LETTER TO THE EDITOR : Adrenocorticotropic hormone-independent macronodular adrenal hyperplasia with abnormal cortisol secretion mediated by catecholamines

( Harin Rhee ),( Yun Kyung Jeon ),( Sang Soo Kim ),( Yang Ho Kang ),( Seok Man Son ),( Yong Ki Kim ),( In Joo Kim ) 대한내과학회 2014 The Korean Journal of Internal Medicine Vol.29 No.5

Adrenocorticotropic hormone (ACTH)- independent macronodular adrenal hyperplasia (AIMAH) is a rare cause of Cushing syndrome. In AIMAH, cortisol secretion is independent of ACTH, and various hormones and/or cytokines have been thought to stimulate cortisol secretion via the aberrant expression of adrenal receptors or the increased activity of eutopic hormone receptors. Schorr and Ney [1] f irst proposed this concept, and subsequently the ectopic expression of gastric inhibitory peptide (GIP), V2 and V3-vasopressin, β -adrenergic, luteinizing hormone (LH)/human chorionic gonadotropin (hCG), serotonin, and angiotensin receptors, as well as increased activity of a eutopic V1-vasopressin receptor, have been identified in the adrenal gland [1,2]. Several genetic factors, such as Gs α-subunit mutations associated with McCune-Albright syndrome and MC2R (ACTH receptor gene) mutations, have also been postulated as causes of AIMAH. A 50-year-old male was referred and admitted to our hospital due to uncontrolled hypertension. He had suffered from hypertension for 6 years. His blood pressure was originally well controlled for the first 5 years using a calcium channel blocker, but poorly controlled for 1 year before he visited our hospital, despite his regular use of antihypertensive agents. He was initially referred to the Cardiology Department and underwent cardiologic evaluation after complaining of paroxysmal palpitation and dizziness. His 24-hour Holter monitoring and coronary angiographic results were normal, except for several antigen- presenting cells and a minimal coronary arterial obstruction at the middle left anterior descending artery. He had a past history of major depression and had been prescribed an antidepressive agent 18 months before he visited our hospital. On physical examination, he had a moon face, marked central obesity (height, 167 cm; weight, 77.65 kg; body mass index, 27.84 kg/m2), and multiple bruises on his extremities. He also had prominent purple abdominal striae, and all of his morphological features were consistent with Cushing syndrome. Laboratory examinations revealed 145.7 mEq/L serum sodium and 2.86 mEq/L serum potassium. Arterial blood gas analysis revealed metabolic alkalosis (pH 7.519, HCO3, 37.4 mM/L). His hemoglobin A1c level was 5.9%, and his serum fasting blood glucose was 118 mg/dL. The results of basal endocrinological examinations are summarized in Table 1. The circadian variation in serum cortisol production was disrupted, and basal ACTH levels were suppressed. A 24-hour urinary free cortisol test and overnight dexamethasone suppression test (DMST) were both suggestive of Cushing syndrome. Low- and high-dose DMST revealed Cushing syndrome of primary adrenal origin. An abdominal computed tomography scan and magnetic resonance imaging (MRI) revealed bilateral large macronodular adrenal tumors. His pituitary gland was normal on brain MRI scans. We thus diagnosed this patient with Cushing syndrome secondary to AIMAH. To identify aberrant receptors on the adrenal gland, we followed the investigative protocol described by Lacroix et al. [3]. Postural and various provocation tests, including ACTH (250 μg, intravascular), arginine vasopressin (AVP; 10 IU, intramuscular), 5-hydroxy triptamine (5-HT; 10 mg, intravascular), isoproterenol (20 ng/kg/min, intravascular for 30 minutes) and mixed meal tests, were performed. His serum cortisol level showed a positive response to ACTH, AVP, and isoproterenol provocation tests, but a negative response to the postural stimulation test. The results are summarized in Fig. 1A. If the patient had β-adrenergic or AVP receptors on his adrenal gland, then he would have responded to the postural stimulation test; but he did not. We repeated the postural stimulation test, and checked his endogenous antidiuretic hormone (ADH) level. He exhibited an increased ADH level on the postural test, but no cortisol secretion (Fig. 1B). A bilateral adrenalectomy was performed. The subsequent pathological examination of both adrenal glands showed hyperplasia with a multinodular growth pattern: the right and left adrenal glands were sized 14.0 × 5.0 × 3.0 cm and 9.0 × 5.0 × 3.0 cm, respectively, and multiple golden yellow nodules measuring up to 4 cm in diameter were present. Microscopic findings showed that the nodules consisted of variable- sized nests of lipid-laden clear cells similar to those of the normal fasiculata layer (Fig. 2). The final clinical and pathological diagnosis was Cushing syndrome secondary to β-adrenergic agonist-responding AIMAH. After the operation, he took physiological doses of prednisolone and f ludrocortisone. He then lost weight gradually and achieved optimal blood pressure with reduced doses of antihypertensive agents. Kirschner et al. [4] first described AIMAH in 1964. They demonstrated that hypercortisolism was ACTH-independent, and that the resected adrenal glands contained multiple nodules. Since then, a number of cases have been described, and the cause of AIMAH has been characterized more precisely. Previously, steroid production in AIMAH was believed to be autonomous. In the previous study that compared the adrenal glands of patients with AIMAH to those in patients with long-standing Cushing disease, and concluded that prolonged adrenal stimulation by ACTH resulted in adrenal bilateral nodular formation and varying ranges of adrenal autonomy [5]. There were also some cases in which autonomy of the adrenal gland was the result of chronic ACTH stimulation, which eventually resulted in ACTH suppression. However, the rarity of Nelson syndrome following bilateral adrenalectomy in patients with AIMAH strongly argued against the adrenal autonomy hypothesis. In 1971, Schorr and Ney [1] first introduced the concept of aberrant adrenal receptor expression in adrenocortical tissue. They performed in vitro studies, and found that cyclic adenosine monophosphate and corticosterone production in rat adrenocortical carcinoma cells were stimulated by non-ACTH hormones such as catecholamines, thyroid stimulating hormone, follicle stimulating hormone, LH, and prostaglandin E1. This hypothesis was later validated in humans by additional in vitro and in vivo studies. Several ectopic receptors such as GIP, β-adrenergic receptors, vasopressin (V2-V3-vasopressin receptor), serotonin (5-HT7 receptors), and angiotensin II receptors, and increased expression or altered activity of eutopic receptors in- cluding the V1-vasopressin receptors, LH/hCG receptors, serotonin (5-HT4 receptor), and leptin receptors was found [5]. In our patient, the serum cortisol level was increased by ACTH stimulation, exogenous AVP, and isoproterenol. Because exogenous AVP could naturally stimulate ACTH and increase serum cortisol levels, we checked serum ACTH levels during an AVP stimulation test. His serum cortisol level was increased by 82%, and serum ACTH level was increased by 11.5%. We were unable to confirm if AVP itself stimulated the adrenal cortex directly, or whether the induced ACTH caused cortisol secretion. A postural test was performed to screen for the aberrant expression of the AVP, β-adrenergic, or angiotensin II receptors. Interestingly, cortisol secretion was stimulated by exogenous AVP and a β-adrenergic agonist; however, a postural test failed to stimulate cortisol secretion. We repeated the postural test, and also checked the patient`s aldosterone level to verify if the test was accurate and determined serum ADH levels to confirm if endogenous ADH stimulated adrenal cortisol secretion. Because serum aldosterone levels increase in response to postural stimulation, the test itself was working; however, the cortisol response was negative. This suggests that the patient`s β-adrenergic receptor showed a blunted response to the test. Because we did not determine the serum catecholamine levels during postural stimulation, it was unclear whether the postural test induced sufficient endogenous catecholamine. Although a stronger stimulus (such as a treadmill test) would have induced endogenous catecholamine and increased serum cortisol levels, the patient refused because he had ischemic heart disease. In our case, exogenous AVP, but not endogenous ADH, stimulated adrenal cortisol secretion. This suggests that the cortisol response to exogenous pharmacological levels of vasopressin was mediated by AVP-induced catecholamine release [3]. We finally concluded that this patient had ectopic β-adrenergic receptors on the adrenal cortex, and recommended long-term propranolol therapy. However, because he strongly desired to undergo treatment with a rapid response, we consulted the Urological Department who recommended bilateral adrenalectomy. The identification of aberrant adrenal hormone receptors in AIMAH provides novel opportunities for specific pharmacological therapies as alternatives to adrenalectomy. In 1997, Lacroix et al. [3] reported the use of propranolol therapy for ectopic β-adrenergic receptors in adrenal Cushing syndrome in 1997. Some studies have revealed aberrant receptor expression in vitro using reverse transcription polymerase chain reaction. However, a limitation of our study is that we did not confirm aberrant receptor expression using in vitro analyses. In conclusion, we report a rare case of an AIMAH patient. In vivo examinations suggested that altered cortisol regulation due to a β-adrenergic agonist was involved in the pathogenesis of the AIMAH patient.

Effect of Cancer-Related Dysfunctional Beliefs About Sleep on Fear of Cancer Progression in the Coronavirus Pandemic

Kim Harin,Cho Inn-Kyu,Lee Dongin,Kim Kyumin,Lee Joohee,Cho Eulah,Park C. Hyung Keun,Chung Seockhoon 대한의학회 2022 Journal of Korean medical science Vol.37 No.36

Background: This study aimed to explore clinical correlates of fear of progression (FoP) among patients with cancer during the coronavirus disease 2019 (COVID-19) pandemic and examine the mediation effect of cancer-related dysfunctional beliefs about sleep (C-DBS). Methods: Medical charts of patients with cancer who visited a psycho-oncology clinic between July and November 2021 were reviewed. Baseline socio-demographic and cancer-related variables were collected. Patients’ self-report questionnaires, regarding FoP, depression (Patient Health Questionnaire-9 items; PHQ-9), viral anxiety (Stress and Anxiety to Viral Epidemics-6 items; SAVE-6), C-DBS, and other distress, were investigated. Pearson’s correlation and linear regression were performed to examine the risk factors of FoP. Mediation effect analysis with the bootstrap method with 2,000 resamples was implemented. Results: A total of 231 patients were included in the analysis. Linear regression revealed that FoP was predicted by age (β = −0.14, P = 0.003), PHQ-9 (β = 0.48, P < 0.001), SAVE-6 (β = 0.34, P < 0.001), and C-DBS (β = 0.15, P = 0.005). FoP was directly influenced by SAVE-6 and mediated by C-DBS, while it was directly influenced by PHQ-9 with no mediation effect. Conclusion: During the COVID-19 pandemic, the FoP of patients with cancer was associated with younger age, depression, viral anxiety, and C-DBS. Depression and viral anxiety directly influenced FoP, while C-DBS mediated the association between viral anxiety and FoP. Therefore, oncology healthcare professionals are recommended to assess C-DBS of their patients when they are highly distressed from FoP.

Psychological Impact of Quarantine on Caregivers at a Children's Hospital for Contact with Case of COVID-19

Kim Harin,Park Kee Jeong,Shin Yong-Wook,Lee Jung Sun,Chung Seockhoon,Lee Taeyeop,Kim Min-Jae,Jung Jiwon,Lee Jina,Yum Mi-Sun,Lee Beom Hee,Koh Kyung-Nam,Ko Tae-Sung,Lim Eunyoung,Lee Jung Soo,Lee Jee Yeo 대한의학회 2020 Journal of Korean medical science Vol.35 No.28

Quarantine often provokes negative psychological consequences. Thus, we aimed to identify the psychological and behavioral responses and stressors of caregivers quarantined with young patients after a close contact to a coronavirus disease 2019 case at a children's hospital. More than 90% of the caregivers reported feelings of worry and nervousness, while some of them reported suicidal ideations (4.2%), and/or homicidal ideations (1.4%). Fear of infection of the patient (91.7%) and/or oneself (86.1%) were most frequently reported stressors. A multidisciplinary team including infection control team, pediatrician, psychiatrist, nursing staff and legal department provided supplies and services to reduce caregiver's psychological distress. Psychotropic medication was needed in five (6.9%), one of whom was admitted to the psychiatry department due to suicidality. Quarantine at a children's hospital makes notable psychological impacts on the caregivers and a multidisciplinary approach is required.

Joint Torque Estimation Using sEMG and Deep Neural Network

Harin Kim,Hyeonjun Park,Sangheum Lee,Donghan Kim 대한전기학회 2020 Journal of Electrical Engineering & Technology Vol.15 No.5

With the aid of various physical and biological sensors, research is actively being conducted to understand the intention of wearer’s motions through parameters such as joint torque. sEMG signals can be measured faster than physical sensors, which are often used in the fi eld of behavioral intent identifi cation studies. However, electrodes must be placed in the correct positions, and due to the high volume of noise, professional knowledge and accurate hardware design are required. In this paper, a system is constructed to improve the sEMG signal measurement environment by producing small multichannel sEMG modules. In addition, deep neural network supervised learning algorithms are implemented to estimate the torque using only the sEMG signal. Based on this, we analyze the organization of algorithms, the processing of the sEMG data, and how the number of channels aff ects learning. The optimal deep natural network model selected by the analysis is implanted to embedded after learning. The implanted model performs a portable real-time torque optimization (PRTE) according to the sEMG signal entered. In this paper, we study the deep natural network algorithm for estimating sEMG hardware and torque, and how it is implanted into a portable embedded system for use in estimating real-time motion intent. The proposed deep natural network algorithm and the usefulness of the PRTE system are verifi ed through experiments.

Cancer-Related Dysfunctional Beliefs About Sleep Mediate the Influence of Sleep Disturbance on Fear of Progression Among Patients With Surgically Resected Lung Cancer

Kim Harin,Ji Wonjun,Lee Jong Won,Jo Min-Woo,Yun Sung-Chol,Lee Sei Won,Choi Chang-Min,Lee Geun Dong,Lee Hui Jeong,Cho Eulah,Lee Yura,Chung Seockhoon 대한의학회 2023 Journal of Korean medical science Vol.38 No.31

Background: Lung cancer is associated with significant psychological distress, including fear of progression (FoP). Because insomnia and depression are highly prevalent and associated with FoP, we examined the association between FoP, insomnia, and depression in cancer patients. Furthermore, we tested the mediation effect of cancer-related dysfunctional beliefs about sleep (C-DBS) on this association. Methods: We analyzed data collected from patients with surgically resected non-small cell lung cancer from a single-center randomized controlled study investigating digital healthcare applications. Baseline demographic and clinical variables were collected. In addition, selfreported questionnaires including the Fear of Progression Questionnaire-Short Form, Patients Health Questionnaire-9 items (PHQ-9), Insomnia Severity Index, and C-DBS were administered. Results: Among the 320 enrolled patients with lung cancer, a regression model showed that FoP was predicted by age (β = −0.13, P = 0.007), PHQ-9 (β = 0.35, P < 0.001), and C-DBS (β = 0.28, P < 0.001). Insomnia did not directly influence FoP, but C-DBS mediated the association. Depression directly influenced FoP, but C-DBS did not mediate this association. Conclusion: Among patients with surgically resected lung cancer, C-DBS mediated the effects of severity of insomnia on FoP. Depression directly influenced FoP, but C-DBS did not influence this association. To reduce FoP among patients with lung cancer, C-DBS should be addressed in the cognitive behavioral therapy module.

The expression of two isoforms of matrix metalloproteinase-2 in aged mouse models of diabetes mellitus and chronic kidney disease

( Harin Rhee ),( Miyeun Han ),( Sang Soo Kim ),( Il Young Kim ),( Hye Won Lee ),( Sun Sik Bae ),( Hong Koo Ha ),( Eun Soon Jung ),( Min Young Lee ),( Eun Young Seong ),( Dong Won Lee ),( Soo Bong Lee 대한신장학회 2018 Kidney Research and Clinical Practice Vol.37 No.3

Background: This study was undertaken to explore the effects of aging on the kidneys in mouse models of diabetes and chronic kidney disease (CKD), and to compare the expression of two isoforms of matrix metalloproteinase-2 (MMP-2)-secretory full-length MMP-2 and intracellular N-terminal truncated MMP-2 (NTT-MMP-2)-in these models. Methods: Two experimental ICR mouse models were used: a streptozotocin (STZ)-induced type 1 diabetes mellitus model and a 5/6 nephrectomized (5/6Nx) CKD model. The abundance of each isoform of MMP-2 was determined by quantitative polymerase chain reaction (qPCR), and functional analyses were conducted. Moreover, the protein levels of the two MMP-2 isoforms were determined semi-quantitatively by immunohistochemical staining, and their association with tissue damage was assessed. Results: Both isoforms of MMP-2 were upregulated in the kidney tissues of STZ-induced diabetic mice and 5/6Nx mice, irrespective of age. Characteristically, NTT-MMP-2 protein expression was elevated in old control mice, in line with the qPCR results. NTT-MMP-2 expression was limited to the renal cortex, and to the tubulointerstitial area rather than the glomerular area. In terms of tissue damage, tubulointerstitial fibrosis was more severe in old 5/6Nx mice than in their young counterparts, whereas glomerulosclerosis was comparable in old and young 5/6Nx mice. Conclusion: The intracellular isoform of MMP-2 was induced by ageing, irrespective of the presence of diabetes or CKD, and its induction may be related to tubulointerstitial fibrosis in chronic kidney disease.

Overexpression of <i>OsERF48</i> causes regulation of <i>OsCML16</i> , a calmodulin‐like protein gene that enhances root growth and drought tolerance

Jung, Harin,Chung, Pil Joong,Park, Su‐,Hyun,Redillas, Mark Christian Felipe Reveche,Kim, Youn Shic,Suh, Joo‐,Won,Kim, Ju‐,Kon BLACKWELL 2017 PLANT BIOTECHNOLOGY JOURNAL Vol.15 No.10

<P><B>Summary</B></P><P>The AP2/ERF family is a plant‐specific transcription factor family whose members have been associated with various developmental processes and stress tolerance. Here, we functionally characterized the drought‐inducible <I>OsERF48</I>, a group Ib member of the rice ERF family with four conserved motifs, CMI‐1, ‐2, ‐3 and ‐4. A transactivation assay in yeast revealed that the C‐terminal CMI‐1 motif was essential for OsERF48 transcriptional activity. When <I>OsERF48</I> was overexpressed in an either a root‐specific (ROXO<SUP><I>s</I></SUP>ERF<SUP><I>48</I></SUP>) or whole‐body (OXO<SUP><I>s</I></SUP>ERF<SUP><I>48</I></SUP>) manner, transgenic plants showed a longer and denser root phenotype compared to the nontransgenic (NT) controls. When plants were grown on a 40% polyethylene glycol‐infused medium under <I>in vitro</I> drought conditions, ROXO<SUP><I>s</I></SUP>ERF<SUP><I>48</I></SUP> plants showed a more vigorous root growth than OXO<SUP><I>s</I></SUP>ERF<SUP><I>48</I></SUP> and NT plants. In addition, the ROXO<SUP><I>s</I></SUP>ERF<SUP><I>48</I></SUP> plants exhibited higher grain yield than OXO<SUP><I>s</I></SUP>ERF<SUP><I>48</I></SUP> and NT plants under field‐drought conditions. We constructed a putative <I>OsERF48</I> regulatory network by cross‐referencing ROXO<SUP><I>s</I></SUP>ERF<SUP><I>48</I></SUP> root‐specific RNA‐seq data with a co‐expression network database, from which we inferred the involvement of 20 drought‐related genes in <I>OsERF48</I>‐mediated responses. These included genes annotated as being involved in stress signalling, carbohydrate metabolism, cell‐wall proteins and drought responses. They included, <I>OsCML16</I>, a key gene in calcium signalling during abiotic stress, which was shown to be a direct target of OsERF48 by chromatin immunoprecipitation‐qPCR analysis and a transient protoplast expression assay. Our results demonstrated that OsERF48 regulates <I>OsCML16</I>, a calmodulin‐like protein gene that enhances root growth and drought tolerance.</P>

Hospital mortality and prognostic factors in critically ill patients with acute kidney injury and cancer undergoing continuous renal replacement therapy

( Da Woon Kim ),( Geum Suk Jang ),( Kyoung Suk Jung ),( Hyuk Jae Jung ),( Hyo Jin Kim ),( Harin Rhee ),( Eun Young Seong ),( Sang Heon Song ) 대한신장학회 2022 Kidney Research and Clinical Practice Vol.41 No.6

Background: Whether continuous renal replacement therapy (CRRT) should be applied to critically ill patients with both acute kidney injury (AKI) and cancer remains controversial because of poor expected outcomes. The present study determined prognostic factors for all-cause in-hospital mortality in patients with AKI and cancer undergoing CRRT. Methods: We included 471 patients with AKI and cancer who underwent CRRT at the intensive care unit of a Korean tertiary hospital from 2013 to 2020, and classified them by malignancy type. The primary outcomes were 28-day all-cause mortality rate and prognostic factors for in-hospital mortality. The secondary outcome was renal replacement therapy (RRT) dependency at hospital discharge. Results: The 28-day mortality rates were 58.8% and 82% in the solid and hematologic malignancy groups, respectively. Body mass index (BMI), presence of oliguria, Sequential Organ Failure Assessment (SOFA) score, and albumin level were common predictors of 28-day mortality in the solid and hematologic malignancy groups. A high heart rate and the presence of severe acidosis were prognostic factors only in the solid malignancy group. Among the survivors, the proportion with RRT dependency was 25.0% and 33.3% in the solid and hematologic malignancy groups, respectively. Conclusion: The 28-day mortality rate of cancer patients with AKI undergoing CRRT was high in both the solid and hematologic malignancy groups. BMI, presence of oliguria, SOFA score, and albumin level were common predictors of 28-day mortality in the solid and hematologic malignancy groups, but a high heart rate and severe acidosis were prognostic factors only in the solid malignancy group.

Effect and Safety of Pressure Sensor-equipped Handpiece in Phacoemulsification System

Jin Yeong Kim,Harin Kim,Ikhyun Jun,Tae-Im Kim,Kyoung Yul Seo 대한안과학회 2023 Korean Journal of Ophthalmology Vol.37 No.5

Purpose: To evaluate the effect of the Active Sentry handpiece of the Centurion Vision System compared to the Centurion Ozil handpiece for phacoemulsification in cataract surgery. Methods: A retrospective study was conducted on 281 patients (449 eyes) who underwent cataract surgery between August 2020 and June 2021. Preoperative measurements, intraoperative parameters, complication rate, and postoperative outcomes were compared between the Active Sentry handpiece and the Centurion Ozil handpiece groups. Additionally, the parameters were compared in different cataract severity groups and multiple predictive factors for the number of active surge mitigation (ASM) actuations were assessed with the Active Sentry handpiece. Results: There were 198 eyes in the Active Sentry group and 251 eyes in the Centurion Ozil group. There were no statistically significant differences between the two groups, as the cumulative dissipated energy in the Active Sentry and Centurion Ozil groups were 8.32 ± 7.74 and 7.87 ± 9.25 μJ, respectively (p = 0.576). Total surgery time, ultrasound usage time, aspiration time, amount of fluid aspirated, postoperative corrected distant visual acuity, and postoperative decrease in corneal endothelial cell density were comparable between the two groups. The significant contributors to the number of ASM actuations were age, preoperative corrected distant visual acuity, axial length, and total ultrasound time. Conclusions: There was no clear advantage of the Active Sentry handpiece compared to the Centurion Ozil handpiece. ASM actuation increases with age, poor visual acuity before surgery, short axial length, and prolonged ultrasound usage time. It is expected that in more severe and high-risk cataract surgery, the Active Sentry handpiece functions more effectively, possibly affecting the safety and prognosis.

3D 바운딩박스 객체 인식을 통한 센서융합 기반 동적격자지도 갱신기법 연구

김태현(Taehyun Kim),안경재(Kyungjae Ahn),장하린(Harin Jang),김진우(Jinwoo Kim),허세종(Sejong Heo),강연식(Yeonsik Kang) 한국자동차공학회 2023 한국자동차공학회 학술대회 및 전시회 Vol.2023 No.11