The advantage of this method is to provide real-time image during surgery. To use ICG for image guided lymph node dissection, a surgeon needs to know initial appearing time and duration. METHODS: A 52-year-old woman undertook surgery diagnosed with endometrial cancer. She had no past medical history and her body mass index was 25.3 kg/m2. Preoperative magnetic resonance imaging examination revealed 2.7 cm sized cancerous mass in the endometrial cavity with superficial myometrial invasion without lymph node enlargement. Four mL (1.25 mg/mL) of ICG solution was prepared for injection. For each site, 1 mL of solution was injected superficially, 2-3 mm into the cervical submucosa and another 1 mL was injected deep, 1-2 cm into the stroma of the cervix. We recorded video with 30° 10 mm scope equipped with a specific lens and light source emitting both visible and NIR light (KARL STORZ GmbH & Co. KG, Tuttlingen, Germany). RESULTS: Pelvic lymph node was visualized from around 5 minutes. ICG was dispersed into organs after hysterectomy (53 minutes after ICG injection), yet we could clearly identify sentinel lymph node (SLN). Pathology revealed endometriod adenocarcinoma grade I, myometrial invasion with less than half of myometrium and no lymph node metastasis. CONCLUSION: Cervical injection of ICG provides good visualization of SLN from 5 minutes to over an hour. Our film gives an idea about time management to make a plan for surgery and not to miss SNLs.

Nutritional Factors Affecting Mental Health

Dietary intake and nutritional status of individuals are important factors affecting mental health and the development of psychiatric disorders. Majority of scientific evidence relating to mental health focuses on depression, cognitive function, and dementia, and limited evidence is available about other psychiatric disorders including schizophrenia. As life span of human being is increasing, the more the prevalence of mental disorders is, the more attention rises. Lists of suggested nutritional components that may be beneficial for mental health are omega-3 fatty acids, phospholipids, cholesterol, niacin, folate, vitamin B6, and vitamin B12. Saturated fat and simple sugar are considered detrimental to cognitive function. Evidence on the effect of cholesterol is conflicting; however, in general, blood cholesterol levels are negatively associated with the risk of depression. Collectively, the aims of this review are to introduce known nutritional factors for mental health, and to discuss recent issues of the nutritional impact on cognitive function and healthy brain aging.

Development and Validation of the Korean Version of Hand-Foot Skin Reaction and Quality of Life Questionnaire (HF-QoL-K)

Given the growing number of cancer patients and the resulting increase in the administration of chemotherapeutic agents, convenient and effective methods for measuring the symptoms and quality of life associated with the hand-foot syndrome (HFS) are needed. Therefore, the aim of this study was to develop and validate the Korean version of the hand-foot skin reaction and quality of life questionnaire (HF-QoL-K), comprising a 20-item symptom domain and an 18-item daily activity domain. After we developed the HF-QoL-K, 209 Korean patients with gynecologic cancer who were undergoing chemotherapeutic agents relating the HFS were asked to fill in the questionnaire. The content validity, internal consistency reliability, and test-retest reliability were evaluated. The internal validity index, Cronbach’s alpha coefficient, and intra-class correlation coefficient of the HF-QoL-K were 0.90, 0.958, and 0.825 (95% confidence interval [CI], 0.774–0.865), respectively. The scatter plot (Pearson correlation coefficient, 0.826) and the Bland-Altman plot for test-retest reliability were also acceptable. The HF-QoL-K instrument is a valid and reliable questionnaire for the measurement of the symptoms and quality of life in Korean cancer patients suffering HFS.

Long-term outcomes of magnetic resonance imaging-invisible endometrial cancer / 부인종양

OBJECTIVE: Magnetic resonance imaging (MRI) is useful for staging endometrial cancer. The treatment and prognosis of MRI-invisible endometrial cancer remain unclear. The purpose of this study was to retrospectively evaluate the long-term outcomes of patients with MRI-invisible endometrial cancer. METHODS: Between February 1995 and December 2011, we reviewed the medical records of 433 patients with endometrial cancer, which was staged IA on MRI. Of these patients, 89 had MRI-invisible cancer and 344 had MRI-visible cancer. Both cancers were treated with simple hysterectomy with or without lymph node dissection according to the surgeon's decision. Both cancers were compared regarding pathologic findings, recurrence rates, and survival rates. RESULTS: The median sizes of MRI-invisible and MRI-visible cancers were 4 mm (0 to 40 mm) and 20 mm (0 to 89 mm), respectively (p<0.001). Myometrial invasion of these groups were detected in 20.2% (18/89) and 56.7% (195/344), respectively (p<0.001). Lymphadenectomy and follow-up imaging revealed no lymph node metastasis in patients with MRI-invisible cancers, while those revealed in 4.7% (16/344) of patients with MRI-visible cancers (p=0.052). The recurrence rates of MRI-invisible and MRI-visible cancers were 1.1% (1/89) and 7.8% (27/344), respectively (p=0.026). The recurrence-free survival rates of these groups were 98.9% (88/89) and 91.6% (315/344), respectively (p=0.022). CONCLUSION: MRI-invisible endometrial cancer can be treated with less invasive surgery because of its lower tumor burden and better prognosis. This cancer may not require lymphadenectomy because of no metastasis or recurrence in lymph nodes.

Long-term outcomes of magnetic resonance imaging-invisible endometrial cancer / 부인종양

OBJECTIVE: Magnetic resonance imaging (MRI) is useful for staging endometrial cancer. The treatment and prognosis of MRI-invisible endometrial cancer remain unclear. The purpose of this study was to retrospectively evaluate the long-term outcomes of patients with MRI-invisible endometrial cancer. METHODS: Between February 1995 and December 2011, we reviewed the medical records of 433 patients with endometrial cancer, which was staged IA on MRI. Of these patients, 89 had MRI-invisible cancer and 344 had MRI-visible cancer. Both cancers were treated with simple hysterectomy with or without lymph node dissection according to the surgeon's decision. Both cancers were compared regarding pathologic findings, recurrence rates, and survival rates. RESULTS: The median sizes of MRI-invisible and MRI-visible cancers were 4 mm (0 to 40 mm) and 20 mm (0 to 89 mm), respectively (p<0.001). Myometrial invasion of these groups were detected in 20.2% (18/89) and 56.7% (195/344), respectively (p<0.001). Lymphadenectomy and follow-up imaging revealed no lymph node metastasis in patients with MRI-invisible cancers, while those revealed in 4.7% (16/344) of patients with MRI-visible cancers (p=0.052). The recurrence rates of MRI-invisible and MRI-visible cancers were 1.1% (1/89) and 7.8% (27/344), respectively (p=0.026). The recurrence-free survival rates of these groups were 98.9% (88/89) and 91.6% (315/344), respectively (p=0.022). CONCLUSION: MRI-invisible endometrial cancer can be treated with less invasive surgery because of its lower tumor burden and better prognosis. This cancer may not require lymphadenectomy because of no metastasis or recurrence in lymph nodes.

The Relationships among Quality of Life and Stress, Health-related Habits and Food Intake in Korean Healthy Adults Based on 2013 Korea National Health and Nutrition Examination Survey / 대한지역사회영양학회지

OBJECTIVES: This study investigated the socioeconomic factors that affect quality of life (QL) in healthy adults and to study the relationship between QL and health-related habits and food intake. METHODS: Subjects consisted of 1,154 healthy adults without any known disease, aged 19 to 65 years from the 2013 Korean National Health and Nutrition Examination Survey data. We used SPSS statistical program version 20.0 for data analysis. RESULTS: The average age and QL score of the study population were 36.7 years and 0.99 points, respectively. Males had a significantly higher QL score than the females (p < 0.001), and employed subjects and those employed in permanent positions had significantly higher scores as compared respectively with unemployed subjects and those employed in temporary positions (p < 0.001, p < 0.05). The group that responded "almost every day" to the "frequency of binge drinking" and "frequency of disruption of daily life due to drinking" had significantly lower QL scores as compared to other groups (p < 0.05). Further, the scores were significantly higher for individuals who practiced "intense physical activities" and "walking" (p < 0.001). The groups that responded that they were "very stressed" showed significantly lower QL scores in comparison to the other groups (p < 0.05). There were no significant differences in QL scores according to anthropometric or biochemical indices. When subjects were divided into two groups based on average QL scores, the frequency of intake of "barbecued beef" was significantly higher while the frequency of intake of "fried eggs or rolled omelet," and "soy milk" was significantly lower in the high QL group. CONCLUSIONS: Based on these findings, it is evident that in healthy adults without any known underlying illnesses, psychological factors such as economic activity, occupational environment, and stress are considered to have a greater impact on their QL than are nutrient intake, blood biochemical indices, and anthropometric status.

Shiga toxin-associated hemolytic uremic syndrome complicated by intestinal perforation in a child with typical hemolytic uremic syndrome / 소아과

Hemolytic uremic syndrome (HUS) is one of the most common causes of acute renal failure in childhood and is primarily diagnosed in up to 4.5% of children who undergo chronic renal replacement therapy. Escherichia coli serotype O157:H7 is the predominant bacterial strain identified in patients with HUS; more than 100 types of Shiga toxin-producing enterohemorrhagic E. coli (EHEC) subtypes have also been isolated. The typical HUS manifestations are microangiopathic hemolytic anemia, thrombocytopenia, and renal insufficiency. In typical HUS cases, more serious EHEC manifestations include severe hemorrhagic colitis, bowel necrosis and perforation, rectal prolapse, peritonitis, and intussusceptions. Colonic perforation, which has an incidence of 1%-2%, can be a fatal complication. In this study, we report a typical Shiga toxin-associated HUS case complicated by small intestinal perforation with refractory peritonitis that was possibly because of ischemic enteritis. Although the degree of renal damage is the main concern in HUS, extrarenal complications should also be considered in severe cases, as presented in our case.

The burden of illness for meconium aspiration syndrome and cost prediction related to surfactant therapy for meconium aspiration syndrome in Korea

Meconium aspiration syndrome (MAS) is an important cause of respiratory distress in neonates. Surfactant therapy has been used to improve oxygenation for infants with MAS recently. The object of this study is to estimate the number of candidates for surfactant use in MAS and the cost for surfactant, and to analyze its cost-effectiveness in Korea. Using Korean Health Insurance Review and Assessment Service reimbursement data, the number of neonates with a diagnosis of MAS receiving mechanical ventilation was counted. The annual cost for surfactant use was calculated using the number of patients receiving mechanical ventilation for at least three days who were considered potential candidates for surfactant use. The cost-effectiveness was evaluated using the effectiveness data from a previous meta-analysis. Infants with a diagnosis of MAS receiving mechanical ventilation were 0.92 per 1,000 live births annually. Among them, 55% were potential candidates for surfactant use. The expected annual cost for surfactant was 990 million Korean won and 500 million Korean won and the number needed to treat was 14.3 and 6.7 in surfactant bolus therapy and surfactant lavage therapy, respectively. Sixty-four million won was estimated as the cost to prevent one infant death by surfactant bolus therapy and 15 million won by surfactant lavage therapy. The surfactant therapy for MAS is presently not covered by the Korean national health insurance and its application to MAS is limited because of the high financial burden to the patients' family. This study's results could help healthcare decision makers establish a policy in the future.

The Effect on Pulmonary Indices of Surfactant Therapy for Meconium Aspiration Syndrome: Systematic Review and Meta-analysis

PURPOSE: Surfactants have been used to improve oxygenation for infants with meconium aspiration syndrome (MAS). We evaluated the change of pulmonary indices after surfactant therapy for MAS through a systematic meta-analysis. METHODS: Relevant randomized controlled studies (RCTs) were identified by database searches in MEDLINE, EMBASE, and CENTRAL, up to June 2011, and by additional hand searches. Data were extracted regarding pulmonary indices, such as the oxygen index and arterial alveolar oxygen gradient. Meta-analyses were separately conducted for the studies of surfactant lavage therapy and surfactant bolus therapy. The risk of bias was assessed, and clinical as well as statistical heterogeneities were also investigated. RESULTS: Two RCTs for bolus surfactant therapy and two RCTs for surfactant lavage therapy were identified. The oxygenation index results were heterogeneous between the two studies in which bolus surfactant therapy was given, while a/A PO2 showed significantly better results in the treatment group over time after use of surfactant (12 hours: WMD 0.08, 95% CI 0.04-0.12; 24 hours: WMD 0.17, 95% CI 0.06-0.28). For surfactant lavage therapy, both studies consistently suggested an interventional benefit in terms of the pulmonary indices although it did not reach statistical significance. CONCLUSION: Surfactant therapy appeared to improve oxygenation of infants with MAS. Since a limited number of RCTs are available in the current literature and those studies were also clinically heterogeneous in terms of illness severity and the method of surfactant use, further research is needed to gather evidence to support surfactant therapy in MAS.

Inactivation of Aconitase by Tetrahydrobiopterin in DArgic Cells: Relevance to PD

Oxidative damage is thought to be a major cause of the progression of dopamine (DA)rgic neurodegeneration as in Parkinson's disease. We have previously reported that tetrahydrobiopterin (BH4), an endogenous molecule required for DA synthesis, exerts oxidative stress to DA-producing cells and facilitates the production of DA quinone. It is known that aconitase, present in both mitochondrial and cytosolic forms, act as an reactive oxygen species (ROS) sensor, and that their inactivation leads to further generation of ROS. In the present study we investigated whether the BH4-associated vulnerability of DA cells might involve aconitase. In DArgic cell line CATH.a, BH4 treatment caused reduction of activity of both mitochondrial and cytosolic aconitases, and this appeared to be due to direct inactivation of the pre-existing enzyme molecules. Although most of the activity reduced by BH4 was increased upon reactivation reaction under a reducing condition, the restoration was not complete, suggesting that irreversible and covalent modification has occurred. The aconitase inactivation was exacerbated in the presence of DA and attenuated in the presence of tyrosine hydroxylase inhibitor a-methyl-p-tyrosine, suggesting the involvement of DA. The degree of inactivation increased when the cells were treated with the quinone reductase inhibitor dicoumarol and decreased in the presence of quinone reductase inducer sulforaphane. Taken together, BH4 appeared to lead to both reversible and irreversible inactivation of aconitase and that this is facilitated by the presence of DA and accumulation of DA quinone.