Determination of ovarian transposition through prediction of postoperative adjuvant therapy in young patients with early stage cervical cancer undergoing surgery: a Korean multicenter retrospective study (KGOG 1042).

OBJECTIVE: We aimed to predict the risk of postoperative adjuvant therapy using preoperative variables in young patients with early stage cervical cancer. The predicted risk can guide whether ovarian transposition should be performed during surgery. METHODS: In total, 886 patients with stage IB1-IIA cervical cancer aged 20-45 years who underwent modified radical or radical hysterectomy between January 2000 and December 2008 were included. Preoperative variables, preoperative laboratory findings, International Federation of Gynaecology and Obstetrics stage, tumor size, and pathological variables were collected. Patients with high risk factors or those who met the Sedlis criteria were considered adjuvant therapy risk (+); others were considered adjuvant therapy risk (-). A decision-tree model using preoperative variables was constructed to predict the risk of adjuvant therapy. RESULTS: Of 886 patients, 362 were adjuvant therapy risk (+) (40.9%). The decision-tree model with four distinct adjuvant therapy risks using tumor size and age were generated. Specifically, patients with tumor size ≤2.45 cm had low risk (49/367; 13.4%), those with tumor size ≤3.85 cm and >2.45 cm had moderate risk (136/314; 43.3%), those with tumor size >3.85 cm and age ≤39.5 years had high risk (92/109; 84.4%), and those with tumor size >3.85 cm and age >39.5 years had the highest risk (85/96; 88.5%). CONCLUSION: The risk of postoperative adjuvant therapy in young patients with early stage cervical cancer can be predicted using preoperative variables. We can decide whether ovarian transposition should be performed using the predicted risk.

Effect of menopausal hormonal therapy on cardiovascular risks in Korean postmenopausal women: A nationwide cohort study.

OBJECTIVE: To evaluate the association between menopausal hormonal therapy (MHT) and the risk of cardiovascular disease (CVD), according to various regimens, dosages, routes of administration and starting ages of MHT. DESIGN: A population-based cohort study using the Korean National Health Insurance Services database. SETTING: Nationwide health insurance database. POPULATION: Women who reported entering menopause at an age of ≥40 years with no history of CVD in the national health examination. METHODS: The study population comprised 1 120 705 subjects enrolled between 2002 and 2019, categorised according to MHT status (MHT group, n = 319 007; non-MHT group, n = 801 698). MAIN OUTCOME MEASURES: Incidence of CVD (a composite of myocardial infarction and stroke). RESULTS: The incidence of CVD was 59 266 (7.4%) in the non-MHT group and 17 674 (5.5%) in the MHT group. After adjusting for confounding factors, an increased risk of CVD was observed with the administration of tibolone (hazard ratio, HR 1.143, 95% CI 1.117-1.170), oral estrogen (HR 1.246, 95% CI 1.198-1.295) or transdermal estrogen (HR 1.289, 95% CI 1.066-1.558), compared with the non-MHT group; the risk was based on an increased risk of stroke. The risk trends were consistent regardless of the age of starting MHT or the physicians' specialty. Among tibolone users, a longer period from entering menopause to taking tibolone and the use of any dosage (1.25 or 2.5 mg) were linked with a higher risk of CVD, compared with non-MHT users. CONCLUSIONS: This nationwide cohort study demonstrated an increased risk of CVD, driven mainly by an increased risk of stroke, among tibolone and oral or transdermal estrogen users, compared with that of non-MHT users.

Case Report: Upper limb superficial venous thrombosis associated with oral contraceptives mimicking soft tissue mass.

Background: Venous thrombosis associated with the use of oral contraceptives (OCs) occurs mostly in the deep veins of the lower extremity. A lesion of the upper extremity is rare, and the majority of thrombotic events that occur in the superficial vein of the upper extremity are caused by intravenous catheters. We present a rare case of superficial venous thrombus on the upper extremity in a woman with a history of long-term OC use. Case presentation: A 35-year-old woman, with an 8-year history of OC use, presented with a 2-year history of painfully palpable masses on her left forearm. The lesion mimicking soft tissue mass was confirmed to be superficial venous thrombi through ultrasound and magnetic resonance imaging. Conservative treatment including non-steroidal anti-inflammatory drugs, vasoprotective agents, and aspirin was prescribed. Through consultation with the Department of Obstetrics and Gynecology, it was confirmed that the current OCs could be discontinued, and the pain was almost relieved after conservative treatment. Conclusions: If thrombotic events occur in the superficial vein of the upper extremity without intravenous catheters, detailed medical history taking and the possibility of OCs should be considered.

Skin cancer risk of menopausal hormone therapy in a Korean cohort.

Conflicting studies exist on the association between menopausal hormone therapy (MHT) and skin cancers, such as melanoma and non-melanoma skin cancer (NMSC). This retrospective cohort study aimed to evaluate the risk of skin cancer from MHT using data from 2002 to 2019 from the National Health Insurance Service in South Korea. We included 192,202 patients with MHT and 494,343 healthy controls. Women > 40 years who had menopause between 2002 and 2011 were included. Patients with MHT had at least one MHT for at least 6 months and healthy controls had never been prescribed MHT agents. We measured the incidence of melanoma and NMSC. Melanoma developed in 70 (0.03%) patients with MHT and 249 (0.05%) controls, while the incidence of NMSC was 417 (0.22%) in the MHT group and 1680 (0.34%) in the controls. Tibolone (hazard ratio [HR] 0.812, 95% confidence interval [CI] 0.694-0.949) and combined oestrogen plus progestin by the manufacturer (COPM; HR 0.777, 95% CI 0.63-0.962) lowered the risk of NMSC, while other hormone groups did not change the risk. Overall, MHT was not associated with melanoma incidence in menopausal Korean women. Instead, tibolone and COPM were associated with a decrease in NMSC occurrence.

Association of Early Hysterectomy With Risk of Cardiovascular Disease in Korean Women.

Importance: Women who undergo surgical hysterectomy before natural menopause may have an earlier increase in hematocrit and storage iron levels than those who continue menstruation, thereby increasing the risk of cardiovascular disease (CVD) at ages younger than usually seen. Examining this issue may provide important implications for women's cardiovascular health to both physicians and patients. Objective: To evaluate the association of hysterectomy with the risk of incident CVD among women before age 50 years. Design, Setting, and Participants: In this Korean population-based cohort study, 135 575 women aged 40 to 49 years were evaluated from January 1, 2011, to December 31, 2014. After propensity score matching in covariates including age, socioeconomic status, region, Charlson Comorbidity Index, hypertension, diabetes, dyslipidemia, menopause, menopausal hormone therapy, and adnexal surgery before inclusion, 55 539 pairs were included in the hysterectomy and nonhysterectomy groups. Participants were followed up until December 31, 2020. Data analysis was conducted from December 20, 2021, to February 17, 2022. Main Outcomes and Measures: The primary outcome was an incidental CVD, a composite of myocardial infarction, coronary artery revascularization, and stroke. The individual components of the primary outcome were also evaluated. Results: A total of 55 539 pairs were included; median age in the combined groups was 45 (IQR, 42-47) years. During median follow-up periods in the hysterectomy group of 7.9 (IQR, 6.8-8.9) years and nonhysterectomy group of 7.9 (IQR, 6.8-8.8) years, the incidence of CVD was 115 per 100 000 person-years for the hysterectomy group and 96 per 100 000 person-years for the nonhysterectomy group. After adjusting for confounding factors, the hysterectomy group had an increased risk of CVD compared with the nonhysterectomy group (hazard ratio [HR], 1.25; 95% CI, 1.09-1.44). The incidences of myocardial infarction and coronary artery revascularization were comparable between the groups, whereas the risk of stroke was significantly higher in the hysterectomy group (HR, 1.31; 95% CI, 1.12-1.53). Even after excluding women who underwent oophorectomy, the hysterectomy group had higher risks of CVD (HR, 1.24; 95% CI, 1.06-1.44). Conclusions and Relevance: The findings of this cohort study suggest early menopause owing to hysterectomy was associated with increased risks for a composite of CVD, particularly stroke.

Effects of menopausal hormone therapy on the risk of ovarian cancer: Health Insurance Database in South Korea-based cohort study.

OBJECTIVE: This study aimed to evaluate the risk of ovarian cancer associated with hormone therapy regimens using a Korean population-based study. METHODS: This retrospective cohort study used national health checkup and insurance data from January 1, 2002, to December 31, 2019, provided by Korea's National Health Insurance Service. Women older than 40 years who recorded "menopause" in the questionnaire from 2002 to 2011 were included in this study. Menopausal hormone therapy (MHT) preparations were classified into tibolone, combined estrogen plus progestin by the manufacturer, combined estrogen plus progestin by physician, estrogen, and topical estrogen groups. The number of participants recorded as menopausal during the national health examination between 2002 and 2011 was 2,506,271. The MHT and non-MHT groups consisted of 373,271 and 1,382,653 patients, respectively. The hazard ratios (HR) of ovarian cancer according to MHT type, age at inclusion, body mass index, region, socioeconomic status, Charlson comorbidity index, age at menarche, age at menopause, parity, smoking, alcohol consumption, physical exercise, and period from menopause to inclusion were evaluated. RESULTS: The risk of ovarian cancer was reduced in the tibolone group (HR, 0.84; 95% confidence interval, 0.75-0.93; P = 0.003) and in patients in rural areas (HR, 0.90; 95% confidence interval, 0.845-0.98; P = 0.013). The risk of ovarian cancer was not related to the other MHT treatments. CONCLUSION: Tibolone was associated with a lower risk of ovarian cancer. No other MHT was associated with ovarian cancer.

Risk of Gestational Diabetes and Pregnancy-Induced Hypertension with a History of Polycystic Ovary Syndrome: A Nationwide Population-Based Cohort Study.

OBJECTIVE: To evaluate the risks of developing gestational diabetes (GDM) and pregnancy-induced hypertension (PIH) in women with polycystic ovary syndrome (PCOS) using data from Korea's National Health Insurance Service. METHOD: The PCOS group comprised women aged 20 to 49 years diagnosed with PCOS between 1 January 2012, and 31 December 2020. The control group comprised women aged 20 to 49 years who visited medical institutions for health checkups during the same period. Women with any cancer within 180 days of the inclusion day were excluded from both the PCOS and control groups, as were women without a delivery record within 180 days after the inclusion day, as well as women who visited a medical institution more than once before the inclusion day due to hypertension, diabetes mellitus (DM), hyperlipidemia, DM in pregnancy, or PIH. GDM and PIH were defined as cases with at least three visits to a medical institution with a GDM diagnostic code and a PIH diagnostic code, respectively. RESULTS: Overall, 27,687 and 45,594 women with and without a history of PCOS experienced childbirth during the study period. GDM and PIH cases were significantly higher in the PCOS group than in the control group. When adjusted for age, SES, region, CCI, parity, multiple pregnancies, adnexal surgery, uterine leiomyoma, endometriosis, PIH, and GDM, an increased risk of GDM (OR = 1.719, 95% CI = 1.616-1.828) was observed among women with a history of PCOS. There was no increase in the risk of PIH among women with a history of PCOS (OR = 1.243, 95% CI = 0.940-1.644). CONCLUSION: A history of PCOS itself might increase the risk of GDM, but its relationship with PIH remains unclear. These findings would be helpful in the prenatal counseling and management of patients with PCOS-related pregnancy outcomes.

Tet Enzyme-Mediated Response in Environmental Stress and Stress-Related Psychiatric Diseases.

Mental disorders caused by stress have become a worldwide public health problem. These mental disorders are often the results of a combination of genes and environment, in which epigenetic modifications play a crucial role. At present, the genetic and epigenetic mechanisms of mental disorders such as posttraumatic stress disorder or depression caused by environmental stress are not entirely clear. Although many epigenetic modifications affect gene regulation, the most well-known modification in eukaryotic cells is the DNA methylation of CpG islands. Stress causes changes in DNA methylation in the brain to participate in the neuronal function or mood-modulating behaviors, and these epigenetic modifications can be passed on to offspring. Ten-eleven translocation (Tet) enzymes are the 5-methylcytosine (5mC) hydroxylases of DNA, which recognize 5mC on the DNA sequence and oxidize it to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC). Tet regulates gene expression at the transcriptional level through the demethylation of DNA. This review will elaborate on the molecular mechanism and the functions of Tet enzymes in environmental stress-related disorders and discuss future research directions.

Cognitive and behavioral effects of the anti-epileptic drug cenobamate (YKP3089) and underlying synaptic and cellular mechanisms.

Antiseizure medication is the mainstay of treatment for seizures, and adjunctive therapy is widely used to achieve adequate seizure control in patients with epilepsy who fail to respond to the first monotherapy. The newly developed antiepileptic drug cenobamate (YKP3089) as an adjunctive therapy improved seizure control in patients with uncontrolled focal seizures. Cenobamate is thought to reduce neuronal excitability through action on multiple targets, including GABA A receptors (GABAARs) and voltage-gated sodium channels. However, its effects on brain function and synaptic plasticity are unclear. Here, we explored the behavioral, synaptic, and cellular actions of cenobamate. Cenobamate influenced novel object recognition, object location memory, and Morris water maze performance in mice. Cenobamate enhanced inhibitory postsynaptic potentials by prolonging inhibitory postsynaptic current (IPSC) decay without affecting presynaptic GABA release or the peak amplitude of IPSCs. In addition, cenobamate suppressed hippocampal excitatory synaptic transmission by reducing the excitability of Schaffer collaterals and interfered with the induction of long-term potentiation. A reduction in neuronal excitability induced by cenobamate was associated with an elevation of action potential (AP) threshold, and which progressively increased in later APs during repetitive firing, indicating the activity-dependent modulation of neuronal sodium currents. Cenobamate suppressed neuronal excitability under the condition that GABAergic neurotransmission is excitatory, and administration of cenobamate rapidly enhanced the phosphorylation of eukaryotic elongation factor 2 in the hippocampus of adult and neonatal mice. Collectively, these results suggest that the combined action of cenobamate on sodium currents and GABAAR-mediated synapse responses results in reduced excitability in neurons.

Suppression of exaggerated NMDAR activity by memantine treatment ameliorates neurological and behavioral deficits in aminopeptidase P1-deficient mice.

Inborn errors of metabolism (IEMs) are common causes of neurodevelopmental disorders, including microcephaly, hyperactivity, and intellectual disability. However, the synaptic mechanisms of and pharmacological interventions for the neurological complications of most IEMs are unclear. Here, we report that metabolic dysfunction perturbs neuronal NMDA receptor (NMDAR) homeostasis and that the restoration of NMDAR signaling ameliorates neurodevelopmental and cognitive deficits in IEM model mice that lack aminopeptidase P1. Aminopeptidase P1-deficient (Xpnpep1-/-) mice, with a disruption of the proline-specific metalloprotease gene Xpnpep1, exhibit hippocampal neurodegeneration, behavioral hyperactivity, and impaired hippocampus-dependent learning. In this study, we found that GluN1 and GluN2A expression, NMDAR activity, and the NMDAR-dependent long-term potentiation (LTP) of excitatory synaptic transmission were markedly enhanced in the hippocampi of Xpnpep1-/- mice. The exaggerated NMDAR activity and NMDAR-dependent LTP were reversed by the NMDAR antagonist memantine. A single administration of memantine reversed hyperactivity in adult Xpnpep1-/- mice without improving learning and memory. Furthermore, chronic administration of memantine ameliorated hippocampal neurodegeneration, hyperactivity, and impaired learning and memory in Xpnpep1-/- mice. In addition, abnormally enhanced NMDAR-dependent LTP and NMDAR downstream signaling in the hippocampi of Xpnpep1-/- mice were reversed by chronic memantine treatment. These results suggest that the metabolic dysfunction caused by aminopeptidase P1 deficiency leads to synaptic dysfunction with excessive NMDAR activity, and the restoration of synaptic function may be a potential therapeutic strategy for the treatment of neurological complications related to IEMs.

Bioanalytical methods for the detection of duloxetine and thioctic acid in plasma using ultra performance liquid chromatography with tandem mass spectrometry (UPLC-MS/MS).

Duloxetine and thioctic acid (TA) are standard drugs for treating diabetic neuropathy, a primary complication associated with diabetes. In this study, ultra performance liquid chromatography coupled with tandem mass spectrometry methods was successfully developed and validated for quantifying duloxetine and TA in biological samples. The protein precipitation method was used to extract duloxetine, TA and their internal standards from beagle dog plasma. A Hypersil Gold C18 column (150 × 2.1 mm, 1.9 µm) was used for the experiment. Isocratic elution with 0.1% formic acid in acetonitrile (A) and 0.1% formic acid (B) was used for duloxetine, whereas a gradient elution with 0.03% acetic acid (A) and acetonitrile (B) was used for TA. The validated parameters included linearity, sensitivity, accuracy, precision, selectivity, matrix effect, stability, and recovery under different conditions. The linear ranges of the calibration curves for duloxetine and TA were 5-800 ng/mL and 5-1,000 ng/mL, respectively. An intra- and inter-run precision of ± 15% can be observed in all quality control samples. These methods were successfully used for pharmacokinetics (PKs) studies in beagle dogs to compare PK differences in a fixed-dose combination including duloxetine and TA and co-administration of the 2 drugs.

Long-term risk of uterine malignancies in women with uterine fibroids confirmed by myomectomy: a population-based study.

Leiomyosarcomas may originate from pre-existing uterine fibroids. However, recent studies showed that leiomyosarcomas do not arise from malignant changes in fibroids. Epidemiological data on the long-term risk of uterine malignancy with uterine fibroids are lacking. We aimed to determine whether uterine fibroids are a risk factor for uterine cancer. Patient data (2007-2020) from the Korean Health Insurance program were obtained. Using the procedure and diagnostic codes, data from patients who underwent myomectomy and appendicitis (control group) were extracted Using 1:1 propensity-score matching, 84,507 women were each allocated to the uterine fibroids and control groups. Endometrial cancer occurred in 36 44 and 44 36 women in the uterine fibroids and control groups (p = .371), respectively; 6/36 46 and 4 5/44 37 cases of uterine corpus cancer sarcoma occurred in the respective groups. Total uterine cancer (excluding cervical cancer) occurred in 46 and 39 37patients in the uterine fibroids and control groups, respectively (p = .323). A higher risk of uterine malignancy was not found in women with uterine fibroids confirmed by myomectomy. If surgery is indicated, a myomectomy can be safely performed without increasing the cancer risk. IMPACT STATEMENTWhat is already known on this subject? Traditionally, leiomyosarcomas were considered to originate from pre-existing uterine fibroids. However, recent studies suggest that leiomyosarcomas do not arise from the malignant change of fibroids. Meanwhile, there is a dearth of real-world evidence on the risk of uterine cancer in patients with uterine fibroids.What do the results of this study add? No evidence of a higher risk of uterine malignancy was found in women having uterine fibroids confirmed by myomectomy in this population-based study. In our cohort of women with uterine fibroids, tissue injury by myomectomy does not appear to cause malignant transformation.What are the implications of these findings for clinical practice and/or further research? Uterine fibroids doesn't appear to be a risk factor for uterine malignancies, and tissue injury by myomectomy does not appear to cause malignant transformation. If surgery is indicated, myomectomy can be performed safely, given that the long-term risk of uterine malignancy does not increase.

Incidence Rates of Myomectomy-Related Mortality and Venous Thromboembolism in South Korea: A Population-Based Study.

Background: Uterine leiomyomas are the most commonly observed pathologies, with an estimated prevalence of 4. 5-68.6%. We aimed to calculate myomectomy-related mortality and venous thromboembolism incidence rates in the Republic of Korea. Methods: The data of patients who underwent myomectomy (2009-2018) were obtained from the Health Insurance Review and Assessment Service-National Inpatient Sample. The mortality rate after myomectomy was calculated using the leiomyoma diagnostic codes and myomectomy procedure codes. The incidence rates of venous thromboembolism, deep vein thrombosis, and pulmonary embolism were calculated using their diagnostic codes, with concomitant use of an antithrombotic agent during the same period or within 90 days after myomectomy. Results: The data of 23,549 women aged 15-55 years who underwent myomectomy were extracted. The myomectomy rate was 14.6 ± 0.1 per 10,000 patients. The average age was 39.39 ± 0.04 years. One patient who underwent myomectomy died; this patient did not have concomitant venous thromboembolism. The post-myomectomy mortality rate was 1.3 ± 0.8 per 10,000 patients. The incidence rates of venous thromboembolism, deep vein thrombosis, and pulmonary embolism after myomectomy were 5.7 ± 1.6 per 10,000 patients, 4.4 ± 1.4 per 10,000 patients, and 2.5 ± 1 per 10,000 patients, respectively. The conversion rate to hysterectomy was 2.9 ± 1.1 per 10,000 patients. Conclusion: The current mortality rate after myomectomy (0.013%) is substantially lower than that described in previous studies at the turn of the 20th century. The incidence of venous thromboembolism is also considerably lower than that in the general population worldwide.

Tunable near-infrared Gires-Tournois resonators based on vanadium dioxide on gold film.

Vanadium dioxide (VO2) has been proposed as a phase-change material in tunable photonic and optoelectronic devices. In such devices, a thin layer of VO2 is typically deposited on metallic or insulating surfaces. In this Letter, we report the reflectance spectra of a subwavelength structure consisting of a thin layer of VO2 deposited on a gold film in the near-infrared spectral range, particularly near the wavelength of 1550 nm, which is significant for telecommunication applications. Our results indicate that in the insulating phase of VO2, the air/VO2/Au structure can be considered as a Gires-Tournois resonant cavity whose maximum absorption wavelength can be tuned by adjusting the thickness of the VO2 layer. In contrast, in the metallic phase of VO2, the reflectance of the structure increases by an amount of the order of a few tens of units. The proposed structure can prospectively lead to new design concepts in tunable photonic and optoelectronic devices.

Rupture-mediated large uterine defect at 30th gestational week with protruded amniotic sac and fetal head without fetal compromise after laparoscopic electromyolysis: Case report and literature review.

BACKGROUND: We describe a case of a rupture-mediated large uterine defect, which occurred on the 30th gestation week presenting a protruding amniotic sac sac without fetal compromise after a laparoscopic electromyolysis. CASE PRESENTATION: A 28-year-old woman in her 30th week of gestation (gravida 2, para 0) presented with whole abdominal and right lower quadrant pain at Sanggye Paik Hospital. Ultrasound examination showed normal amniotic fluid and placentation but with breech presentation. She had undergone laparoscopic right ovarian cystectomy due to endometriosis 5 years earlier. Cardiotocography revealed an intermittent variable deceleration and no uterine contraction. Magnetic resonance imaging ruled out acute appendicitis. Four hours later, we observed a protrusion of the amniotic sac with the fetal head through a large uterine defect on magnetic resonance imaging, and performed emergency cesarean section. A boy was delivered without fetal compromise. During the cesarean section, multiple myometric wall defects and thinning were identified. After reconstruction of the uterine wall, the flaccid uterus bled persistently; thus, a cesarean hysterectomy was performed. Packed red cells and frozen plasma were transfused. The mother and neonate had uneventful puerperal and neonatal courses, respectively. After cesarean hysterectomy, we were informed that the mother had undergone a combined laparoscopic electromyolysis during the laparoscopic right ovarian cystectomy. Three years later, the child showed normal neural development. CONCLUSIONS: Before myomectomy or electromyolysis, patients should be informed of the possibility of uterine rupture during subsequent pregnancies. If a pregnant woman has abdominal pain, clinicians should take a detailed history of uterine surgery and consider uterine rupture. Although, fortunately, the outcomes in this case were uneventful, urgent delivery is required when uterine rupture is diagnosed.

Does the Summer Season Affect the Amniotic Fluid Volume during Pregnancy?

Amniotic fluid is crucial for the well-being of the fetus. Recent studies suggest that dehydration in a pregnant woman leads to oligohydramnios. We assessed the variation in the amniotic fluid index (AFI) during the summer and non-summer seasons and evaluated neonatal outcomes. We retrospectively reviewed electrical medical records of pregnant women who visited the Konkuk University Medical Center for antenatal care, between July 2005 and July 2019. A total of 19,724 cases from 6438 singleton pregnant women were included after excluding unsuitable cases. All AFI values were classified as 2nd and 3rd trimester values. Additionally, borderline oligohydramnios (AFI, 5-8) and normal AFI (AFI, 8-24) were assessed according to the seasons. The average AFI between the summer and non-summer season was statistically different only in the 3rd trimester; but the results were not clinically significant. In the 3rd trimester, the summer season influenced the increased incidence of borderline oligohydramnios. The borderline oligohydramnios group showed an increased small-for-gestational-age (SGA) rate and NICU admission rate. In the summer season, the incidence of borderline oligohydramnios was seen to increase. This result would be significant for both physicians and pregnant women.

The phosphorylation status of eukaryotic elongation factor-2 indicates neural activity in the brain.

Assessment of neural activity in the specific brain area is critical for understanding the circuit mechanisms underlying altered brain function and behaviors. A number of immediate early genes (IEGs) that are rapidly transcribed in neuronal cells in response to synaptic activity have been used as markers for neuronal activity. However, protein detection of IEGs requires translation, and the amount of newly synthesized gene product is usually insufficient to detect using western blotting, limiting their utility in western blot analysis of brain tissues for comparison of basal activity between control and genetically modified animals. Here, we show that the phosphorylation status of eukaryotic elongation factor-2 (eEF2) rapidly changes in response to synaptic and neural activities. Intraperitoneal injections of the GABA A receptor (GABAAR) antagonist picrotoxin and the glycine receptor antagonist brucine rapidly dephosphorylated eEF2. Conversely, potentiation of GABAARs or inhibition of AMPA receptors (AMPARs) induced rapid phosphorylation of eEF2 in both the hippocampus and forebrain of mice. Chemogenetic suppression of hippocampal principal neuron activity promoted eEF2 phosphorylation. Novel context exploration and acute restraint stress rapidly modified the phosphorylation status of hippocampal eEF2. Furthermore, the hippocampal eEF2 phosphorylation levels under basal conditions were reduced in mice exhibiting epilepsy and abnormally enhanced excitability in CA3 pyramidal neurons. Collectively, the results indicated that eEF2 phosphorylation status is sensitive to neural activity and the ratio of phosphorylated eEF2 to total eEF2 could be a molecular signature for estimating neural activity in a specific brain area.

Altered hippocampal gene expression, glial cell population, and neuronal excitability in aminopeptidase P1 deficiency.

Inborn errors of metabolism are often associated with neurodevelopmental disorders and brain injury. A deficiency of aminopeptidase P1, a proline-specific endopeptidase encoded by the Xpnpep1 gene, causes neurological complications in both humans and mice. In addition, aminopeptidase P1-deficient mice exhibit hippocampal neurodegeneration and impaired hippocampus-dependent learning and memory. However, the molecular and cellular changes associated with hippocampal pathology in aminopeptidase P1 deficiency are unclear. We show here that a deficiency of aminopeptidase P1 modifies the glial population and neuronal excitability in the hippocampus. Microarray and real-time quantitative reverse transcription-polymerase chain reaction analyses identified 14 differentially expressed genes (Casp1, Ccnd1, Myoc, Opalin, Aldh1a2, Aspa, Spp1, Gstm6, Serpinb1a, Pdlim1, Dsp, Tnfaip6, Slc6a20a, Slc22a2) in the Xpnpep1-/- hippocampus. In the hippocampus, aminopeptidase P1-expression signals were mainly detected in neurons. However, deficiency of aminopeptidase P1 resulted in fewer hippocampal astrocytes and increased density of microglia in the hippocampal CA3 area. In addition, Xpnpep1-/- CA3b pyramidal neurons were more excitable than wild-type neurons. These results indicate that insufficient astrocytic neuroprotection and enhanced neuronal excitability may underlie neurodegeneration and hippocampal dysfunction in aminopeptidase P1 deficiency.

Incidence and prevalence of primary ovarian insufficiency in South Korea: a population-based study.

AIM: We investigated the incidence and prevalence of primary ovarian insufficiency (POI) in the Republic of Korea using population-based data. METHODS: Data of patients diagnosed with POI from 2009 to 2017 were obtained from the Health Insurance Review and Assessment Service-National Patient Sample (HIRA-NPS). The incidence and prevalence of POI were measured as defined using follicle stimulating hormone (FSH) test, POI diagnostic codes, and age. RESULTS: Data from 6,617,139 women were extracted. Of those under the age of 40, 239 had been newly diagnosed with POI. The incidence of POI was 9.2 ± 0.6 per 100,000 (0.0092%). The mean age of the women with newly diagnosed POI was 22.2 ± 0.6 years. Logistic regression analysis determined that the incidence of POI decreased with increasing age at 5 year increments [odds ratio (OR) 0.82; 95% confidence interval (CI) 0.75-0.88]; however, socioeconomic status was not associated with POI (OR 1.12; 95% CI 0.5-2.53). Among diseases in the Charlson comorbidity index (CCI), cancer, diabetes mellitus (DM) without complications, and renal disease were associated with an increased incidence of POI (OR 5.54; 95% CI 2.92-10.49; OR 11.83; 95% CI 6.37-22; OR 7.08; 95% CI 1.41-35.5, respectively). When excluding the Q96 (Turner syndrome) diagnostic code, the incidence of POI was 3.7 ± 0.4 per 100,000 (0.0037%), and the prevalence of POI was 12.3 ± 0.4 per 100,000 (0.0123%). CONCLUSION: We found the incidence of POI to be 9.2 ± 0.6 per 100,000 (0.0092%). Cancer, DM without complications, and renal disease were associated with the increased incidence of POI. The incidence and prevalence of POI is considerably lower than reported in previous studies.