Curcumin Enhances the Anticancer Effects of Binimetinib on Melanoma Cells by Inducing Mitochondrial Dysfunction and Cell Apoptosis with Necroptosis

Background@#Recent studies suggest that MEK1/2 inhibitors, including binimetinib, significantly improve malignant melanoma (MM) patient survival. Growing evidence suggests that phytochemicals, especially curcumin, can overcome drug resistance in cancer cells through a variety of mechanisms. @*Objective@#This study aims to examine curcumin’s efficacy in vitro combined with binimetinib in human MM cells. @*Methods@#We used 2D monolayer and 3D spheroid human epidermal melanocyte culture models, HEMn-MP (human epidermal melanocytes, neonatal, moderately pigmented), and two human MM cell lines, G361 and SK-MEL-2, to evaluate cell viability, proliferation, migration, death, and reactive oxygen species (ROS) production following single therapy treatment, with either curcumin or binimetinib, or a combination of both. @*Results@#Compared to MM cells treated with single therapy, those with combination therapy showed significantly decreased cell viability and increased ROS production. We observed apoptosis following both single and combination therapies. However only those who had had combination therapy had necroptosis. @*Conclusion@#Collectively, our data demonstrates that curcumin exerts significant synergistic anticancer effects on MM cells by inducing ROS and necroptosis when combined with binimetinib. Therefore, a strategy of adding curcumin to conventional anticancer agents holds promise for treating MM.

Human kidney organoids model the tacrolimus nephrotoxicity and elucidate the role of autophagy

Background/Aims@#Tacrolimus has been used as an immunosuppressive agent in organ transplantation. Despite the therapeutic benefits, tacrolimus’s use is limited due to its nephrotoxicity. To reduce tacrolimus nephrotoxicity, effective humanized experimental models may be helpful. Here, we modeled tacrolimus nephrotoxicity using kidney organoids derived from human inducible pluripotent stem cells (iPSCs) in vitro. @*Methods@#Kidney organoids were differentiated from the CMC11 iPSC cell line, re-seeded in 96-well plates, and treated with tacrolimus at doses of 0, 30, or 60 μM for 24 hours. This in vitro model was compared to a mouse model of tacrolimus nephrotoxicity and the associated mechanisms were investigated. @*Results@#The size of the kidney organoids and cell viability decreased in dose-dependent manners after treatment with tacrolimus. The number of tubular cells decreased with a loss of polarity, similar to the effects seen in mouse tacrolimus nephrotoxicity. Ultrastructural analysis showed numerous vacuoles in the proximal tubular cells of the kidney organoids treated with tacrolimus. Tacrolimus treatment induced oxidative stress and mitochondrial dysfunction, and autophagic activity was enhanced in the kidney organoids. Rapamycin, an autophagy inducer, accelerated cell death in the kidney organoid model of tacrolimus nephrotoxicity, which was attenuated by treatment with 3-methyladenine, an autophagy inhibitor. These findings indicate that the augmentation of autophagy by rapamycin treatment accelerated tacrolimus nephrotoxicity. @*Conclusions@#Our data suggest that human kidney organoids are an effective in vitro model of tacrolimus nephrotoxicity and that autophagy plays a critical role in tacrolimus nephrotoxicity.

Association between defoliant exposure and survival to discharge after out-of-hospital cardiac arrest

Purpose@#We investigated the association between defoliant exposure and survival to discharge after out-of-hospital cardiac arrest. @*Methods@#This is a retrospective case-control study based on the cardiopulmonary resuscitation (CPR) registry. The electronic medical records of out-of-hospital cardiac arrest victims from 6/9/2008 to 12/31/2016 were analyzed statistically. The case patients group had a history of defoliant exposure while the control group did not. Among the 401 victims studied, a total of 110 patients were male out-of-hospital cardiac arrest patients. Baseline characteristics and the parameters involved in cardiac arrest were analyzed and compared between the two groups after propensity score matching. The primary outcome was survival to discharge, and secondary outcomes were sustained return of spontaneous circulation (ROSC) and survival to admission. @*Results@#After propensity score matching a total of 50 patients (case=25, control=25) were analyzed. Primary outcome (survival to discharge) was not significantly different between case and control groups [(OR, 1.759; 95% C.I., 0.491-6.309) and (OR, 1.842;95% C.I., 0.515-6.593), respectively]. In the subgroup analysis, there were also no significant differences between the control group and subgroups in primary and secondary outcomes according to defoliant exposure severity. @*Conclusion@#There is no statistically significant association between defoliant exposure and survival of out-of-hospital cardiac arrest.

The Effects of Agent Orange in Patient with Pneumonia

Purpose@#Agent Orange (AO) is a herbicide and defoliant used by the United States and its military allies during the Vietnam War. Pneumonia is a common cause of death among Vietnam veterans in our hospital. There have been no previous studies researching any association between AO exposure and the prognosis for pneumonia. The primary objective of this study was to investigate associations between AO exposure and 30-day mortality due to pneumonia. The secondary objective was to examine the clinical factors associated with therapeutic outcomes in veterans with pneumonia, and to assess the prevalence of combined diseases in AO-exposed veterans. @*Methods@#This study retrospectively included veteran patients diagnosed with pneumonia in the emergency department and hospitalized between February 2014 and March 2018. The enrolled patients were grouped according to their defoliant exposure history, and the clinical information of defoliant-exposed and non-defoliant-exposed groups were compared. Patients were divided according to 30-day mortality, and significant factors influencing mortality were evaluated by using univariate analysis and multivariate analysis. The final multivariate model revealed the effect of AO exposure on therapeutic outcomes of pneumonia. @*Results@#A total of 1006 patients were analyzed. Of these, 276 patients had a history of AO exposure, whereas 730 patients had not been exposed. Factors positively associated with 30-day mortality were malignancy, respiratory rate, blood urea nitrogen, and albumin which was negatively associated with mortality. @*Conclusion@#Exposure to defoliant is not associated with 30-day mortality in patients with pneumonia. However, veterans with defoliant exposure are associated with a high prevalence of diabetes mellitus, hypertension, cerebrovascular accident, malignancy, and chronic kidney disease.

Conservative condylectomy alone for the correction of mandibular asymmetry caused by osteochondroma of the mandibular condyle: a report of five cases

We describe our experience with conservative condylectomy for the correction of facial asymmetry in five patients with osteochondroma of the mandibular condyle. All five patients presented with malocclusion and facial asymmetry, which are common clinical findings of osteochondroma involving the mandibular condyle. We performed conservative condylectomy without additional orthognathic surgery for all five patients, preserving the vertical height of the condylar process as much as possible. Following surgery, intermaxillary traction using a skeletal anchorage system with rubber elastics was performed on all patients to improve occlusion, and, when necessary, additional minimal orthodontic treatment was performed. The mean follow-up period was 42 months. At the last follow-up visit, all patients exhibited satisfactory facial symmetry and remodeling of the remaining condyle, with stable health and no signs of recurrence. In conclusion, conservative condylectomy alone, without subsequent orthognathic surgery, is adequate for the restoration of facial symmetry and the preservation of vertical condylar height in select patients with condylar osteochondroma.

Surgery for Bilateral Large Intracranial Traumatic Hematomas: Evacuation in a Single Session

OBJECTIVE: Management guidelines for single intracranial hematomas have been established, but the optimal management of multiple hematomas has little known. We present bilateral traumatic supratentorial hematomas that each has enough volume to be evacuated and discuss how to operate effectively it in a single anesthesia. METHODS: In total, 203 patients underwent evacuation and/or decompressive craniectomies for acute intracranial hematomas over 5 years. Among them, only eight cases (3.9%) underwent operations for bilateral intracranial hematomas in a single session. Injury mechanism, initial Glasgow Coma Scale score, types of intracranial lesions, surgical methods, and Glasgow outcome scale were evaluated. RESULTS: The most common injury mechanism was a fall (four cases). The types of intracranial lesions were epidural hematoma (EDH)/intracerebral hematoma (ICH) in five, EDH/EDH in one, EDH/subdural hematoma (SDH) in one, and ICH/SDH in one. All cases except one had an EDH. The EDH was addressed first in all cases. Then, the evacuation of the ICH was performed through a small craniotomy or burr hole. All patients except one survived. CONCLUSION: Bilateral intracranial hematomas that should be removed in a single-session operation are rare. Epidural hematomas almost always occur in these cases and should be removed first to prevent the hematoma from growing during the surgery. Then, the other hematoma, contralateral to the EDH, can be evacuated with a small craniotomy.

The Patterns of Intraosseous Venography before Percutaneous Vertebroplasty for Osteoporotic Compression Fractures

OBJECTIVE: Bone cement leakage is a well-known potential complication of percutaneous vertebroplasty (PVP) in patients with osteoporotic compression fracture. Even though there has been a controversy in the efficacy of antecedent venography to prevent this complication, many authors have performed intraosseous venography before bone cement injection. The goal of this study was to classify the venous drainage patterns of spine before PVP, and compare their patterns at different vertebral levels. METHODS: The authors retrospectively reviewed 1,042 intraosseous venographic patterns in 321 patients with 574 osteoporotic compression fractures during six-year period in one institution. To classify venogram patterns, we selected simple lateral X-ray of spine taken immediately after injection of the contrast dye. We classified the venography patterns according to contrast leakage pattern and leakage direction as follows; trabecular (TR), trabecular anterior (TA), trabecular posterior (TP), trabecular anterior-posterior (TAP), trabecular lateral (TL), venous anterior(VA), venous posterior (VP), venous anterior-posterior (VAP), soft tissue (ST). Also, we compared venogram patterns according to different spinal levels. RESULTS: In overall, the most common pattern was TP type accounting for 37.4% (390/1042) of all intraosseous venograms. This is followed by TAP in 21.5%, TR 17.4%, TA 11.6%, TL 5.8%, ST 4.1%, VA 1.2%, VP 0.6%, and VAP 0.4% in descending order of frequency. According to the spinal level, TR and TAP types were most common in thoracic spine (T6-T10), TP type was most common in thoraco-lumbar spine (T11-L2), and TP and TAP types were most common in lumbo-sacral spine (L3-S1). Contrast dye leakage to soft tissue such as psoas muscle or disc were detected in 43 (4.1%) venograms. Direct venous drainage without staining of vertebral body was found in 23 (2.2%) venograms. The 8.3% of thoracic venogram showed direct venous drainage. Thoracic level showed a more tendency of direct venous drainage than other spine levels (p<0.01). CONCLUSION: The authors propose a new classification system of intraosseous venography during PVP. The trabecular-posterior (TP) type is most common through all spine, and venous-filling (V) type was most frequent in thoracic spine. Further study would be necessary to elucidate the efficacy of this classification system to prevent bone cement leakage during PVP.

Development of MRI Phantom for Assessing MR Image Quality

PURPOSE : To evaluate MR image qualities we developed a new MRI phantom with the fixation structures necessary to position it into coil firmly. MATERIALS AND METHODS : We designed MRI phantom for eight evaluation items such as slice thickness accuracy, high contrast spatial resolution, low contrast object detectability, geometry accuracy, slice position accuracy, image intensity uniformity, percent signal ghosting and signal to noise ratio. For the positioning of phantom at coils, the fixation structures were set up on the surface of phantom. Six different MRI units were used for test the possibility for the clinical application and their image qualities were evaluated. RESULTS : We acquired appropriate MR image qualities enough for the evaluation on all used MR units and confirmed that their evaluations were within reliable values compared to real ones for some items. The positioning of our phantom into head coils with fixation structures worked well for proper imaging. CONCLUSION : We found that our prototype of MRI phantom had the possibility of clinical application for MR image quality assessment.

1H MR Spectroscopic Patterns of Normal Adult Brain

PURPOSE: To evaluate regional differences of 1H magnetic resonance(MR) spectral patterns in normal adulthuman brains. MATERIALS AND METHODS: A total of 44 1H MR spectra in 25 volunteers aged 27-45 were obtained infive regions including the frontal lobe(10), parietal lobe(10), temporal lobe(5), basal ganglia(10) and thalamus(9). 1H MR spectroscopy(MRS) was performed using a PRESS sequence with a TR of 2000ms and a TE of 270msfrom a volume of cm on a 1.5T clinical MR unit. Relative metabolite ratios of NAA/Cho, NAA/Cr and CR/Cho in eachregion were measured and compared. RESULTS: A total of 44 reliable spectra were successfully obtained in allregions. NAA/Cho, NAA/Cr and Cr/Cho ratios varied considerably, ranging from 1.09 +/-0.2 to 2.46 +/-0.25, from1.72 +/-0.35 to 2.45 +/-0.25 and from 0.64 +/-0.1 to 1.01 +/-0.12, respectively. Significant regional difference sin metabolite ratios were observed; higher NAA/Cho and NAA/Cr ratios in the parietal lobe, lower NAA/Cho ratios inthe temporal lobe, and lower Cr/Cho ratios in the temporal lobe compared to those of other regions(p<0.05). Differences in metabolite ratios between the right and left frontal lobes, and between the right and left basalganglias were not significant. CONCLUSION: 1H MR spectra of the normal adult human brains using in vivo singlevoxel 1H MRS represented significant regional differences in metabolite ratios of NAA/Cho, NAA/Cr and Cr/Cho. Our1H MR spectroscopic results are a useful ueference for assessing the 1H MRS pattern of various intracranial diseases.

In Vivo Single Voxel 1H MR Spectroscopy in Cerebral Glioma

PURPOSE: To assess the metabolite ratios in gliomas to determine whether the metabolic information obtained by using by using in vivo single vexel 1H magnetic resonance spectroscopy(MRS) can be used as a marker for the grading of malignancy. MATERIALS AND METHODS: A total of 28 1H MR spectra from brain tumors in 27 patients with pathologically-proven gliomas were recorded. Seven patients had low grade gliomas (grade II astrocytoma in three, oligodendroglioma in three and mixed glioma in one), six had anaplastic gliomas (grade III astrocytoma in three and oligodendroglioma in three), and 14 had glioblastoma multiformes (grade IV), 1H MRS was performed on a 1.5T MRunit using PRESS sequence with a TR of 2000ms, a TE of 270 or 135ms and a voxel size of cm for all spectra. Relative lactate levels, NAA/Cho, NAA/Cr and Cho/Cr ratios were measured based on the peak heights of each resonance and compared among gliomas. RESULTS: Most tumors demonstrated decreased NAA, elevated Cho and lactate. Relatively high lactate and Cho levels and markedly decreased NAA level were more frequently observed in the high grade gliomas than in low grade gliomas. Marked elevation of lactate level in the solid component of the tumor was mostly observed in high grade gliomas. In a patient with gliomatosis cerebri, 1H MRS demonstrated a spectral pattern of tumor in filtration in an area that on MR images was apparently normal. However, NAA/Cr, NAA/Cho and Cho/Cr ratios did not significantly correlate, however, with the histologic grading of malignancy. Because of the partial volume effect, the heterogeneity of tumors containing solid and cystic or necrotic components within avoxel limited the interpretation of 1H MRS data for the grading of malignancy. CONCLUSION: The results suggest that in some patients in vivo single voxel 1H MRS may be useful for grading the malignancy of gliomas and evaluating the exact extent of tumors. In solid gliomas, the relative level of lactate appears to be a good markerfor the grading of malignancy.

1H MR Spectroscopy in Parkinson's Disease and Progressive Supranuclear Palsy: Preliminary Study

PURPOSE: To determine whether 1H magnetic resonance spectroscopy (MRS) is useful in differentiating idiopathic Parkinson's disease (IPD) from progressive supranuclear palsy (PSP), based on metabolite ratios. MATERIALS AND METHODS: Using a 1.5 T MR Unit, single voxel 1H MRS using STEAM with a TR of 2000ms and a TE of 135ms was performed in seven PD and eight PSP patients. Five age-matched volunteers(mean age, 63 years) andanother five younger healthy volunteers(mean age, 30 years) were studied as normal controls. The regions of interest were the putamen and pallidum, with a size of 2 X 2 X 2cm. After measuring the spectral intensities ofeach metabolite (N-acetylaspartate=NAA, choline=Cho, creatine=Cr and lactate), relative peak height ratios ofNAA/Cr, Cho/Cr and Naa/Cho, and lactate levels among four groups were compared. ESULTS: NAA/Cho and NAA/Crratios were statistically lower in the PSP group than the IPD group (1.21 +/-0.26 versus 1.45 +/-0.20, and 1.26 +/-.23 versus 1.38 +/-0.19, respectively : p0.05). Cho/Cr ratios were not different among four groups. Lactate was not detectedin any patients. CONCLUSION: NAA/Cho and NAA/Cr ratios in the corpus striatum were significantly lower in the PSP group than in the age-matched control and IPD groups. These results suggest that loss of neuron cells in thecorpus striatum is more prominent in PSP than in IPD, and that NAA/Cho and NAA/Cr ratios may help in differential diagnosis of IPD and PSP.

A Case of Distal Renal Tubular Acidosis

Distal renal tubular acidosis (RTA) is a biochemical syndrome as a deficiency of hydrogen in secretion by the distal tubule and collecting duct. Owing to the nature of the defect, hyperchloremic non-anion gap metabolic acidosis and high urine pH despite severe systemic acidosis is characterized. Typical manifestations of distal RTA are growth retardation, rickets, polyuria and nephrocalcinosis. We experienced a case of distal renal tubular acidosis in a 4 years old female child who complained of growth retardation and gait disturbance. She showed typical hyperchloremic non-anion gap metabolic acidosis and persistent high urine pH. In radiographic examination. we found delayed bone age and severe rachitic changes of wrist, elbow, and knee as well as nephrocalcinosis. In ammonium chloride loading test, high urine pH persisted despite the lowering blood HCO3- concentration. After alkali therapy, she is in well condition with excellent growth velocity and absence of rachitic changes.

A clinical evaluation of urethral stricture / 대한비뇨기과학회지

The results with management of urethral stricture are disappointing, with a high rate of early and late recurrence. Recently, the success of internal urethrotomy has made us question the role of open urethroplasty in the management of urethral strictures. Thus a clinical evaluation was made on 116 patients with urethral stricture in the Department of Urology, Masan Koryo General Hospital, during the period from May 1985 to July 1991. The or stricture was incomplete in 92 cases and complete in 24 cases. The length of stricture was less than 1cm in 86 cases, 1 to 2cm in 19 cases, more than 2cm in 3 cases and multiple strictures in 8 cases. The treatment modality of incomplete urethral stricture was internal urethrotomy in 68 cases and urethroplasty in 9 cases regardless of length, and dilatation in 15 cases with mild stricture. Incomplete urethral stricture, internal urethrotomy was carried out in 7 cases with less than 1cm long stricture and urethroplasty in 17 cases regardless of length. The overall success rate in incomplete urethral stricture was 88.2 % in internal urethrotomy and 88.9 % in urethroplasty, and in complete urethral stricture, 85.7 % in internal urethrotomy and 82. 4% in urethroplasty. We think that visual internal urethrotomy is a valuable initial method, when stricture is incomplete or less than 1cm in length in cases of complete urethral stricture.

High-Dose intravenous immune globulin therapy for hyperbilirubinemia caused by ABO incompatibility

Four newborn infants with hyperbilirubinemia, caused by ABO blood group incompatibility, were treated with high-dose intravenous immune globulin(IVIG). As soon as the diagnosis was clinically suspected, these infants received conventional treatment including phototherapy and were monitored closely for bilirubin levels. When bilirubin concentrations reached the risk point in spite of phototherapy, IVIG was given at a dose of 1g/kg for 6 hours. In all cases, bilirubin levels declined within 12 hours after LVIG therapy, and to rebound effect was seen, No side effects of IVIG treatment were observed. We suggest that high-dose IVIG therapy may be useful in the treatment of hyperbilirubinemia due to ABO incompatibility, and reduce the need for exchange transfusion.

Penile paraffinoma: 39 cases / 대한비뇨기과학회지

Penile paraffinoma chiefly resulting from injudicious paraffin injection into the penile tissue for the purpose or enlarging the penis and facilitating erection provokes a lot of serious undesirable effects. The only successful therapy for the complicated penile paraffinoma is adequate surgical excision of the involved tissue and repair of the denuded penis. But it is not easy to resurface the completely denuded penis after complete removal of extensive paraffinoma. Herein we present 39 eases of penile paraffinoma who underwent the surgical correction. The extent of paraffinoma was confined within the distal penile skin in 13 cases and spread to the whole penile skin with or without involvement of scrotum and prepubic soft tissue in 26 cases. The treatment modalities for covering the denuded penis after complete excision of the granulomatous tissue were bilateral pedicle scrotal flap in 23 cases. primary closure in 15 cases and Cecil`s scrotal implantation in 1 case. Bilateral pedicle scrotal flaps based on the lateral scrotal blood supply were extremely advantageous for repair of a extensively denuded penis because of their great elasticity and the cosmetic and functional results of the scrotal flap were satisfactory in all patients.

A Case of Complete Duplication of the Urethra in Male / 대한비뇨기과학회지

Duplication of the urethra is an unusual congenital anomaly. It exists in two distinct forms, either complete or incomplete : complete form is a rarer anomaly. We presented a case of complete duplication of the urethra in 27-year-old male with brief review or literature.

A Case of Primary Hyperparathyroidism in Childhood

No abstract available.