Compliance with new drug use and the effect of discrepant drug susceptibility testing on MDR/RR-TB treatment.

BACKGROUND: Following the WHO???s announcement in 2018, the use of new drugs was recommended for all patients with multidrug-resistant TB (MDR-TB) in Korea. This study aimed to evaluate adherence to new anti-TB drug regimens and implementation of molecular drug susceptibility testing (mDST) in Korea.METHODS: Nationwide, 560 patients were reported as having MDR-TB in 2021. The implementation of mDST and new anti-TB drug use were analysed. The discrepancy between mDST and phenotypic DST (pDST) results and their implications on the use of new anti-TB drugs were also analysed. The use of novel anti-TB drugs has been approved by the National TB Expert Committee.RESULTS: The non-adherence rate in MDR-TB patients was 14.3%. The mDST implementation rate was 96.1%. Of the 459 patients who underwent both mDST and pDST, the discordance rate for rifampicin (RIF) resistance was 22.6% (n = 104), of which 72.1% (n = 75) were resistant on mDST but susceptible on pDST. The discrepancy in mDST and pDST results related to RIF resistance was found to be the main cause of non-adherence to new drug regimen.CONCLUSION: Comprehensive training on how to interpret conflicting results between mDST and pDST could enhance the utilisation of new drugs in the treatment of MDR/RIF-resistant TB.

Hemorrhagic morbidity in nulliparous patients with placenta previa without placenta accrete spectrum disorders.

Background: Placental adhesion spectrum (PAS) is a disease in which the trophoblast invades the myometrium, and is a well-known high-risk condition associated with placental previa. Aim: The morbidity of nulliparous women with placenta previa without PAS disorders is unknown. Patients and Methods: The data from nulliparous women who underwent cesarean delivery were collected retrospectively. The women were dichotomized into malpresentation (MP) and placenta previa groups. The placenta previa group was categorized into previa (PS) and low-lying (LL) groups. When the placenta covers the internal cervical os, it is called placenta previa, when the placenta is near the cervical os, it is called the low-lying placenta. Their maternal hemorrhagic morbidity and neonatal outcomes were analyzed and adjusted using multivariate analysis based on univariate analysis. Results: A total of 1269 women were enrolled: 781 women in the MP group and 488 women in the PP-LL group. Regarding packed red blood cell transfusion, PP and LL had adjusted odds ratio (aOR) of 14.7 (95% confidence interval (CI): 6.6 - 32.5), and 11.3 (95% CI: 4.9 - 26) during admission, and 51.2 (95% CI: 22.1 - 122.7) and 10.3 (95% CI: 3.9 - 26.6) during operation, respectively. For intensive care unit admission, PS and LL had aOR of 15.9 (95% CI: 6.5 - 39.1) and 3.5 (95% CI: 1.1 - 10.9), respectively. No women had cesarean hysterectomy, major surgical complications, or maternal death. Conclusion: Despite placenta previa without PAS disorders, maternal hemorrhagic morbidity was significantly increased. Thus, our results highlight the need for resources for those women with evidence of placenta previa including a low-lying placenta, even if those women do not meet PAS disorder criteria. In addition, placenta previa without PAS disorder was not associated with critical maternal complications.

Treatment outcomes of multidrug-resistant TB with selective use of new drugs.

SETTING: This was a nationwide cohort study.OBJECTIVE: To assess the treatment outcomes in patients with multidrug-resistant TB (MDR-TB) who underwent treatment guided by a national TB expert review committee in South Korea.DESIGN: We enrolled all patients with MDR-TB submitted for approval for the use of new TB drugs, including bedaquiline and delamanid, from 2016 to 2019. Patients were classified into two groups: those on new TB drugs and those not on new TB drugs. We compared the final treatment outcomes between the groups and analysed the prognostic factors.RESULTS: Of a total of 785 patients, respectively 754 (96.1%) and 31 (3.9%) were classified into the "new TB drugs" group and "no new TB drugs" group. The new TB drugs group had a higher acid-fast bacilli smear positivity rate and higher resistance rate to second-line injectable drugs or fluoroquinolones. Of all the patients, 97.8% achieved culture conversion (97.7% vs. 100%), and 80.4% achieved treatment success (80.2% vs. 86.7%); there was no difference between the two groups.CONCLUSIONS: New drugs are currently recommended for use in all MDR-TB treatment regimens, and the use of new drugs, as determined by an expert committee, in mainly quinolone-susceptible MDR-TB, did not compromise the treatment success rate.

Incidence of idiopathic benign paroxysmal positional vertigo subtype by hospital visit type: experience of a single tertiary referral centre.

OBJECTIVE: To investigate the incidence of benign paroxysmal positional vertigo subtype by hospital visit type (i.e. out-patient department vs emergency room), in a single tertiary referral centre. METHODS: A total of 772 consecutive patients with benign paroxysmal positional vertigo were included. Using head-roll and Dix-Hallpike tests, benign paroxysmal positional vertigo subtype was determined as canalolithiasis posterior semicircular canal benign paroxysmal positional vertigo, geotropic horizontal semicircular canal benign paroxysmal positional vertigo or apogeotropic benign paroxysmal positional vertigo. RESULTS: The posterior semicircular canal benign paroxysmal positional vertigo patients who were evaluated via the out-patient department outnumbered those evaluated via the emergency room, while those with horizontal semicircular canal benign paroxysmal positional vertigo who were evaluated via the emergency room outnumbered those evaluated via the out-patient department. CONCLUSION: A significantly higher proportion of patients who visited the emergency room had horizontal semicircular canal benign paroxysmal positional vertigo than posterior semicircular canal benign paroxysmal positional vertigo. These results suggest that the true incidence of horizontal semicircular canal benign paroxysmal positional vertigo might be higher than previously reported.

Procedural and obstetric outcomes after embryo reduction vs fetal reduction in multifetal pregnancy.

OBJECTIVE: To compare the obstetric outcome and incidence of procedure-related adverse events after embryo reduction (ER) vs fetal reduction (FR), in multifetal pregnancies undergoing reduction to twins or singletons. METHODS: We analyzed retrospectively data from multifetal pregnancies that underwent transvaginal ER (n = 181) at a mean gestational age of 7.6 weeks or transabdominal FR (n = 115) at a mean gestational age of 12.9 weeks between December 2006 and January 2017. FR was performed after a detailed fetal anomaly scan. The two groups were compared with respect to obstetric outcomes, such as incidence of miscarriage, early or late preterm delivery, maternal complications and fetal loss, and procedure-related adverse events, including incidence of subchorionic hematoma and procedure-related fetal loss. RESULTS: Compared with pregnancies that underwent ER, the incidence of procedure-related fetal loss was lower in the FR group (7.2% vs 0.9%; P = 0.039; odds ratio (OR), 0.12; 95% CI, 0.02-0.89). Mean gestational age at delivery for twins was 34.2 weeks in the ER group and 35.7 weeks in the FR group (P = 0.014). Compared with the ER group, the FR group had lower miscarriage (8.8% vs 2.6%; P = 0.045; OR, 0.28; 95% CI, 0.08-0.97) and overall fetal loss (13.3% vs 5.2%; P = 0.031; OR, 0.36; 95% CI, 0.14-0.91) rates. CONCLUSIONS: The FR procedure is, overall, a better and safer approach to reducing morbidity and mortality in multifetal pregnancies. Spontaneous demise of one fetus may occur after ER, and FR has the advantage that chorionic villus sampling and ultrasound screening for increased nuchal translucency and anatomical defects can be conducted before the procedure. The ER approach is still reasonable when a patient's religious or other ethical concerns are of primary importance. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Relative bioavailability of copper in tribasic copper chloride to copper in copper sulfate for laying hens based on egg yolk and feather copper concentrations.

This experiment was conducted to determine the relative bioavailability (RBV) of Cu in tribasic copper chloride (TBCC) to Cu in copper sulfate (monohydrate form; CuSO4·H2O) for layer diets based on egg yolk and feather Cu concentrations. A total of 252, 72-wk-old Hy-Line Brown laying hens were allotted to 1 of 7 treatments with 6 replicates consisting of 6 hens per replicate in a completely randomized design. Hens were fed corn-soybean meal-based basal diets supplemented with 0 (basal), 100, 200, or 300 mg/kg Cu from CuSO4 or TBCC for 4 wk. Results indicated that egg production, egg weight, and egg mass were not affected by dietary treatments. However, increasing inclusion levels of Cu in diets from CuSO4 decreased (P < 0.05) feed conversion ratio (FCR), whereas increasing inclusion levels of Cu in diets from TBCC did not affect FCR, indicating significant interaction (P < 0.05). Increasing inclusion levels of Cu from TBCC or CuSO4 increased (P < 0.05) Cu concentrations of egg yolk and feathers. Feather Cu concentrations were greater (P < 0.01) for hens fed diets containing CuSO4 than for hens fed diets containing TBCC. The values for the RBV of Cu in TBCC to Cu in CuSO4 based on log10 transformed egg yolk and feather Cu concentrations were 107.4% and 69.5%, respectively. These values for the RBV of Cu in TBCC did not differ from Cu in CuSO4 (100%). The RBV measured in egg yolk did not differ from the RBV measured in feather. In conclusion, the RBV of Cu in TBCC to Cu in CuSO4 can be determined using Cu concentrations of egg yolk and feathers although the values depend largely on target tissues of laying hens. For a practical application, however, the RBV value of Cu in TBCC to Cu in CuSO4 could be 88.5% when the RBV values determined using egg yolk and feather Cu concentrations were averaged.

Vertical components of head-shaking nystagmus in vestibular neuritis, Meniere's disease and migrainous vertigo.

OBJECTIVES: To describe vertical and horizontal components of head-shaking nystagmus (HSN) in various vestibular disorders. DESIGN: Retrospective case review. SETTING: Tertiary care academic referral centre. PARTICIPANTS: Head-shaking nystagmus was assessed in 66 vestibular neuritis (VN) patients at acute (<7 days) and follow-up (2 months), and 65 Meniere's disease (MD) and 76 migrainous vertigo (MV) in interictal period. MAIN OUTCOME MEASURES: Head-shaking nystagmus was categorised as pure horizontal, pure vertical or mixed. Horizontal HSN was classified as monophasic or biphasic and paretic or recovery. Vertical HSN was classified as upbeat or downbeat. RESULTS: Abnormal HSN (pathologic monophasic, biphasic or delayed-peak HSN) showed different positive rates depending on the vestibular disorders and compensation (94% in acute VN; 89% in FU VN; 78% in MD; 50% in MV). Paretic HSN with the nystagmus towards the lesioned side was the most common type in VN and MD; however, recovery HSN with the nystagmus towards the intact side could be rarely observed especially in patients with MD or compensated VN. Vertical nystagmus could be combined with horizontal HSN, and upbeat HSN was observed in most (83%) of the patients with acute VN, but downbeat HSN was common in follow-up VN (83%), MD (97%) and MV (85%). Weak perverted HSN, which is assumed to be a central nystagmus, was rarely observed in MD and MV (6-9%), but not in VN. CONCLUSIONS: Head-shaking nystagmus (HSN) in horizontal plane is a valuable tool in the assessment of vestibular imbalance. Common observation of upbeat HSN in acute VN and downbeat HSN in follow-up VN, MD and MV suggests that vertical components are possibly related to the involvement of vestibular apparatus and compensation. Weak perverted HSN and delayed-peak HSN were rarely observed in MD and MV, and never observed in VN, suggesting that it is possibly related to either asymmetrically impaired vertical canals or misorientation of the velocity-storage system.

Two-dimensional analysis of head-shaking nystagmus in patients with Meniere's disease.

The HSN test is a simple examination that can be easily performed by clinicians, however only a few studies have analyzed the 2-dimensional characteristics of HSN in patients with MD. The objective of the study was to characterize different types of 2-dimensional head-shaking nystagmus (HSN) in patients with Meniere's disease (MD). Sixty-five patients with definite MD were enrolled. HSN was considered pathologic, if slow-phase velocity (SPV) was ≥ 4°/s and was classified as paretic or recovery according to the direction, and as monophasic or biphasic according to the presence of direction change. HSN was categorized as pure horizontal, mixed or pure vertical. When vertical SPV was larger than horizontal SPV, HSN was categorized as perverted. Forty-four patients (68%) had pathologic HSN and 28 patients (43%) had pathologic canal paresis. Monophasic-paretic HSN was the most common and followed by biphasic-paretic HSN, monophasic-recovery HSN and biphasic-recovery HSN. Delayed-peak monophasic-paretic HSN, which was not observed in vestibular neuritis, was found in 6 patients with MD. Thirty-three patients (51%) had a vertical component, which was monophasic and downbeat in 32 (97%). Every pathologic HSN in horizontal plane had higher SPV in horizontal plane than that of vertical plane. Perverted HSN was found in 4 patients, of whom 3 had pure vertical and one had mixed type HSN. Our data showed that HSN is a sensitive detector of vestibular dysfunction. HSN showed diverse types with a new type of delayed-peak HSN. Vertical components of HSN were observed in about half, but they were negligible compared to horizontal components. Weak perverted HSN (vertical SPV ≤ 4°/s) could be found in patients with MD.

Clinical outcomes and risk factors of post-polypectomy coagulation syndrome: a multicenter, retrospective, case-control study.

BACKGROUND AND STUDY AIMS: Post-polypectomy coagulation syndrome (PPCS) is a well known complication of colonoscopic polypectomy. However, no previous studies have reported on the clinical outcomes or risk factors of PPCS. The aim of the current study was to analyze the clinical outcomes and risk factors of PPCS developing after a colonoscopic polypectomy. PATIENTS AND METHODS: Data for all patients who underwent colonoscopic polypectomies and required hospitalization in nine university hospitals were analyzed retrospectively. The incidence, clinicopathological characteristics, and clinical outcomes of PPCS cases were examined. Additionally, patients who developed PPCS were compared with controls who were matched by age and sex, in order to assess for possible risk factors. RESULTS: The rate of PPCS that required hospitalization after colonoscopic polypectomy was 0.7/1000. All patients with PPCS were treated medically without the need for surgical interventions. The median durations of therapeutic fasting, hospitalization, and antibiotic use were 3 days, 5.5 days, and 7 days, respectively. The rates of major PPCS and mortality were 2.9 % and 0 %, respectively. On multivariate analysis, hypertension (OR = 3.023, 95 %CI 1.034 - 8.832), large lesion size (OR = 2.855, 95 %CI 1.027 - 7.937), and non-polypoid configuration (OR = 3.332, 95 %CI 1.029 - 10.791) were found to be independent risk factors related to the development of PPCS. CONCLUSIONS: In this study, the rates of major PPCS and mortality were only 2.9 % and 0 %, respectively. Hypertension, large lesion size, and non-polypoid configuration of the lesion were independently associated with PPCS. Therefore, patients may be reassured by the excellent prognosis of PPCS, while endoscopists should be especially careful when performing colonoscopic polypectomies in patients with hypertension or large and non-polypoid lesions.

Criteria for decision making after endoscopic resection of well-differentiated rectal carcinoids with regard to potential lymphatic spread.

BACKGROUND AND STUDY AIM: Rectal carcinoids are low-grade malignancies that are usually treated by endoscopic resection. However, on pathologic examination, resection margins that are positive for carcinoid cells are frequently found. Patient outcomes were reviewed after endoscopic resection of rectal carcinoids and the clinical significance of possible residual disease, as defined by pathologic and endoscopic examination, was evaluated. PATIENTS AND METHODS: The medical records and endoscopic findings of 347 patients presenting with rectal carcinoids to 14 university hospitals in Korea between January 1999 and June 2007 were retrospectively analyzed. RESULTS: A total of 304 patients were treated with endoscopic resection, and 43 patents were treated with surgery. In the endoscopic resection group, the complete resection rate was 88.2% based on endoscopic appearance (CR-E) and 60.2% based on pathologic evaluation (CR-P). The agreement between CR-E and CR-P was low (κ=0.192). No residual tumors were found in 77 of 85 patients (90.6%) who were CR-E but not CR-P and who had endoscopic biopsy taken at 24-month follow-up. The receiver-operating characteristic curve identified an optimal cut-off value of 10.5 mm, at which the sensitivity and the specificity for metastasis were 100% and 89%, respectively. The risk factors for metastasis by multivariate analysis were tumor size, increased mitotic rate, and lymphovascular invasion. CONCLUSIONS: Endoscopic resection is a safe and effective modality for treating well-differentiated rectal carcinoids smaller than 10 mm in diameter. Discrepancies were observed between CR-E and CR-P. The risk factors for metastasis were tumor size, increased mitotic rate, and lymphovascular invasion.

Cancer cells promote survival through depletion of the von Hippel-Lindau tumor suppressor by protein crosslinking.

Nuclear factor-κB (NF-κB) and insulin-like growth factor-1 (IGF-1)-mediated signaling is associated with different tumors including renal cell carcinoma. NF-κB- and IGF-1-mediated signaling is found to be inhibited in the presence of wild-type von Hippel-Lindau (VHL) tumor suppresser gene. Therefore, negative regulator of VHL may be a good target for regulating NF-κB and IGF-1R. In this study, we found that VHL, a tumor suppressor protein that downregulates the NF-κB activity and the stability of IGF-1R was depleted by TGase 2 through polymerization via crosslinking and proteasomal degradation in kidney, breast and ovary cancer cell lines. We also found that TGase 2 knockdown promotes hypoxia-inducible factor 1α (HIF-1α) degradation, and thereby decrease HIF-1α transcriptional activity. Importantly, VHL expression was decreased in vivo in TGase-2-transgenic mice, and this was associated with increased NF-κB activity and the levels of expression of IGF-1R, HIF-1α and erythropoietin in kidney tissue. These results suggest a novel mechanism of regulation of the VHL tumor suppressor by TGase 2 that appears to be independent of the known cancer regulatory mechanisms.

Outcome evaluation of carotid stenting in high-risk patients with symptomatic carotid near occlusion.

Management of symptomatic carotid near occlusion especially in high-risk patients is different from outcome analysis of NASCET. We evaluated outcome in high-risk patients with symptomatic near occlusion. For 48 patients with near occlusion out of 166 symptomatic high-risk patients who underwent carotid stenting, we assessed the procedural success defined as residual stenosis <30%, modified Rankin Scale (mRS) at one and six months following stenting, and the 13 cerebrovascular factors related to the outcome. Initial National Institutes of Health Stroke Scale (NIHSS) ≥4, 1-3 and 0 were 13, 14 and 21 patients each. We compared the outcome with patients who underwent CAS (n=118) due to symptomatic stenosis without near occlusion during the same period. Our procedural success rate was 98%. A good outcome (mRS ≤2) was achieved in 44 patients (92%) at six months. There were five events (10%) within six months, i.e. three minor strokes, one major stroke caused by hemorrhage, and one death excluding two deaths not related to stroke. Hyperperfusion (n=4) was the most common cause of events leading to two minor strokes and a major stroke. Although initial NIHSS (P = .012) was related to poor outcome (mRS >2) compared to the CAS group, there was no statistical significance between two groups in the event rate of stroke, death or restenosis. The outcome of carotid stenting in high-risk patients with symptomatic near occlusion did not reveal any difference compared with CAS. Poor outcome was related to the initial NIHSS (≥4). Hyperperfusion tended to be more commonly related to an event occurring after stenting.

Modified sleeve tympanotomy approach for removal of congenital cholesteatoma.

OBJECTIVE: We present a technique which we have found useful for the management of congenital cholesteatoma extensively involving the middle ear. CASE REPORT: A five-year-old boy was presented to our department for management of a white mass on the right tympanic membrane. This congenital cholesteatoma extensively occupied the tympanic cavity. It was removed through an extended tympanotomy approach using our modified sleeve technique. The conventional tympanotomy approach was extended by gently separating the tympanic annulus from its sulcus in a circular manner. The firm attachment of the tympanic membrane at the umbo was not severed, in order to avoid lateralisation of the tympanic membrane. CONCLUSION: Although various operative techniques can be used, our modified sleeve tympanotomy approach provides a similarly sufficient and direct visualisation of the entire middle ear, with, theoretically, no possibility of lateralisation of the tympanic membrane and subsequent conductive hearing loss.

Clinical significance of vibration-induced nystagmus.

The aims of the study were to characterize the vibration-induced nystagmus (VIN) in patients with unilateral vestibular neuritis (VN) and Ménière's disease (MD), and to clarify the clinical significance of VIN by comparing it with caloric results in patients with VN and MD. We recorded eye movements from 22 VN patients and 24 MD patients using unilateral 100-Hz vibration on the mastoid bone. Eye movements were analyzed and the maximum value of slow-phase eye velocity was obtained during vibration on each mastoid. The average value of slow-phase velocities was calculated. Spontaneous nystagmus was subtracted from the slow-phase velocity, whenever it was present. A canal paresis (CP) greater than 25% was considered pathologic. All but one VN patient showed pathologic CP with the direction of the slow-phase eye movement of VIN toward the lesioned side. Fifteen (63%) out of 24 MD patients showed VIN with the slow-phase eye movement directed to the lesioned side. Pathologic CP was present in 9 (38%) out of 24 MD patients and 8 of them showed slow-phase eye movements of VIN directed to the lesioned side. There were also 8 other MD patients who showed slow-phase eye movement of VIN directed to the intact side. Among them, 3 patients with the slow-phase eye movement more than 5 degrees /s showed CP on the intact side. The amplitude of slow-phase eye velocity showed a significant correlation with CP in patients with either VN or MD. There was no significant difference in the slope of the regression lines between the VN and MD groups. Our results suggest that VIN may probe imbalance of canal responses to low-frequency stimulation similar to the caloric test. It also shows that VIN can help in detecting vestibular imbalance using a stimulation mechanism different from the caloric test. The VIN test can be helpful in determining the lesioned side in patients with VN; however, it has some limitations in localizing the lesioned side in patients with MD.

Changing trends in clinical manifestations of laryngeal tuberculosis.

OBJECTIVES/HYPOTHESIS: Despite the dramatic decrease in the incidence of laryngeal tuberculosis, the disease has gained new interest as a result of claims that it has changed its clinical patterns. The aim of this study is to evaluate the changing trends in clinical manifestations of laryngeal tuberculosis. STUDY DESIGN: Retrospective clinical analysis. METHODS: Clinical analysis of 22 patients with pathologically confirmed laryngeal tuberculosis was carried out retrospectively. RESULTS: Patients' ages ranged from 22 to 75 years. The male-to-female ratio was 2.14 to 1. The most frequent chief complaint was hoarseness. The true vocal cord and the false vocal cord were commonly involved, and 11 patients showed single lesions. Among 22 patients, only 7 had active pulmonary tuberculosis, and 9 were proven to have normal lung status. The patients with active pulmonary tuberculosis showed more ulcerative and multiple lesions. The patients with normal lung status showed nonspecific, polypoid, and single lesions. All patients responded satisfactorily to antituberculous medication. CONCLUSIONS: The clinical manifestations of laryngeal tuberculosis have changed and seem to be different from those of classic reports. It can even occur without pulmonary tuberculosis, and the characteristics of lesions seem to be more nonspecific. It might be important to consider tuberculosis in the differential diagnosis of nonspecific laryngeal disease.

Salivary gland choristoma of the middle ear: a case report.

A choristoma is a nonneoplastic proliferation of histologically normal tissue that forms at an abnormal site. It is extremely uncommon in the middle ear space. It appears to be a developmental abnormality and may be associated with abnormalities of adjacent structures. It usually occurs with unilateral conductive hearing loss and requires a differential diagnosis from other mass lesions in the middle ear cavity. This article discusses a case of salivary gland choristoma of the middle ear that we believe to be the 24th case reported on this subject.

Protective effects of asiaticoside derivatives against beta-amyloid neurotoxicity.

Asiaticoside (AS) derivatives were tested for potential protective effects against Abeta-induced cell death. Of the 28 AS derivatives tested, asiatic acid (AA), asiaticoside 6 (AS6), and SM2 showed strong inhibition of Abeta-induced death of B103 cells at 1 microM. The three AS derivatives were further tested for their effects on free radical injury and apoptosis. All three AS derivatives reduced H(2)O(2)-induced cell death and lowered intracellular free radical concentration, but AA showed the strongest protection. In contrast, SM2 was the most effective blocker of staurosporine-induced apoptosis. These results suggest that the three AS derivatives block Abeta toxicity by acting through different cellular mechanisms. When applied to hippocampal slices, AA, SM2, and AS6 did not alter n-methyl-D-aspartic acid (NMDA) or non-NMDA receptor-mediated synaptic transmission, paired-pulse facilitation or induction of long-term potentiation in the field CA1. These results indicate that the three AS derivatives do not alter physiological properties of the hippocampus at the concentration that blocks Abeta-induced cell death. Therefore AS6, AA, and SM2 can be regarded as reasonable candidates for a therapeutic Alzheimer's disease drug that protects neurons from Abeta toxicity.

Presenilin 1 mediates protein kinase C dependent alpha-secretase derived amyloid precursor protein secretion and mitogen-activated protein kinase activation in presenilin 1 transfected human embryonic kidney 293 cell.

We investigated the role of presenilin 1 (PS1) in the secretion of alpha-secretase derived amyloid precursor protein (sAPP alpha) and associated intracellular signaling pathways. Human embryonic kidney (HEK) 293 cells were transfected with exon 9 deletion (deltaE9) mutant PS1 cDNA in an ecdyson-inducible system. sAPPalpha secretion was lower in the mutant PS1 expressing cells compared with non-expressing cells. When activated by PDBu, secretion of sAPPalpha and the level of phosphorylated mitogen activated protein kinase (MAPK) were greatly enhanced in deltaE9 PS1 uninduced cells, but not in the mutant PS1 induced cells. PD98059, a MAPK inhibitor, blocked PDBu induced sAPPalpha secretion from deltaE9 PS1 uninduced cells but had no effect on the mutant PS1 induced cells. These data indicate that PS1 mediates PDBu-induced sAPPalpha secretion and MAPK activation.