Nusinersen for Spinal Muscular Atrophy Type I with Chronic Respiratory Failure: A Retrospective Study in South Korea

Purpose@#To analyze the efficacy and safety of nusinersen in patients with spinal muscular atrophy (SMA) type I with chronic respiratory failure. @*Materials and Methods@#We retrospectively reviewed seven patients diagnosed with SMA type I and chronic respiratory failure who were on permanent ventilation and treated with nusinersen at Gangnam Severance Hospital between January 2018 and July 2023. Patient demographics and clinical characteristics were recorded, and treatment progress was evaluated according to Hammersmith Infant Neurological Examination (HINE-2) and Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) scores. @*Results@#Patients initially developed hypotonia at a mean age of 3.7 months. Mean age at start of nusinersen was 7.3 years; the mean duration of follow-up after starting nusinersen was 46.2 months. At 6-, 18-, 38-, 58-, and 74-month follow-up, the mean changes in CHOP-INTEND scores were 1.0, 2.9, 1.8, 1.5, and 1.5, respectively, and the proportions of patients who showed disease amelioration were 28.6%, 71.4%, 75.0%, 100%, and 100%, respectively. @*Conclusion@#Nusinersen is safe and effective in patients with SMA type I, even those with chronic respiratory failure and those on permanent ventilation. No significant adverse effects of nusinersen were observed.

The Relationship Between Zonulin and Asthma: A Mouse Model Study

Background and Objectives@#Zonulin is a human protein that regulates intercellular tight junctions and increases the permeability of the intestinal epithelium. In light of the increasing focus on zonulin’s role in numerous chronic inflammatory diseases, this study aimed to investigate whether differences exist in serum zonulin levels and bronchial epithelium zonulin expression in vivo between asthma and normal groups, using a mouse model. @*Methods@#Sixteen mice were utilized in this study, divided evenly between the normal and asthma groups. Serum zonulin levels, the expression of zonulin antibody in the bronchial epithelium, and serum cytokine levels were evaluated in both groups. Enzyme-linked immunosorbent assay and RNA in situ hybridization were utilized for the analysis. @*Results@#The asthma group exhibited significantly higher levels of serum zonulin. High zonulin antibody expression was also observed in the bronchial epithelium of the asthma group. Given that our mouse model demonstrated a significant difference in interleukin (IL)-4 and IL-6 between the normal and asthma groups, zonulin may be associated not only with type 2 responses but also with various subtypes of asthma. Further studies are required to investigate this relationship in greater detail. @*Conclusion@#Zonulin may play a role in the complex pathophysiology of asthma and could serve as a biomarker in various asthma-related situations.

A female patient with Xp21 gene deletion syndrome

Xp21 contiguous gene deletion syndrome is associated with complex glycerol kinase deficiency, congenital adrenal hypoplasia, Duchene muscular dystrophy, and intellectual disability. Xp21 gene deletion syndrome is X-linked recessive, so most symptomatic patients are male, and only a few female symptomatic patients have been reported. We report the first female Korean case of an Xp21 deletion. NGS data were analyzed for copy number variation, and the Xp21 deletion (chr X:29301056-31838200) was confirmed using real-time PCR.

A case of Galloway-Mowat syndrome with novel compound heterozygous variants in the WDR4 gene

The combination of central nervous system abnormalities and renal impairment is a notable characteristic of GallowayMowat syndrome (GAMOS), a disease which often accompanies microcephaly, developmental delay, and nephrotic syndrome. Many subtypes exist having various phenotypes and genotypes, and many genetic causes are still being identified.An 18-month-old boy first visited our clinic for seizure, delayed development, and microcephaly. During follow-up visits he developed proteinuria and nephrotic syndrome at the age of 6. Nephrotic syndrome became refractory to treatment. These phenotypes were suggestive of GAMOS. Next generation sequencing was performed for genetic analysis and revealed novel compound heterozygous variants in the WDR4 gene: c.494G>A (p.Arg165Gln) and c.540C>G (p.Ile180Met). This is the first case in Korea of GAMOS involving the WDR4 gene.

A case of Galloway-Mowat syndrome with novel compound heterozygous variants in the WDR4 gene

The combination of central nervous system abnormalities and renal impairment is a notable characteristic of GallowayMowat syndrome (GAMOS), a disease which often accompanies microcephaly, developmental delay, and nephrotic syndrome. Many subtypes exist having various phenotypes and genotypes, and many genetic causes are still being identified.An 18-month-old boy first visited our clinic for seizure, delayed development, and microcephaly. During follow-up visits he developed proteinuria and nephrotic syndrome at the age of 6. Nephrotic syndrome became refractory to treatment. These phenotypes were suggestive of GAMOS. Next generation sequencing was performed for genetic analysis and revealed novel compound heterozygous variants in the WDR4 gene: c.494G>A (p.Arg165Gln) and c.540C>G (p.Ile180Met). This is the first case in Korea of GAMOS involving the WDR4 gene.

Implementation of a Targeted Next-Generation Sequencing Panel for Constitutional Newborn Screening in High-Risk Neonates

PURPOSE: Newborn screening (NBS) programs are important for appropriate management of susceptible neonates to prevent serious clinical problems. Neonates admitted to neonatal intensive care units (NICU) are at a potentially high risk of false-positive results, and repetitive NBS after total parenteral nutrition is completely off results in delayed diagnosis. Here, we present the usefulness of a targeted next-generation sequencing (TNGS) panel to complement NBS for early diagnosis in high-risk neonates. MATERIALS AND METHODS: The TNGS panel covered 198 genes associated with actionable genetic and metabolic diseases that are typically included in NBS programs in Korea using tandem mass spectrometry. The panel was applied to 48 infants admitted to the NICU of Severance Children's Hospital between May 2017 and September 2017. The infants were not selected for suspected metabolic disorders. RESULTS: A total of 13 variants classified as likely pathogenic or pathogenic were detected in 11 (22.9%) neonates, including six genes (DHCR7, PCBD1, GAA, ALDOB, ATP7B, and GBA) associated with metabolic diseases not covered in NBS. One of the 48 infants was diagnosed with an isobutyl-CoA dehydrogenase deficiency, and false positive results of tandem mass screening were confirmed in two infants using the TNGS panel. CONCLUSION: The implementation of TNGS in conjunction with conventional NBS can allow for better management of and earlier diagnosis in susceptible infants, thus preventing the development of critical conditions in these sick infants.

The Efficacy of Body Mass Index and Total Body Fat Percent in Diagnosis Obesity according to Menopausal Status

OBJECTIVES: Body mass index (BMI) is commonly used in epidemiological study or clinical center. However, it is not exactly correlated with body fat composition and does not reflect sex, age, or race. The aim of this article is to evaluate the validity of BMI standards relative to total body fat (TBF) and to estimate new BMI criteria that correspond to TBF for obesity, especially for Asian postmenopausal women. METHODS: A total 3,936 patients were included in this cross-sectional study, including 1,565 premenopausal and 2,371 postmenopausal women. At the time of visit, demographic data were collected. We demonstrated the validity of BMI cut-point of 25 kg/m2 by using area under the curve (AUC), and presented the empirical optimal BMI cut-point by using Youden's index and overall accuracy in both premenopausal and postmenopausal women. RESULTS: BMI-defined obesity (≥ 25 kg/m2) represents high AUC values (> 0.9) for each TBF. In premenopausal women, TBF ≥ 38% and corresponding BMI value was 29.45 kg/m2 indicated the highest both Youden's index and overall accuracy. In comparison, postmenopausal women who were TBF ≥ 38% showed the highest Youden's index and overall accuracy, and corresponding BMI value was 26.45 kg/m2. CONCLUSIONS: We proposed new BMI criteria for obesity by using TBF reference. With application of bioelectrical impedance analysis, the diagnosis of obesity using BMI criteria may differ between premenopausal and postmenopausal women.

A Novel Heterozygous ANO3 Mutation with Basal Ganglia Dysfunction in a Patient with Adult-Onset Isolated Segmental Dystonia

No abstract available.

Doctors' Ageism towards the Elderly Cancer Patients: Focusing on Disclosure of Cancer Diagnosis and Explanation on Treatment

BACKGROUND: This research is an exploratory study that is based on previous studies focusing on relationship between the doctors and the elderly cancer patients; moreover, the research focuses on the doctors' negative attitudes and discriminative behaviors towards the elderly cancer patients so that we may be able to suggest the ways to decrease the ageism. METHODS: Qualitative method and quantitative method were applied sequently. In this research, we practiced in-depth interviews with 8 doctors and then the surveys with 274 doctors. The in-depth interview questions were categorized depending on meaningful testimonies and the survey data were analyzed in the descriptive statistic analysis and paired t-test using PASW statistics 18. RESULTS: Through the in-depth interviews, the following is observed: the doctors rarely notify the elderly cancer patients directly; the family members of patients avoids the doctors to do so; and the doctors even show different attitudes or discriminatory actions to the elderly. Based on the in-depth interview results, the questions on notifying methods of the diagnosis and how to explain for treatment were developed and performed as a survey. Through the survey, only 8.4% of the doctors reported they directly notify the elderly cancer patient; moreover, they also reported they provide less information on treatment, side-effects, prognosis, and medical cost to the elderly than the middle-aged. CONCLUSIONS: This research not only discovered the presence of discrimination towards the elderly cancer patients but also suggested the causes of it. In order to resolve the phenomenon, doctors must consider individualized difference and variability of physiological function and should be aware of the psychological change after the cancer diagnosis to better communicate with them. Additionally, the social family culture which overprotects the elderly must be changed.

The Mediating Role of Optimism and Pessimism on the Relationship between Spirituality and Depression among Elderly Cancer Patients

BACKGROUND: Numerous studies have demonstrated that spirituality has protective effects on depression. However, there are only few studies on the theoretical mechanism showing how spirituality effects on depression. Thus, to find mediating variables explaining the relationship between the spirituality and depression may help to develop appropriate program for reducing depression in elderly cancer patients. In this study, we examined the effect of optimism and pessimism as their mediating effects on depression. METHODS: This study is to verify the relationships between spirituality and depression along with the mediating effects of optimism and pessimism among 600 South Korean elderly cancer patients who participated in a community-based study about their mental health. RESULTS: Optimism and pessimism are linked with spirituality and depression. Higher spirituality levels were associated with increased optimistic thinking, and then optimistic thinking is associated with low possibility of depression, whereas lower spirituality levels were associated with more pessimistic thinking, and in turn pessimistic thinking is associated with high depression scores. CONCLUSIONS: Understanding optimism and pessimism affecting depression level is critical for developing spirituality-based programs to reduce depression in elderly cancer patients.

Prognostic Significance of Heat Shock Protein 70 Expression in Early Gastric Carcinoma

BACKGROUND: Overexpression of heat shock protein 70 (HSP70) has been observed in many types of cancer including gastric adenocarcinomas, although the exact role of HSP70 in carcinogenesis remains unclear. METHODS: The study analyzed a total of 458 radical gastrectomy specimens which were immunohistochemically stained with HSP70, p53, and Ki-67 antibodies. RESULTS: The study determined that the expression of HSP70 was significantly increased in early gastric cancer (EGC) compared to advanced gastric cancer (p<0.001). The HSP70 expression was correlated with well-differentiated tumor type, intestinal type of Lauren classification and the lower pT and pN stage. Negative expression of Ki-67 and p53 expression was associated with poor prognosis. The study did not find any correlation between HSP70 and p53 expression. The study determined that HSP70 expression in the EGC subgroup was associated with a poor prognosis (p=0.009), as well as negative Ki-67 expression (p=0.006), but was not associated with p53. Based on multivariate analysis, HSP70 expression (p=0.024), negative expression of Ki-67, invasion depth and lymph node metastasis were determined to be independent prognostic markers. CONCLUSIONS: HSP70 is expressed in the early stages of gastric adenocarcinoma. In EGC, HSP70 is a poor independent prognostic marker and is correlated with a low proliferation index.

Expression of SIRT1 and DBC1 in Gastric Adenocarcinoma

BACKGROUND: Sirtuin 1 (SIRT1) and deleted in breast cancer 1 (DBC1) are known as tumor suppressor or promoter genes. This may be due to their diverse functions and interaction with other proteins. Gastric adenocarcinoma is one of the most common malignancies, but little is known about its carcinogenesis. Therefore, we investigated the association of immunohistochemical expression of SIRT1, DBC1, p53, and beta-catenin and their variable clinicopathological characteristics. METHODS: We obtained samples from 452 patients who underwent gastrectomy. Tissue microarray blocks were constructed and immonohistochemical staining was performed. RESULTS: Expression of DBC1 and SIRT1 was associated with lower histologic grade, intestinal type of Lauren classification, and lower pT (p<0.001) and pN stage (DBC1, p=0.002; SIRT1, p<0.001). Association between absence of lymphatic invasion, and SIRT1 (p=0.001) and DBC1 (p=0.004) was observed. Cytoplasmic beta-catenin expression was associated with lower histologic grade, pT, pN, tumor-node-metastasis (TNM) stage, DBC1 (p<0.001), and SIRT1 (p=0.001). Expression of SIRT1 and DBC1 was not associated with p53 (p=0.063 and p=0.060). DBC1 was an independent good prognostic factor in multivariate analysis (p=0.012). CONCLUSIONS: SIRC1 and DBC1 can be considered to be good prognostic factors in gastric adenocarcinoma.

Clinicopathologic Features of Cases with Negative Pathologic Results after Endoscopic Submucosal Dissection / 대한소화기학회지

BACKGROUND/AIMS: Endoscopic submucosal dissection (ESD) is accepted as a standard treatment of early gastric cancer (EGC) and gastric adenoma. Occasionally, tumorous lesion is not found and pathologic discrepancies can occur after ESD. The aim of this study was to analyze the factors affecting the negative pathologic results after ESD. METHODS: We retrospectively reviewed the data from all patients with gastric neoplasm (276 EGC and 516 gastric adenomas) who were treated with ESD during past 3 years and enrolled the patients who had negative pathologic results. RESULTS: Out of 792 patients treated with ESD, 27 patients (3.4%) were eligible for inclusion. Among the 27 patients, factors affecting the negative pathologic results were, most commonly, the focal lesion (n=13, 48.2%) which was small enough to be removed completely during pre-ESD biopsy, followed by pathologic discrepancies (n=11, 40.7%) between pathologists and lastly the operator factor (n=3, 11.1%) dissecting incorrect lesions. Of the focal lesions, the initial pathologic diagnoses were adenocarcinoma in 11 cases (84.6%). In cases with pathologic discrepancies, all the pretreatment diagnoses were adenoma with low grade dysplasia. In cases caused by operator factors, intestinal metaplasia was accompanied by elevated adenoma in all cases. CONCLUSIONS: To decrease negative pathologic results after ESD, an endoscopist should perform ESD after sufficient communication with pathologists, especially for adenoma with low grade dysplasia, and choose correct lesion, especially located at the antrum and associated with intestinal metaplasia. The possibility of total removal of small lesions even by forcep biopsy should be considered.

Pathological Characteristics of 20 Cases of Langerhans Cell Histiocytosis and Specificity of Immunohistochemical Stain of Langerin (CD207)

BACKGROUND: Langerhans cell histiocytosis (LCH) is a well-known neoplastic disorder of Langerhans cells which has characteristic findings, however, LCH has not been adequately studied in Korea. METHODS: We analyzed the clinicopathologic features of 20 patients with LCH who were diagnosed between 1997 and 2006 at the Korea University Guro and Anam Hospitals. RESULTS: The M:F ratio was 3:1 and the age ranged from 2-60 years (mean, 23.8 years [4 in 1st decade, 6 in 2nd decade, 2 in 3rd decade, 5 in 4th decade and 3> or =40 years of age). The cases were classified as unifocal unisystemic in 13 patients, multifocal unisystemic in 4 patients, and multifocal multisystemic in 3 patients. The bone was the most commonly involved organ (14), followed by lymph node (5), lung (2), skin (2) and ureter (1). The Langerhans cells were immunohistochemically stained with Langerin, CD1a, S-100 protein, and CD68. Langerin and CD1a were specific for Langerhans cells. CONCLUSIONS: The distribution of the involved organs in patients with LCH was similar to the distribution in Western countries, but lymph node involvement was more frequent, whereas lung involvement was less common. Langerin is considered to be a specific marker for Langerhans cells.

Real-time One-dimensional Brain-Computer Interface (BCI) Using Prefrontal Cortex Neuronal Activities of Rats

The aim of this study is to verify the feasibility of control of one-dimensional (1-D) rotating machine using neural activities of Prefrontal cortex (PFC) in a BCI system. In this study, adult male Sprague-Dawley rats received bilateral implantation of recording micro-electrodes in PFC area. The spontaneous activities of a pair of PFC neurons of water-deprived rats were encoded and converted through a triple-step threshold comparator algorithm to three commands for one-dimensional movement control of a robotic wheel for accessing water. Averaged activities of two PFC neurons were quantized in every 200 ms to four ranges of activities around the mean firing rates (+/-0.5 SD) and were converted to four values. After comparison of the values of two chosen neuron units, direction and speed of rotation were decided. Rats were trained to complete one-dimensional control task to obtain water reward. The results indicated the percentage of stop event increased alone with more training. Different brain activity significantly influenced total water-drinking duration and non-water-drinking duration. Events generated from neuronal activity differed according to variant experimental sessions. Correlation between two signal units impacted controlling performance. Overall, the results of this study suggest that rats were able to manipulate the 1-D BCI system by differentially modulating PFC single neuron activities according to different circumstances.

Malignant Glomus Tumors of the Stomach: A Report of 2 Cases with Multiple Metastases

Glomus tumors are mesenchymal neoplasms usually developing in the dermis or subcutis of the extremities. The majority of glomus tumors are entirely benign, and malignant glomus tumors are very rare, especially those arising in the visceral organs. Here, we are presenting two cases of malignant glomus tumor, initially diagnosed in the stomach by endoscopic biopsy. Case 1 was found in the stomach, right kidney, brain and humerus of a 65-year-old woman, and Case 2 in the stomach and liver of a 63-year-old man. Histologically, the tumor was composed of solid sheets and nests of round and short-spindle shaped tumor cells with vesicular nucleus and prominent nucleolus. The tumor cells were closely admixed with blood vessels of varying size. Immunohistochemically, the tumor cells showed diffuse and strong positive staining for smooth muscle actin and paranuclear, dot-like staining for synaptophysin, but negative for desmin, c-kit, CD34 and S-100 protein. These two are rare cases of a malignant glomus tumor with widespread metastases.

Classification of BMI Control Commands Using Extreme Learning Machine from Spike Trains of Simultaneously Recorded 34 CA1 Single Neural Signals

A recently developed machine learning algorithm referred to as Extreme Learning Machine (ELM) was used to classify machine control commands out of time series of spike trains of ensembles of CA1 hippocampus neurons (n=34) of a rat, which was performing a target-to-goal task on a two-dimensional space through a brain-machine interface system. Performance of ELM was analyzed in terms of training time and classification accuracy. The results showed that some processes such as class code prefix, redundancy code suffix and smoothing effect of the classifiers' outputs could improve the accuracy of classification of robot control commands for a brain-machine interface system.

The Clinicopathological Characteristics of Gastrointestinal Neuroendocrine Tumors; An Analysis of 65 Cases

Background : This study was designed to investigate gastrointestinal neuroendocrine tumors with an emphasis on their clinicopathological characteristics. Methods : Sixty-five cases were reviewed and classified as typical carcinoid (TC), atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC) and small cell carcinoma (SmCC). We performed immunohistochemistry to characterize the expression of the immunoreactivity for synaptophysin, chromogranin, gastrin, somatostatin, thyroid transcription factor-1, p53 and Ki-67. Results : Most commonly, the tumors were located in the rectum (54%), followed by the stomach (23%) and colon (9%). Histologically, the tumors were classified as 49 TCs, 4 ACs, 6 LCNECs and 6 SmCCs. Most tumors were stained positive for synaptophysin and/or chromogranin. Four LCNECs and one SmCC were p53-positive. The carcinoids revealed a low level ( or =30% of the cells showed reactivity for Ki-67 in the majority of LCNECs and SmCCs. Six patients with metastatic carcinoids were older than those patients without metastasis (64 vs 48 years, respectively, p=0.004). Furthermore, the size of tumors was larger for the patients with metastatic carcinoids than for the patients with nonmetastatic carcinoids (2.3 vs 0.5 cm, respectively, p=0.005). Conclusion : Old age, large tumor size and muscle invasion are associated with high grade neuroendocrine tumor and lymph node metastasis for those patients with carcinoids.

Micropapillary Variant of Urothelial Carcinoma of the Urinary Bladder: Report of a Case with Cytologic Diagnosis in Urine Specimen / 대한세포병리학회지

A micropapillary variant of urothelial carcinoma (MPC) is a distinct entity with an aggressive clinical course. It has a micropapillary configuration resembling that of ovarian papillary serous carcinoma. Its cytologic features have rarely been reported. We report a case of MPC detected by urine cytology. A woman aged 93 years presented with a chief complaint of macroscopic hematuria. Cytology of her voided urine showed clusters of malignant cells in a micropapillary configuration. Each tumor cell had a vacuolated cytoplasm, a high nuclear:cytoplasmic ratio, and irregular hyperchromatic nuclei. An ureteroscopic examination revealed exophytic sessile papillary masses extending from the left lateral wall to the anterolateral wall of the urinary bladder. A transurethral resection of the tumor was carried out. The tumor was characterized by delicate papillae with a thin, well-developed fibrovascular stromal core and numerous secondary micropapillae lined with small cuboidal cells containing uniform low- to intermediate-grade nuclei and occasional intracytoplasmic mucinous inclusions. These tumor cells infiltrated the muscle layers of the bladder, and lymphatic tumor emboli were frequently seen. Recognizing that the presence of MPC components in urinary cytology is important for distinguishing this lesion from low-grade papillary lesions and high-grade urothelial carcinomas can result in early detection and earlier treatment for an improved treatment outcome.

REM-related Sleep-Disordered Breathing / 수면정신생리

Sleep is associated with definite changes in respiratory function in normal human beings. During sleep, there is loss of voluntary control of breathing and a decrease in the usual ventilatory response to both low oxygen and high carbon dioxide levels. Especially, rapid eye movement (REM) sleep is a distinct neurophysiological state associated with significant changes in breathing pattern and ventilatory control as compared with both wakefulness and non-rapid eye movement (NREM) sleep. REM sleep is characterized by erratic, shallow breathing with irregularities both in amplitude and frequency owing to marked reduction in intercostal and upper airway muscle activity. These blunted ventilatory responses during sleep are clinically important. They permit the marked hypoxemia that occurs during REM sleep in patients with lung or chest wall disease. In addition, sleep-disordered breathing (SDB) is more frequent and longer and hypoventilation is more pronounced during REM sleep. Although apneic episodes are most frequent and severe during REM sleep, most adults spend less than 20% to 25% of total sleep time in REM. It is therefore possible for patients to have frequent apneas and hypopneas during REM sleep and still have a normal apnea-hypopnea index if the event-rich REM periods are diluted by event-poor periods of NREM sleep. In this review, we address respiratory physiology according to sleep stage, and the clinical implications of SDB and hypoventilation aggravated during REM sleep.