The Role of Glutamate Underlying Treatment-resistant Depression

The monoamine hypothesis has significantly improved our understanding of mood disorders and their treatment by linking monoaminergic abnormalities to the pathophysiology of mood disorders. Even 50 years after the monoamine hypothesis was established, some patients do not respond to treatments for depression, including selective serotonin reuptake drugs. Accumulating evidence shows that patients with treatment-resistant depression (TRD) have severe abnormalities in the neuroplasticity and neurotrophic factor pathways, indicating that different treatment approaches may be necessary. Therefore, the glutamate hypothesis is gaining attention as a novel hypothesis that can overcome monoamine restrictions. Glutamate has been linked to structural and maladaptive morphological alterations in several brain areas associated with mood disorders. Recently, ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, has shown efficacy in TRD treatment and has received the U.S. Food and Drug Administration approval, revitalizing psychiatry research. However, the mechanism by which ketamine improves TRD remains unclear. In this review, we re-examined the glutamate hypothesis, bringing the glutamate system onboard to join the modulation of the monoamine systems, emphasizing the most prominent ketamine antidepressant mechanisms, such as NMDAR inhibition and NMDAR disinhibition in GABAergic interneurons. Furthermore, we discuss the animal models used in preclinical studies and the sex differences in the effects of ketamine.

Lactobacillus reuteri ATG-F4 Alleviates Chronic Stress-induced Anhedonia by Modulating the Prefrontal Serotonergic System

Mental health is influenced by the gut-brain axis; for example, gut dysbiosis has been observed in patients with major depressive disorder (MDD).Gut microbial changes by fecal microbiota transplantation or probiotics treatment reportedly modulates depressive symptoms. However, it remains unclear how gut dysbiosis contributes to mental dysfunction, and how correction of the gut microbiota alleviates neuropsychiatric disorders. Our previous study showed that chronic consumption of Lactobacillus reuteri ATG-F4 (F4) induced neurometabolic alterations in healthy mice. Here, we investigated whether F4 exerted therapeutic effects on depressive-like behavior by influencing the central nervous system. Using chronic unpredictable stress (CUS) to induce anhedonia, a key symptom of MDD, we found that chronic F4 consumption alleviated CUS-induced anhedonic behaviors, accompanied by biochemical changes in the gut, serum, and brain. Serum and brain metabolite concentrations involved in tryptophan metabolism were regulated by CUS and F4. F4 consumption reduced the elevated levels of serotonin (5-HT) in the brain observed in the CUS group. Additionally, the increased expression of Htr1a, a subtype of the 5-HT receptor, in the medial prefrontal cortex (mPFC) of stressed mice was restored to levels observed in stress-naïve mice following F4 supplementation. We further demonstrated the role of Htr1a using AAV-shRNA to downregulate Htr1a in the mPFC of CUS mice, effectively reversing CUS-induced anhedonic behavior. Together, our findings suggest F4 as a potential therapeutic approach for relieving some depressive symptoms and highlight the involvement of the tryptophan metabolism in mitigating CUS-induced depressive-like behaviors through the action of this bacterium.

Efficacy and safety of losartan in childhood immunoglobulin A nephropathy: a prospective multicenter study

Purpose@#Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers (ARBs) are frequently employed to counteract the detrimental effects of proteinuria on glomerular diseases. However, the effects of ARBs remain poorly examined in pediatric patients with immunoglobulin A (IgA) nephropathy. Herein, we evaluated the efficacy and safety of losartan, an ARB, in pediatric IgA nephropathy with proteinuria. @*Methods@#This prospective, single-arm, multicenter study included children with IgA nephropathy exhibiting proteinuria. Changes in proteinuria, blood pressure, and kidney function were prospectively evaluated before and 4 and 24 weeks after losartan administration. The primary endpoint was the difference in proteinuria between baseline and 24 weeks. @*Results@#In total, 29 patients were enrolled and received losartan treatment. The full analysis set included 28 patients who received losartan at least once and had pre- and post-urinary protein to creatinine ratio measurements (n=28). The per-protocol analysis group included 22 patients who completed all scheduled visits without any serious violations during the study period. In both groups, the mean log (urine protein to creatinine ratio) value decreased significantly at 6 months. After 24 weeks, the urinary protein to creatinine ratio decreased by more than 50% in approximately 40% of the patients. The glomerular filtration rate was not significantly altered during the observation period. @*Conclusions@#Losartan decreased proteinuria without decreasing kidney function in patients with IgA nephropathy over 24 weeks. Losartan could be safely employed to reduce proteinuria in this patient population. ClinicalTrials.gov trial registration (NCT0223277)

Mental Disorders Linked to Crosstalk between The Gut Microbiome and The Brain

Often called the second brain, the gut communicates extensively with the brain and vice versa. The conversation between these two organs affects a variety of physiological mechanisms that are associated with our mental health. Over the past decade, a growing body of evidence has suggested that the gut microbiome builds a unique ecosystem inside the gastrointestinal tract to maintain the homeostasis and that compositional changes in the gut microbiome are highly correlated with several mental disorders. There are ongoing efforts to treat or prevent mental disorders by regulating the gut microbiome using probiotics. These attempts are based on the seminal findings that probiotics can control the gut microbiome and affect mental conditions. However, some issues have yet to be conclusively addressed, especially the causality between the gut microbiome and mental disorders. In this review, we focus on the mechanisms by which the gut microbiome affects mental health and diseases. Furthermore, we discuss the potential use of probiotics as therapeutic agents for psychiatric disorders.

Mental Disorders Linked to Crosstalk between The Gut Microbiome and The Brain

Often called the second brain, the gut communicates extensively with the brain and vice versa. The conversation between these two organs affects a variety of physiological mechanisms that are associated with our mental health. Over the past decade, a growing body of evidence has suggested that the gut microbiome builds a unique ecosystem inside the gastrointestinal tract to maintain the homeostasis and that compositional changes in the gut microbiome are highly correlated with several mental disorders. There are ongoing efforts to treat or prevent mental disorders by regulating the gut microbiome using probiotics. These attempts are based on the seminal findings that probiotics can control the gut microbiome and affect mental conditions. However, some issues have yet to be conclusively addressed, especially the causality between the gut microbiome and mental disorders. In this review, we focus on the mechanisms by which the gut microbiome affects mental health and diseases. Furthermore, we discuss the potential use of probiotics as therapeutic agents for psychiatric disorders.

Incidence and Management Trends of Osteoporotic Vertebral Compression Fractures in South Korea: A Nationwide Population-Based Study

Methods@#A nationwide database (2012–2016) acquired from the Korean Health Insurance Review and Assessment Service was analyzed. International disease categories in the 10th revision of the International Statistical Classification of Diseases and Related Health Problems codes, medical procedure codes, and examination codes were used to identify and sort OVCF patients aged >50 years. @*Results@#There were 644,500 OVCF cases from 2012 to 2016. OVCF was most common in patients in their seventies (45%) and the number of patients increased from 117,361 in 2012 to 139,889 in 2016 (p <0.001). During 2012–2016, 8.9% of patients visited the emergency department; of those, 54.3% were hospitalized and 35% underwent magnetic resonance imaging. In OVCF treatment, bone cement augmentation rates increased from 23.4% in 2012 to 25.2% in 2016 (p <0.001), while conservative treatment rates slightly decreased from 76.5% in 2012 to 74.7% in 2016 (p <0.001). The total health insurance cost was $193,210,353.55 in 2012 and $281,968,877.65 in 2016. @*Conclusions@#The 5-year incidence of OVCF per 100,000 persons was 852.24 cases, and 45% of OVCF in South Korea occurred in patients in their seventies. The bone cement augmentation rate and total cost of OVCF are continuously increasing.

Is vaginal reflux associated with urinary tract infection in female children under the age of 36 months? / 소아과

PURPOSE: To determine the relationship between vaginal reflux (VR) and urinary tract infection (UTI) in female children aged < 36 months. METHODS: A single center retrospective study was performed for 191 girls aged < 36 months, with a diagnosis of febrile UTI, who underwent a voiding cystourethrography (VCUG) for assessment of vesicoureteral reflux (VUR) at Sanggye Paik Hospital. Fifty-one girls, who underwent VCUG for assessment of congenital hydronephrosis or renal pelvis dilatation, without a UTI, formed the control group. The correlation between the presence and grade of VR and UTI was evaluated. RESULTS: The prevalence rate of VR was higher in the UTI (42.9%) than control (13.7%) group (P < 0.05), with a higher VR severity grade in the UTI (mean, 0.64) than control (mean, 0.18) group (P < 0.05). On subanalysis with age-matching (UTI group: n=126, age, 5.28±2.13 months; control group: n=22, age, 4.79±2.40 months; P=0.33), both VR prevalence (43.65% vs. 18.18%, P < 0.05) and grade (0.65 vs. 0.22, P < 0.05) remained higher in the UTI than control group. Presence and higher grade of VR were associated with UTI recurrence (P < 0.05). VR was correlated to urosepsis (P < 0.05). The renal defect rate of patients with VR (VR [+]/VUR [+]) was not different from that of patients without VR (74% vs. 52%, P=0.143) in the VUR group; however, it was higher than that of VR (+)/VUR (−) patients (74% vs. 32%, P=0.001). If a child with VR (+)/VUR (+) is exposed to a UTI, the risk of renal defect increases. CONCLUSION: Occurrence of VR is associated with UTI recurrence and urosepsis in pediatric female patients.

National Surgical Trends for Distal Radius Fractures in Korea

The objective of this study was to investigate national surgical trends for distal radius fractures (DRFs) in Korea and analyze healthcare institution type-specific surgical trends. We analyzed a nationwide database acquired from the Korean Health Insurance Review and Assessment Service (HIRA) from 2011 to 2015. International Classification of Diseases, 10th revision (ICD-10) codes and procedure codes were used to identify patients aged ≥ 20 years with newly diagnosed DRFs. A total of 459,388 DRFs occurred from 2011 to 2015. The proportion of DRF cases treated by surgery tended to increase over time, from 32.6% in 2011 to 38.3% in 2015 (P < 0.001). Open reduction with internal fixation (ORIF) using a plate steadily gained in popularity each year, increasing from 39.2% of overall surgeries in 2011 to 60.9% in 2015. The type of surgery for DRFs differed depending on the type of healthcare institution. ORIF (91%) was the most popular procedure in tertiary hospitals, whereas percutaneous pinning (58%) was most popular in clinics. In addition, general hospitals and hospitals with 30–100 beds used external fixation more frequently than tertiary hospitals and clinics did. Overall, our findings indicate that surgical treatment of DRF, particularly ORIF, continues to increase, and that the component ratio of operation codes differed according to the healthcare institution type.

Henoch-Schonlein Purpura in Children Hospitalized at a Tertiary Hospital during 2004-2015 in Korea: Epidemiology and Clinical Management / 대한소아소화기영양학회지

PURPOSE: To investigate the epidemiology, clinical manifestations, investigations and management, and prognosis of patients with Henoch-Schonlein purpura (HSP). METHODS: We performed a retrospective review of 212 HSP patients under the age of 18 years who were admitted to Inje University Sanggye Paik Hospital between 2004 and 2015. RESULTS: The mean age of the HSP patients was 6.93 years, and the ratio of boys to girls was 1.23:1. HSP occurred most frequently in the winter (33.0%) and least frequently in the summer (11.3%). Palpable purpura spots were found in 208 patients (98.1%), and gastrointestinal (GI) and joint symptoms were observed in 159 (75.0%) and 148 (69.8%) patients, respectively. There were 57 patients (26.9%) with renal involvement and 10 patients (4.7%) with nephrotic syndrome. The incidence of renal involvement and nephrotic syndrome was significantly higher in patients with severe GI symptoms and in those over 7 years old. The majority of patients (88.7%) were treated with steroids. There was no significant difference in the incidence of renal involvement or nephrotic syndrome among patients receiving different doses of steroids. CONCLUSION: In this study, the epidemiologic features of HSP in children were similar to those described in previous studies, but GI and joint symptoms manifested more frequently. It is essential to carefully monitor renal involvement and progression to chronic renal disease in patients ≥7 years old and in patients affected by severe GI symptoms. It can be assumed that there is no direct association between early doses of steroids and prognosis.

Validity of bag urine culture for predicting urinary tract infections in febrile infants: a paired comparison of urine collection methods / 소아과

PURPOSE: Catheter urine (CATH-U) and suprapubic aspiration (SPA) are reliable urine collection methods for confirming urinary tract infections (UTI) in infants. However, noninvasive and easily accessible collecting bag urine (CBU) is widely used, despite its high contamination rate. This study investigated the validity of CBU cultures for diagnosing UTIs, using CATH-U culture results as the gold standard. METHODS: We retrospectively analyzed 210 infants, 2- to 24-month-old, who presented to a tertiary care hospital's pediatrics department between September 2008 and August 2013. We reviewed the results of CBU and CATH-U cultures from the same infants. RESULTS: CBU results, relative to CATH-U culture results (> or =104 colony-forming units [CFU]/mL) were widely variable, ranging from no growth to > or =105 CFU/mL. A CBU cutoff value of > or =105 CFU/mL resulted in false-positive and false-negative rates of 18% and 24%, respectively. The probability of a UTI increased when the CBU bacterial count was > or =105/mL for all infants, both uncircumcised male infants and female infants (likelihood ratios [LRs], 4.16, 4.11, and 4.11, respectively). UTIs could not be excluded for female infants with a CBU bacterial density of 104-105 (LR, 1.40). The LRs for predicting UTIs based on a positive dipstick test and a positive urinalysis were 4.19 and 3.11, respectively. CONCLUSION: The validity of obtaining urine sample from a sterile bag remains questionable. Inconclusive culture results from CBU should be confirmed with a more reliable method.

Erratum: Validity of bag urine culture for predicting urinary tract infections in febrile infants: a paired comparison of urine collection methods / 소아과

The second sentence in Abstract Results should be modified.

Toxic epidermal necrolysis associated with deflazacort therapy with nephrotic syndrome

Toxic epidermal necrolysis (TEN) is a drug-related fatal disease. Extensive necrosis of the epidermis can lead to serious complications. This report describes two cases of TEN, associated with deflazacort (DFZ), in two boys, aged 4 years and 14 years, with nephrotic syndrome (NS). The 14-year-old male teenager received DFZ following NS relapse. After 17 days, pruritic papules appeared on the lower extremities. Another case involved a 4-year-old boy receiving DFZ and enalapril. After a 41-day DFZ treatment period, erythematous papules appeared on the palms and soles. Within 3 days, both boys developed widespread skin lesions (>50%) and were admitted to the intensive care unit for resuscitative and supportive treatment. The patients showed improvement after intravenous immunoglobulin-G therapy. Owing to the rapid, fatal course of TEN, clinicians need to be aware of the adverse effects of this drug when treating cases of NS.

Intravenous fluid prescription practices among pediatric residents in Korea / 소아과

PURPOSE: Recent studies have established the association between hypotonic fluids administration and hospital-acquired hyponatremia in children, and have contended that hypotonic fluids be removed from routine practice. To assess current intravenous fluid prescription practices among Korean pediatric residents and to call for updated clinical practice education. METHODS: A survey-based analysis was carried out. Pediatric residents at six university hospitals in Korea completed a survey consisting of four questions. Each question supposed a unique scenario in which the respondents were to prescribe either a hypotonic or an isotonic fluid for the patient. RESULTS: Ninety-one responses were collected and analyzed. In three of the four scenarios, a significant majority prescribed the hypotonic fluids (98.9%, 85.7%, and 69.2%, respectively). Notably, 69.2% of the respondents selected the hypotonic fluids for postoperative management. Almost all (96.7%) selected the isotonic fluids for hydration therapy. CONCLUSION: In the given scenarios, the majority of Korean pediatric residents would prescribe a hypotonic fluid, except for initial hydration. The current state of pediatric fluid management, notably, heightens the risk of hospital-acquired hyponatremia. Updated clinical practice education on intravenous fluid prescription, therefore, is urgently required.

A Case of Microscopic Polyangiitis Initially Suspected with Henoch-Schonlein Purpura Nephritis

Microscopic polyangiitis (MPA) is systemic small vessel vasculitis that is very rare in childhood. MPA is characterized by pauci-immune necrotizing small vessel vasculitis without clinical or pathological evidence of necrotizing granulomatous inflammation. Approximately 90% of patients have glomerulonephritis that is accompanied by a variety of other organ involvement. A 10-year-old girl visited our clinic with clinical manifestations suggestive Henoch-Schonlein purpura nephritis such as purpuric skin rash, abdominal pain, arthralgia on both knees, massive proteinuria and microscopic hematuria. So initially we suspected Henoch-Schonlein purpura nephritis. However, later her perinuclear-antineutrophil cytoplasmic antibodies(p-ANCA) test was positive, and her renal biopsy was consistent with microscopic polyangiitis. We began steroid therapy, combined with cyclophosphamide, ACE inhibitor. Currently she is a 12-year old, and until now she has been regularly examined in the outpatient. We report a case of microscopic polyangiitis initially suspected with Henoch-Schonlein purpura nephritis.

Comparison of Clinical Manifestation and Laboratory Findings between H1N1 and Influenza B Infection / 소아알레르기및호흡기학회지

PURPOSE: Influenza virus is one of the most important viruses that cause the respiratory infection seasonally. In April 2009, H1N1 was detected in America and Mexico and then there was pandemic in Korea. We investigated the difference of clinical and laboratory findings between the infections of H1N1 and Influenza B. METHODS: We have retrospectively studied the patients under age of 15 years who visited Inje University Sanggye Paik Hospital from August 2009 to April 2010. Evaluation for influenza infection was performed by rapid antigen test or multiplex reverse transcriptase polymerase chain reaction. Complete blood count with differential counts, C-reactive protein and chest X-ray were checked. RESULTS: Enrolled patients were 2,226 in H1N1-infected group and 288 in influenza B-infected group. Seasonal variation was that H1N1 in autumn and winter but influenza B in spring. The male-to-female sex ratio was same as 1.23 in each group. The mean age of H1N1-infected group was higher than influenza B-infected group (P<0.001). Fever was developed similarly in both groups (P=0.114). However, cough, sputum, rhinorrhea, vomiting, diarrhea, and headache were more prevalent in influenza B infection compared to H1N1 infection (P<0.001). Pneumonia development and admission rate were higher in influenza B infection compared to H1N1 infection (P<0.001, respectively). CONCLUSION: Although H1N1 infection spread rapidly, H1N1 caused not so severe symptoms than influenza B. Because of the possibility that influenza epidemic will develop repeatedly in the future, we need to evaluate more about different characteristics depending on the virus subtype and prepare for them.

Obesity Related Glomerulopathy Progressed to Chronic Renal Failure

Obesity-related glomerulopathy (ORG) is a secondary form of focal and segmental glomerulosclerosis (FSGS) manifesting as proteinuria and progressive renal dysfunction that results from maladaptive glomerular response to increasing adiposity. Reports of ORG progressing to end stage renal diseases in rare in the pediatric population. We report a 9-year-old boy with obesity (body mass index 35 kg/m2) who was diagnosed with ORG presenting with proteinuria. He was diagnosed with obesity-related glomerulopathy based on the laboratory, urinary, and kidney biopsy finding. In spite of treatment with angiotensin-converting enzyme (ACE) inhibitor and/or, angiotensin-receptor blocking agent, the degree or amount of proteinuria increased and renal function declined continuously. His BMI did not decrease and eventually progressed to chronic renal failure. Consequently, obese patients should be monitored for proteinuria, which may be the first manifestation of FSGS, a lesion that may be associated with serious renal sequelae.

Association of RNase3 Polymorphisms with the Susceptibility of Gastric Cancer

PURPOSE: RNase3 is a secretory ribonuclease, which is found in the eosinophilic leukocyte and involved in the innate immune system. Its cytotoxic activity is effective against a wide range of pathogens. We performed a case-control study to examine the relationship between RNase3 polymorphisms and the susceptibility of gastric cancer in Korean people. METHODS: Blood sampling of stomach cancer and healthy persons groups were performed, Taqman in g.-550A>G, polymerase chain reaction-restriction fragment length polymorphism in g.371C>G, and high-resolution melt in g.499C>G were analyzed. The three single nucleotide polymorphisms g.-550A>G, g.371C>G, and g.499C>G in RNase3 and their haplotypes were analyzed. RESULTS: The genotype and allele frequencies of RNase3 g.-550A>G and g.371C>G were not significantly increased in susceptibility of gastric cancer than control group. But, RNase3 CC genotype was associated with a significantly increased susceptibility of gastric cancer than control group (P=0.002). Also, RNase3 CC genotype was more specifically associated with a significantly increased susceptibility of middle and lower gastric cancer than upper gastric cancer (P=0.002). In haplotype of RNase3 SNP g.-550A, g.371G, and g.499C, there was significantly susceptibility of gastric cancer (P=0.004), and more specific influence on middle and lower gastric cancer than upper gastric cancer (P=0.006 vs 0.054). CONCLUSION: RNase3 g.499C>G polymorphism may influence gastric cancers, and have a more specific influence on middle and lower gastric cancer rather than upper gastric cancer. But RNase3 g.-550A>G, g.371C>G polymorphisms need careful interpretation and confirmation in more larger studies.

ERRATUM: Factors Related to the Resolution of Primary Vesicoureteral Reflux

Title change to "Factors Relating with the Resolution of Primary Vesicoureteral Reflux in Infants with Urinary Tract Infection"

Urinary Protein and Enzyme Excretion of Spot Urine in Children with Vesicoureteral Reflux

PURPOSE: The aim of this study was to evaluate the clinical usefulness of measurement of beta2 microglobulin (beta2 MG), N-acetyl-beta-D-glucosaminidase (NAG) of spot urine samples as indices of renal tubular damage and microalbumin of spot urine samples as a parameter of glomerular damage in children with vesicoureteral reflux (VUR) or renal defects. METHODS: We studied 91 children with previous UTI. The children were classified as 62 children without VUR and renal defects (group I), 10 children with VUR, without renal defects (group II), and 19 children with VUR and renal defects (group III). Patients having VUR were separated according to the degree of VUR (mild VUR: VUR grade I-III, severe VUR: VUR grade IV-V). Urinary excretion of beta2 microglobulin (beta2 MG), microalbumin, N-acetyl-beta-D-glucosaminidase (NAG), creatinine were measured in samples of morning urine specimens. Children with VUR or renal defects detected by voiding cystourethrography (VCUG) and DMSA renal scan were investigated. RESULTS: Microalbumin/Cr ratio of spot urine was significantly increased in group III compared group I (42.3+/-27.2 mg/gCr vs 25.2+/-10.9 mg/gCr, P<0.05). NAG/Cr ratio of spot urine was significantly increased in group II compared group I (3.70+/-23.4 mg/gCr vs 18.7+/-12.7 mg/gCr, P<0.05). There was no statistically significant difference of beta2 MG/Cr ratio among three groups. CONCLUSION: Urinary microalbumin excretion of morning urine sample may be a simple and reliable clinical indicators for early identification of renal damage in children with VUR and renal defects. Urinary microalbumin excretion may be useful marker to predict the the severity of VUR.

Factors Related to the Resolution of Primary Vesicoureteral Reflux

PURPOSE: This study was performed to identify factors related to the resolution of primary vesicoureteral reflux (VUR) in infants. METHODS: We reviewed 183 infants (M : F=149 : 34) diagnosed as urinary tract infection (UTI) between February 2002 and July 2007 at Sanggye Paik Hospital. The diagnosis of UTI was made by culture from a urine specimen obtained by suprapubic puncture (n=97), catheterization (n=83), or collection bag method (n=3, twice positive culture of same organism). All of the infants were performed renal ultrasonography, DMSA scan and voiding cystourethrography (VCUG) study. Follow-up imaging consisted of contrast VCUG or direct isotope VCUG at interval of 1 year. We evaluated the relationship of clinical and laboratory finding, radiologic finding in infants with VUR. RESULTS: Among 51 VUR patients, 18 infants had grade I-II, 12 infants had grade III and the other 21 patients had grade IV-V. Abnormal findings including hydronephrosis on renal ultrasonography were not correlated with severity of VUR. However, the incidence of renal defect in the first DMSA scan showed a tendency of direct correlation with severity of VUR in female patients only (P<0.001). There was significant difference of resolution rate in three VUR groups (grade I-II, III, IV-V) in male patients only (P=0.025). Resolution rate was higher for male patients with unilateral VUR than bilateral (P<0.001). But unilaterality had not any affect on VUR resolution in female VUR patients (P=0.786). Resolution rate was higher for VUR patients without renal scar than VUR patients with renal scar (P<0.001). CONCLUSION: According to our findings, grade of VUR, laterality and renal scar are the factors that contribute to resolution of primary VUR in male and female infants differently.