TNF in Human Tuberculosis: A Double-Edged Sword

TNF, a pleiotropic proinflammatory cytokine, is important for protective immunity and immunopathology during Mycobacterium tuberculosis (Mtb) infection, which causes tuberculosis (TB) in humans. TNF is produced primarily by phagocytes in the lungs during the early stages of Mtb infection and performs diverse physiological and pathological functions by binding to its receptors in a context-dependent manner. TNF is essential for granuloma formation, chronic infection prevention, and macrophage recruitment to and activation at the site of infection. In animal models, TNF, in cooperation with chemokines, contributes to the initiation, maintenance, and clearance of mycobacteria in granulomas. Although anti-TNF therapy is effective against immune diseases such as rheumatoid arthritis, it carries the risk of reactivating TB. Furthermore, TNF-associated inflammation contributes to cachexia in patients with TB. This review focuses on the multifaceted role of TNF in the pathogenesis and prevention of TB and underscores the importance of investigating the functions of TNF and its receptors in the establishment of protective immunity against and in the pathology of TB.Such investigations will facilitate the development of therapeutic strategies that target TNF signaling, which makes beneficial and detrimental contributions to the pathogenesis of TB.

A comparative analysis of canine Internal Medicine pancreatic lipase tests for diagnosing pancreatitis in dogs

Objective@#Many qualitative and quantitative commercial cPL tests have been developed and used in veterinary clinics. This study aimed to compare three different methodologies SNAP cPL, Spec cPL, and Vcheck cPL tests to assess the concordance of these assays. @*Methods@#Fifty serum samples were collected from 36 dogs with or without pancreatitis and subjected to SNAP cPL, Spec cPL, and Vcheck cPL tests. Agreement and correlation coefficients were calculated between the test results, and correlations were determined during the management of the patients. @*Results@#The results of the three cPL assays were strongly correlated in 47/50 serum samples (94%). Cohen’s kappa analysis between the Spec cPL and Vcheck cPL showed near perfect agreement (κ = 0.960, p < 0.001), SNAP cPL and Vcheck cPL (κ = 0.920, p < 0.001), and Spec cPL and SNAP cPL (κ = 0.880, p < 0.001). The correlation coefficients (r) between data from Spec cPL and Vcheck cPL tests was calculated by Spearman’s correlation test (r = 0.958, p < 0.001).Furthermore, the patterns of change in serum cPL concentrations determined using Spec cPL and Vcheck cPL were significantly consistent during the monitoring period in 11 patients. @*Conclusions@#and Relevance: Our data illustrated that Spec cPL and Vcheck cPL tests are compatible for clinical use in the diagnosis and monitoring of canine pancreatitis.

Development of the Parental Questionnaire for Cerebral Visual Impairment in Children Younger than 72 Months

Background@#and Purpose: Cerebral visual impairment (CVI) is an underdiagnosed condition in children, and its assessment tools have focused on older children. We aimed to develop a parental questionnaire for cerebral visual impairment (PQCVI) for screening CVI in young children. @*Methods@#The PQCVI comprised 23 questions based on a modified version of Houliston and Dutton’s questionnaire for older children. The PQCVI with neurocognitive function tests was applied to 201 child–parent pairs with typically developing children younger than 72 months (age 32.4±20.1 months, mean±standard deviation). The children were classified into six age groups. The normative data, cutoff scores, and internal reliability were assessed and item analysis was performed. We referred to the total score for all questions as the cerebral visual function (CVF) score. @*Results@#The normative data showed that the CVF score and the scores corresponding to ventral-stream and dorsal-stream visual functions plausibly increased with age. The scores rapidly reached 90% of their maximum values up to the age of 36 months, after which they increased slowly. Cronbach’s alpha for all questions across all age groups was 0.97, showing excellent consistency. The item difficulty and item discrimination coefficients showed that the questions were generally adequate for this age stage. @*Conclusions@#The PQCVI items produced reliable responses in children younger than 72 months. The rapid increase in scores before the age of 3 years supports the importance of early identification of CVI. Following additional clinical verification, the PQCVI may be useful for CVI screening.

Development of the Parental Questionnaire for Cerebral Visual Impairment in Children Younger than 72 Months

Background@#and Purpose: Cerebral visual impairment (CVI) is an underdiagnosed condition in children, and its assessment tools have focused on older children. We aimed to develop a parental questionnaire for cerebral visual impairment (PQCVI) for screening CVI in young children. @*Methods@#The PQCVI comprised 23 questions based on a modified version of Houliston and Dutton’s questionnaire for older children. The PQCVI with neurocognitive function tests was applied to 201 child–parent pairs with typically developing children younger than 72 months (age 32.4±20.1 months, mean±standard deviation). The children were classified into six age groups. The normative data, cutoff scores, and internal reliability were assessed and item analysis was performed. We referred to the total score for all questions as the cerebral visual function (CVF) score. @*Results@#The normative data showed that the CVF score and the scores corresponding to ventral-stream and dorsal-stream visual functions plausibly increased with age. The scores rapidly reached 90% of their maximum values up to the age of 36 months, after which they increased slowly. Cronbach’s alpha for all questions across all age groups was 0.97, showing excellent consistency. The item difficulty and item discrimination coefficients showed that the questions were generally adequate for this age stage. @*Conclusions@#The PQCVI items produced reliable responses in children younger than 72 months. The rapid increase in scores before the age of 3 years supports the importance of early identification of CVI. Following additional clinical verification, the PQCVI may be useful for CVI screening.

A Case of Neonatal Thyrotoxicosis with Cardiac Insufficiency

Neonatal thyrotoxicosis is rare and most of the cases are secondary to maternal Graves’ disease. It is usually transient, but can be associated with significant morbidity and mortality if not recognized promptly and treated adequately. Neonates born to mothers treated with antithyroid drugs or those who receive maternal thyroid blocking antibodies may exhibit normal thyroid function or even hypothyroidism at birth. Since there may not be any obvious symptoms of hyperthyroidism at birth, it may be overlooked. Therefore, such neonates should be evaluated properly and monitored regularly to prevent serious complications of hyperthyroidism. We report a case of a 21-day-old male infant who developed thyrotoxicosis with dyspnea, irritability, tachycardia, and cardiac insufficiency. He was born to a mother who was treated for Graves’ disease with antithyroid drugs during pregnancy. We have also discussed the importance of careful examination and monitoring to prevent the development of clinical hyperthyroidism.

Host-Pathogen Dialogues in Autophagy, Apoptosis, and Necrosis during Mycobacterial Infection

Mycobacterium tuberculosis (Mtb) is an etiologic pathogen of human tuberculosis (TB), a serious infectious disease with high morbidity and mortality. In addition, the threat of drug resistance in anti-TB therapy is of global concern. Despite this, it remains urgent to research for understanding the molecular nature of dynamic interactions between host and pathogens during TB infection. While Mtb evasion from phagolysosomal acidification is a well-known virulence mechanism, the molecular events to promote intracellular parasitism remains elusive. To combat intracellular Mtb infection, several defensive processes, including autophagy and apoptosis, are activated. In addition, Mtb-ingested phagocytes trigger inflammation, and undergo necrotic cell death, potentially harmful responses in case of uncontrolled pathological condition. In this review, we focus on Mtb evasion from phagosomal acidification, and Mtb interaction with host autophagy, apoptosis, and necrosis.Elucidation of the molecular dialogue will shed light on Mtb pathogenesis, host defense, and development of new paradigms of therapeutics.

Results of total knee arthroplasty for painless, stiff knees

Background@#Stiff knees, like completely ankylosed or arthrodesed knees, can be painless. Total knee arthroplasty (TKA) for these painless, stiff knees is technically demanding. However, it can correct the alignment and advance the range of motion to improve quality of life. So, we reviewed the preoperative and postoperative results of functional and pain scores, range of motion (ROM) and complications in painless, stiff knees treated by TKA. @*Methods@#Fifteen painless, stiff knees underwent TKA from January 1998 to January 2017. The mean follow-up period was 15.4 (2.4–22.2) years. All the knees were completely ankylosed or arthrodesed. Clinical outcome and complications were evaluated using medical record review, serial plan radiography, ROM assessment, Knee Society score (KSS), Knee Society function score (FS), and a visual analog scale for pain (VAS). @*Results@#All patients were satisfied with their operated knees. Mean KSS and FS scores were improved from 36 and 50.9 to 76.9 and 67.2, respectively (P < 0.001 and P = 0.01). The mean ROM increased from 0º preoperatively to 77.6º (15–130) at the final follow-up (P < 0.001). The mean VAS had worsened from 0 preoperatively to 0.2 postoperatively, however it was not significant (P = 0.1). Major postoperative complications were reported in five of the knees (33.3%). @*Conclusions@#The results of TKA for painless, stiff knees were satisfactory with improved ROM and quality of life. Although some patients had mild pain and complications postoperatively, they were satisfied with the result. However, our study recommends that surgeons should consider the high rate of complications in the completely ankylosed or arthrodesed knees.

Results of total knee arthroplasty for painless, stiff knees

Background@#Stiff knees, like completely ankylosed or arthrodesed knees, can be painless. Total knee arthroplasty (TKA) for these painless, stiff knees is technically demanding. However, it can correct the alignment and advance the range of motion to improve quality of life. So, we reviewed the preoperative and postoperative results of functional and pain scores, range of motion (ROM) and complications in painless, stiff knees treated by TKA. @*Methods@#Fifteen painless, stiff knees underwent TKA from January 1998 to January 2017. The mean follow-up period was 15.4 (2.4–22.2) years. All the knees were completely ankylosed or arthrodesed. Clinical outcome and complications were evaluated using medical record review, serial plan radiography, ROM assessment, Knee Society score (KSS), Knee Society function score (FS), and a visual analog scale for pain (VAS). @*Results@#All patients were satisfied with their operated knees. Mean KSS and FS scores were improved from 36 and 50.9 to 76.9 and 67.2, respectively (P < 0.001 and P = 0.01). The mean ROM increased from 0º preoperatively to 77.6º (15–130) at the final follow-up (P < 0.001). The mean VAS had worsened from 0 preoperatively to 0.2 postoperatively, however it was not significant (P = 0.1). Major postoperative complications were reported in five of the knees (33.3%). @*Conclusions@#The results of TKA for painless, stiff knees were satisfactory with improved ROM and quality of life. Although some patients had mild pain and complications postoperatively, they were satisfied with the result. However, our study recommends that surgeons should consider the high rate of complications in the completely ankylosed or arthrodesed knees.

Host-Pathogen Dialogues in Autophagy, Apoptosis, and Necrosis during Mycobacterial Infection

Mycobacterium tuberculosis (Mtb) is an etiologic pathogen of human tuberculosis (TB), a serious infectious disease with high morbidity and mortality. In addition, the threat of drug resistance in anti-TB therapy is of global concern. Despite this, it remains urgent to research for understanding the molecular nature of dynamic interactions between host and pathogens during TB infection. While Mtb evasion from phagolysosomal acidification is a well-known virulence mechanism, the molecular events to promote intracellular parasitism remains elusive. To combat intracellular Mtb infection, several defensive processes, including autophagy and apoptosis, are activated. In addition, Mtb-ingested phagocytes trigger inflammation, and undergo necrotic cell death, potentially harmful responses in case of uncontrolled pathological condition. In this review, we focus on Mtb evasion from phagosomal acidification, and Mtb interaction with host autophagy, apoptosis, and necrosis.Elucidation of the molecular dialogue will shed light on Mtb pathogenesis, host defense, and development of new paradigms of therapeutics.

A case of vitamin D hydroxylation-deficient rickets type 1A caused by 2 novel pathogenic variants in CYP27B1 gene

Vitamin D hydroxylation-deficient rickets type 1A (VDDR1A, OMIM 264700) is a rare autosomal recessive inherited disorder. Pathogenic variants in the CYP27B1 gene lead to loss of 1α-hydroxylase activity. We report the case of a 22-month-old toddler who presented with growth retardation and delayed development. The patient exhibited the typical laboratory findings of VDDR1A, including hypocalcemia (calcium: 5.2 mg/dL), elevated serum level of alkaline phosphatase (2,600 U/L), elevated serum level of intact-parathyroid hormone (238 pg/mL), low 1,25(OH)₂D₃ level (11.2 pg/mL), and normal 25(OH)D₃ level (40.7 ng/mL). His height and weight were 76.5 cm and 9.5 kg, respectively (both <3rd percentile). The Bayley Scales of Infant and Toddler Development II indicated significantly delayed development (mental development index <50, psychomotor development index <50). The patient was a compound heterozygous for two novel pathogenic variants in the CYP27B1 gene: c.57_69del (p.Glu20Profs*2) and c.171dupG (p.Leu58Alafs*275), inherited from his mother and father, respectively. The patient showed remarkable improvement after treatment with calcitriol and calcium carbonate.

Relationship between stress and subjective oral dryness in the elderly in a rural region: a pilot study / 대한구강보건학회지

OBJECTIVES: Stress is a psychological reaction to stimuli such as anxiety or threat felt by a person either physically or mentally when placed in a difficult situation. Although a relationship between stress and dry mouth has been reported, it remains understudied. The purpose of this study was to investigate the association between stress and subjective dry mouth among the elderly living in a rural region. METHODS: A total of 214 people aged ≥60 years living in a rural area were recruited with an informed consent for a cross-sectional analysis. Information about stress and subjective dry mouth was obtained by an interview survey with a constructed questionnaire. Data on other potential confounding factors (including oral factors) such as socio-demographic data, health-related behaviors, the number of remaining teeth, and subjective chewing ability were also gathered at the same time. Logistic regression models were used to analyze the relationship of stress and dry mouth using SPSS. RESULTS: The Crude odds ratio (OR) of stress awareness affecting subjective dry mouth was 2.59 (95% confidence interval: 1.43–4.68). After adjusting for sex, education, income, smoking, and alcohol intake, the adjusted OR was 2.52 (95% confidence interval: 1.30–4.87) which was statistically significant. CONCLUSIONS: Elderly people who were stressed had an approximately 2-fold increase in experiencing subjective dry mouth when compared to their stress-free counterparts.

Erratum: Developmental profiles of preschool children with delayed language development / 소아과

In this article, first author's name was misspelled unintentionally.

A successful treatment of hypercalcemia with zoledronic acid in a 15-year-old boy with acute lymphoblastic leukemia

Severe hypercalcemia in children is a rare medical emergency. We present a case of a 15-year-old boy with hypercalcemia (total calcium level, 14.2 mg/dL) with a normal complete blood count, no circulating blasts in the peripheral blood film, and no other signs of acute lymphoblastic leukemia (ALL), including no signs of lymphadenopathy or hepatosplenomegaly. The hypercalcemia was successfully treated with zoledronic acid. As hypercalcemia can be the only presenting symptom of ALL in children, the diagnosis is often delayed. In children presenting with hypercalcemia, malignancies must be considered in the differential diagnosis.

A successful treatment of hypercalcemia with zoledronic acid in a 15-year-old boy with acute lymphoblastic leukemia

Severe hypercalcemia in children is a rare medical emergency. We present a case of a 15-year-old boy with hypercalcemia (total calcium level, 14.2 mg/dL) with a normal complete blood count, no circulating blasts in the peripheral blood film, and no other signs of acute lymphoblastic leukemia (ALL), including no signs of lymphadenopathy or hepatosplenomegaly. The hypercalcemia was successfully treated with zoledronic acid. As hypercalcemia can be the only presenting symptom of ALL in children, the diagnosis is often delayed. In children presenting with hypercalcemia, malignancies must be considered in the differential diagnosis.

In Vitro Antimicrobial Activities of Fusidic Acid and Retapamulin against Mupirocin- and Methicillin-Resistant Staphylococcus aureus

BACKGROUND: The in vitro activities of retapamulin and fusidic acid against clinical isolates of mupirocin-resistant and methicillin-resistant Staphylococcus aureus (MRSA) from Korea are not well understood. OBJECTIVE: This study aimed to determine the activities of retapamulin and fusidic acid against clinical isolates of mupirocin-resistant MRSA. METHODS: Clinical isolates of mupirocin-resistant MRSA were collected from two tertiary hospitals. The minimal inhibitory concentrations of mupirocin, fusidic acid, and retapamulin were determined using agar dilution method. Polymerase chain reaction was used to confirm the identity of the species and the presence of resistance genes. Pulsed-field gel electrophoresis (PFGE) patterns of chromosomal DNA were used to determine the genetic similarity of high-level mupirocin-resistant isolates. RESULTS: Of the 497 MRSA isolates tested, 22 (4.4%) were mupirocin-resistant. Of these, 9 (1.8%) and 13 (2.6%) had high-level and low-level mupirocin resistance, respectively. Analysis of the PFGE patterns of the high-level mupirocin-resistant MRSA isolates identified five clusters. All 13 of the low-level mupirocin-resistant isolates were resistant to fusidic acid but susceptible to retapamulin. However, among the 9 high-level mupirocin-resistant isolates, 56% were resistant to fusidic acid, and all were susceptible to retapamulin. CONCLUSION: Retapamulin is highly active in vitro against Korean clinical isolates of high-level mupirocinand methicillin-resistant Staphylococcus aureus with different genetic backgrounds. Fusidic acid is more active against high-level mupirocin-resistant MRSA than low-level mupirocin-resistant MRSA.

In Vitro Antimicrobial Activities of Fusidic Acid and Retapamulin against Mupirocin- and Methicillin-Resistant Staphylococcus aureus

BACKGROUND: The in vitro activities of retapamulin and fusidic acid against clinical isolates of mupirocin-resistant and methicillin-resistant Staphylococcus aureus (MRSA) from Korea are not well understood. OBJECTIVE: This study aimed to determine the activities of retapamulin and fusidic acid against clinical isolates of mupirocin-resistant MRSA. METHODS: Clinical isolates of mupirocin-resistant MRSA were collected from two tertiary hospitals. The minimal inhibitory concentrations of mupirocin, fusidic acid, and retapamulin were determined using agar dilution method. Polymerase chain reaction was used to confirm the identity of the species and the presence of resistance genes. Pulsed-field gel electrophoresis (PFGE) patterns of chromosomal DNA were used to determine the genetic similarity of high-level mupirocin-resistant isolates. RESULTS: Of the 497 MRSA isolates tested, 22 (4.4%) were mupirocin-resistant. Of these, 9 (1.8%) and 13 (2.6%) had high-level and low-level mupirocin resistance, respectively. Analysis of the PFGE patterns of the high-level mupirocin-resistant MRSA isolates identified five clusters. All 13 of the low-level mupirocin-resistant isolates were resistant to fusidic acid but susceptible to retapamulin. However, among the 9 high-level mupirocin-resistant isolates, 56% were resistant to fusidic acid, and all were susceptible to retapamulin. CONCLUSION: Retapamulin is highly active in vitro against Korean clinical isolates of high-level mupirocinand methicillin-resistant Staphylococcus aureus with different genetic backgrounds. Fusidic acid is more active against high-level mupirocin-resistant MRSA than low-level mupirocin-resistant MRSA.

Zerumbone, Sesquiterpene Photochemical from Ginger, Inhibits Angiogenesis

Here, we investigated the role of zerumbone, a natural cyclic sesquiterpene of Zingiber zerumbet Smith, on angiogenesis using human umbilical vein endothelial cells (HUVECs). Zerumbone inhibited HUVECs proliferation, migration and tubule formation, as well as angiogenic activity by rat aorta explants. In particular, zerumbone inhibited phosphorylation of vascular endothelial growth factor receptor-2 and fibroblast growth factor receptor-1, which are key regulators of endothelial cell function and angiogenesis. In vivo matrigel plug assay in mice demonstrated significant decrease in vascularization and hemoglobin content in the plugs from zerumbone-treated mice, compared with control mice. Overall, these results suggest that zerumbone inhibits various attributes of angiogenesis, which might contribute to its reported antitumor effects.

Novel Pathogenic Variant (c.3178G>A) in the SMC1A Gene in a Family With Cornelia de Lange Syndrome Identified by Exome Sequencing

Cornelia de Lange syndrome (CdLS) is a clinically and genetically heterogeneous congenital anomaly. Mutations in the NIPBL gene account for a half of the affected individuals. We describe a family with CdLS carrying a novel pathogenic variant of the SMC1A gene identified by exome sequencing. The proband was a 3-yr-old boy presenting with a developmental delay. He had distinctive facial features without major structural anomalies and tested negative for the NIPBL gene. His younger sister, mother, and maternal grandmother presented with mild mental retardation. By exome sequencing of the proband, a novel SMC1A variant, c.3178G>A, was identified, which was expected to cause an amino acid substitution (p.Glu1060Lys) in the highly conserved coiled-coil domain of the SMC1A protein. Sanger sequencing confirmed that the three female relatives with mental retardation also carry this variant. Our results reveal that SMC1A gene defects are associated with milder phenotypes of CdLS. Furthermore, we showed that exome sequencing could be a useful tool to identify pathogenic variants in patients with CdLS.

Effects of Dizocilpine (MK-801) via Up-modulation of N-methyl-D-aspartate (NMDA) Receptors on Hypoxic-Ischemic Brain Injury in Neonatal Rats / 대한주산의학회잡지

OBJECTIVE: Several studies have demonstrated the neuroprotective effects of (+)-MK-801 hydrogen maleate (dizocilpine), in various animal models of hypoxic-ischemic (HI) brain injury. However limited data are available on the neonatal model of HI brain injury. The aim of the present study was to investigate the effects of dizocilpine and its mechanisms associated with NMDARs expression in neonatal rat model of HI brain injury. METHODS: In in vivo model, 7d-old rat pups underwent permanent unilateral carotid ligation. The animals were divided into six groups: N, normoxia; H, hypoxia without operation; HS, hypoxia with Sham operation; HO, hypoxia with operation; HV, HO treated with vehicle; HD, HO treated with dizocilpine. Dizocilpine (10 mg/kg) was administered intracerebrally to the rats 30 min before HI brain injury. Rat pups were exposed to hypoxia by placing them for 2 hours in hypoxic incubator (92% N2, 8% O2). In in vitro model, embryonic cortical neuronal cell cultures (from SD rats of embryonic days of 18) were done. The normoxia (N) group was prepared in 5% CO2 incubators. The hypoxia (H), and hypoxia treated with dizocilpine (HD) groups were placed in 1% O2 incubators (94% N2, 5% CO2) for 16 hours. In order to estimation of cell viability and growth, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay was done. The degree of neuronal death was evaluated by morphometric method and the protein expression of each NMDARs was quantified by Real Time-PCR and Western blot. RESULTS: Both in the in vitro and in vivo models, the expressions of NMDAR subunits were lower in the hypoxia group than in the normoxia group, whereas they increased in the hypoxia treated with dizocilpine group compared to the hypoxia group. In vitro model, however, the expressions of NR1, NR2A mRNAs decreased in the H group when compared to the N group, whereas they increased a little in the HD group when compared to the H group. CONCLUSION: Dizocilpine was modulated the degeneration of neuronal cell death in neonatal rat model of HI by preservation of NR expression.

Comparing physicians' reporting propensity with active and passive surveillance systems in South Korea

Passive surveillance (PS) is a traditional approach to communicable disease surveillance. To complement the approach, several countries have adopted active surveillance (AS) systems that involve the voluntary participation of physicians. This study compares AS versus PS systems in Korea based on the systems' reporting propensity of chickenpox. A mail questionnaire survey was conducted with a random sample of physicians involved in the PS system (N=1,955) and all sentinel physicians of the AS system (N=193). Multiple regression analysis was conducted to identify factors associated with reporting propensity. The reporting propensity of physicians in the AS system was significantly higher than that in the PS surveillance system, 2.7 versus 1.9 on a 5-point Likert scale (p<0.05). Multiple regression analysis showed that, in addition to the type of the surveillance system, physician knowledge of chickenpox as a notifiable disease and the type of institution with which a physician was affiliated were significant factors for a physician's reporting propensity. For both systems, the common barriers for reporting were 'lack of confidence in diagnosis,' 'burden from interference by the public health department following reporting,' and 'complexity of the reporting system.' In conclusion, AS of communicable diseases appeared to have a significantly better performance compared to PS in Korea in the case of chickenpox reporting. These findings would be useful for countries concerned with developing more effective strategies for improving the reporting rate of notifiable diseases.