Allosteric inhibition of phosphodiesterase 4D induces biphasic memory-enhancing effects associated with learning-activated signaling pathways.

RATIONALE: Phosphodiesterase 4D negative allosteric modulators (PDE4D NAMs) enhance memory and cognitive function in animal models without emetic-like side effects. However, the relationship between increased cyclic adenosine monophosphate (cAMP) signaling and the effects of PDE4D NAM remains elusive. OBJECTIVE: To investigate the roles of hippocampal cAMP metabolism and synaptic activation in the effects of D159687, a PDE4D NAM, under baseline and learning-stimulated conditions. RESULTS: At 3 mg/kg, D159687 enhanced memory formation and consolidation in contextual fear conditioning; however, neither lower (0.3 mg/kg) nor higher (30 mg/kg) doses induced memory-enhancing effects. A biphasic (bell-shaped) dose-response effect was also observed in a scopolamine-induced model of amnesia in the Y-maze, whereas D159687 dose-dependently caused an emetic-like effect in the xylazine/ketamine anesthesia test. At 3 mg/kg, D159687 increased cAMP levels in the hippocampal CA1 region after conditioning in the fear conditioning test, but not in the home-cage or conditioning cage (i.e., context only). By contrast, 30 mg/kg of D159687 increased hippocampal cAMP levels under all conditions. Although both 3 and 30 mg/kg of D159687 upregulated learning-induced Fos expression in the hippocampal CA1 30 min after conditioning, 3 mg/kg, but not 30 mg/kg, of D159687 induced phosphorylation of synaptic plasticity-related proteins such as cAMP-responsive element-binding protein, synaptosomal-associated protein 25 kDa, and the N-methyl-D-aspartate receptor subunit NR2A. CONCLUSIONS: Our findings suggest that learning-stimulated conditions can alter the effects of a PDE4D NAM on hippocampal cAMP levels and imply that a PDE4D NAM exerts biphasic memory-enhancing effects associated with synaptic plasticity-related signaling activation.

Prolonged second stage of labor in delivery using epidural analgesia is a risk factor for postpartum urinary retention.

AIM: To determine the postpartum urinary retention rate and risk factors after delivery using epidural analgesia. METHODS: This single-center retrospective study targeted 341 women who gave birth after at least 37 weeks of gestation from April to August 2021; from this cohort, 208 patients were examined. The postpartum urinary retention rate was compared between the no epidural analgesia group (n = 107) and epidural analgesia group (n = 101). Subsequently, risk factors for postpartum urinary retention were investigated in the epidural analgesia group. RESULTS: After adjustment by propensity score matching for age, body mass index, being primiparous, and labor induction as covariates, the analysis of the incidence of postpartum urinary retention revealed that the epidural analgesia group exhibited a significantly higher postpartum urinary retention rate than the no epidural analgesia group (30% vs. 11%, p = 0.02). The investigation results regarding risk factors for postpartum urinary retention in the epidural analgesia group obtained through a univariate analysis showed that being primiparous and having a prolonged second stage of labor were significantly correlated with postpartum urinary retention. Multivariate analysis indicated that a prolonged second stage of labor was an independent risk factor for postpartum urinary retention (p = 0.03; odds ratio: 3.18; 95% confidence interval: 1.08-9.77). All patients recovered from postpartum urinary retention by day 4. CONCLUSIONS: The postpartum urinary retention rate after delivery using epidural analgesia was 25.7%. In the case of epidural analgesia deliveries, a prolonged second stage of labor was an independent risk factor for postpartum urinary retention.

Huge Leiomyomas Arising from Bilateral Uterine Remnants in a Mayer-Rokitansky-Küster-Hauser Syndrome Patient with Coexisting Myotonic Dystrophy Type 1: A Case Report and Literature Review.

Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) is a rare congenital anomaly of the genital tract. Since the secretion of sex hormones from the ovaries is preserved, leiomyomas and adenomyomas, which are estrogen-dependent diseases, may develop from the uterine remnant. In contrast, patients with myotonic dystrophy type 1 (DM1), the most common dystrophy in adults, are considered to be at high risk for benign tumors of the female reproductive system, such as uterine leiomyomas and ovarian cysts. A rare case of huge leiomyomas arising from bilateral uterine remnants in a woman with MRKHS with coexisting DM1 is presented. Her chief complaint was abdominal distension. On pelvic magnetic resonance imaging (MRI), two solid pelvic masses showing low signal intensity on T2-weighted imaging were seen. Both the uterine corpus and cervix were unclear, but bilateral ovaries were observed normally on MRI. Two uterine leiomyoma-like masses connected by a band of fibrous tissue were found by laparotomy. As with the MRI findings, the uterine cervix and vagina could not be detected macroscopically. Normal bilateral adnexa and round ligaments were identified. All of her symptoms improved after hysterectomy.

Copper-Catalyzed Asymmetric Sulfonylative Desymmetrization of Glycerol.

Glycerol is the main side product in the biodiesel manufacturing process, and the development of glycerol valorization methods would indirectly contribute the sustainable biodiesel production and decarbonization. Transformation of glycerol to optically active C3 units would be one of the attractive routes for glycerol valorization. We herein present the asymmetric sulfonylative desymmetrization of glycerol by using a CuCN/(R,R)-PhBOX catalyst system to provide an optically active monosulfonylated glycerol in high efficiency. A high degree of enantioselectivity was achieved with a commercially available chiral ligand and an inexpensive carbonate base. The optically active monosulfonylated glycerol was successfully transformed into a C3 unit attached with differentially protected three hydroxy moieties. In addition, the synthetic utility of the present reaction was also demonstrated by the transformation of the monosulfonylated glycerol into an optically active synthetic ceramide, sphingolipid E.

D-dimer level significance for deep vein thrombosis screening in the third trimester: a retrospective study.

BACKGROUND: Venous thromboembolism often develops after surgery and childbirth, resulting in death in some cases. Although early deep vein thrombosis (DVT) detection can predict pulmonary thromboembolism, there is no early screening method for DVT in pregnant women. Lack of consensus regarding significance or setting and cut-off value interpretation of D-dimer levels further impedes venous thromboembolism screening in pregnant women. This study aimed to examine the utility of third-trimester serum D-dimer levels as a screening test for DVT during pregnancy and to determine the frequency of asymptomatic DVT using lower-limb compression ultrasonography. METHODS: This single-center retrospective study included 497 pregnant women who underwent elective cesarean section at term in our hospital between January 2013 and December 2019. Serum D-dimer levels were preoperatively measured at 32-37 weeks' gestation. The presence or absence of DVT in patients with serum D-dimer levels ≥ 3.0 µg/ml, the cut-off value, was examined using compression ultrasonography. In all patients, the presence or absence of clinical venous thrombosis (symptoms such as lower-limb pain, swelling, and heat sensation) was examined within 4 postoperative weeks. The Royal College of Obstetricians and Gynecologists Guideline 2015 was referred to determine risk factors for the onset of venous thrombosis during pregnancy. Among those, we examined the risk factors for DVT that result in high D-dimer levels during pregnancy. RESULTS: The median age and body mass index were 35 (20-47) years and 21.2 (16.4-41.1) kg/m2, respectively. Further, the median gestational age and D-dimer levels were 37 weeks and 2.1 (0.2-16.0) µg/ml, respectively. Compression ultrasonography was performed on 135 (26.5%) patients with a D-dimer level ≥ 3.0 µg/ml, with none of the patients showing DVT. All patients were followed up for 4 postoperative weeks, with none presenting with venous thromboembolism. Multivariate analysis showed that hypertensive disorders of pregnancy are an independent risk factor for venous thromboembolism that causes high D-dimer levels (odds ratio: 2.48, 95% confidence interval: 1.05-6.50, P = 0.04). CONCLUSION: There may be low utility in screening for DVT using D-dimer levels in the third trimester. Further, prepartum asymptomatic DVT has a low frequency, indicating the low utility of compression ultrasonography. TRIAL REGISTRATION: Institutional Review Board of Tottori University Hospital (IRB no. 20A149 ).

Changes in serum D-dimer level and effect of enoxaparin sodium after a cesarean section: a retrospective study.

BACKGROUND: Pregnancy increases the risk of venous thromboembolism (VTE). During pregnancy and a post-cesarean section, an increase in D-dimer levels can be observed. However, to date, the usefulness of the D-dimer level measurement for thrombosis in pregnant women has not been determined. OBJECTS: We aimed to evaluate the changes in D-dimer levels after a cesarean section, the risk factors of high D-dimer levels, and enoxaparin sodium's preventive effects on VTE. METHODS: This retrospective study enrolled 160 pregnant women who underwent a cesarean section. D-dimer levels were measured on postoperative day (POD)1 and POD6. If on POD1, the D-dimer levels were ≥10 µg/mL, enoxaparin sodium was administered until POD7. Regardless of enoxaparin administration, when the D-dimer levels on POD6 were ≥10 µg/mL, lower-limb venous ultrasonography was performed. After a cesarean section, patients were screened for the following: factors causing high D-dimer levels, incidence of deep vein thrombosis (DVT), and need for enoxaparin. RESULTS: The median D-dimer levels on POD1 and POD6 were 7.5 µg/mL (1.1-34.1) and 4.2 µg/mL (0.02-31.4), respectively. Enoxaparin sodium was administered to 56 patients (35%). The D-dimer levels on POD6 decreased more significantly than on POD1. The median D-dimer levels in the enoxaparin administration group significantly dropped from 14.3 (POD1) to 3.9 (POD6) (p<.001). The D-dimer levels on POD1 were higher in patients aged ≥35 years and with a hospitalization history of threatened preterm labor. In addition, on POD6, patients aged ≥35 years and with a high body mass index had high D-levels. Following a multivariate analysis, the elderly represent an independent factor for high D-levels. DVT was not observed. CONCLUSION: When the D-dimer levels on POD1 after a cesarean section are ≥10 µg/mL, enoxaparin reduces D-dimer levels six days after cesarean section. Moreover, patients aged ≥35 years represent an independent factor for high D-levels. These findings should be validated by further studies.

CTLA4 mRNA expression in blood is lower in schizophrenia, but not in affective disorders.

CTL-associated antigen 4 (CTLA4) and its downstream signals compose an important mechanism that suppresses immune activity. Recent studies have shown that immune abnormalities are associated with the pathogenesis of schizophrenia (SCZ), but little research has been performed on the relevance of CTLA4 and SCZ. In the present study, we investigated the relationship between CTLA4 mRNA expression and SCZ. We examined the expression of CTLA4 mRNA in blood from patients with SCZ, bipolar disorder (BD), and major depressive disorder (MDD). We compared 50 SCZ subjects, 46 BD subjects, and 63 MDD subjects with age- and sex-matched healthy controls (HCs). Quantitative real-time PCR was performed to examine CTLA4 mRNA expression in peripheral blood using TaqMan probes. Levels of CTLA4 mRNA expression were significantly lower in patients with SCZ compared with HCs (p < 0.001), whereas no differences were found between affective disorder (BD and MDD) patients and HCs. We analyzed the correlation between CTLA4 mRNA expression and clinical parameters, but no significant correlation was found. The expression of CTLA4 mRNA was lower specifically in SCZ, suggesting that abnormal CTLA4 expression may be particularly related to the pathogenesis of SCZ. CTLA4 may be a useful diagnostic marker and a potential therapeutic target of SCZ.

Olaparib Potentiates Anticancer Drug Cytotoxicity via 53BP1 in Oesophageal Squamous Cell Carcinoma Cells.

BACKGROUND/AIM: Olaparib was previously shown to synergistically enhance the cytotoxicity of DNA synthesis inhibitors in oesophageal carcinoma (OC) cell lines. However, the mechanisms of this synergy are not fully understood. As P53 binding protein 1 (53BP1) expression was previously shown to potentiate the anticancer effect of olaparib, we investigated the involvement of 53BP1 in the synergetic cytotoxic effects of olaparib and anticancer drugs in KYSE70 cells. MATERIALS AND METHODS: Experiments included small interfering RNA transfection, growth inhibition assays, western blots, immunofluorescence, and flow cytometry. RESULTS: The toxicity of DNA synthesis-inhibiting agents plus olaparib was decreased when 53BP1 was depleted. Olaparib cotreatment significantly increased phosphorylated H2A histone family member X (γH2AX) foci as well as 53BP1/γH2AX co-localisation in anticancer drug-treated cells. Silencing of 53BP1 suppressed anticancer drug-induced apoptosis with or without olaparib. CONCLUSION: Olaparib potentiates the cytotoxicity of anticancer drugs through 53BP1 in OC cells.

Synergistic Effects of Olaparib and DNA-damaging Agents in Oesophageal Squamous Cell Carcinoma Cell Lines.

BACKGROUND/AIM: Chemotherapy is an important first-line treatment for oesophageal squamous cell carcinoma (ESCC). However, there are few secondary options. Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, enhances the cytotoxicity of various anticancer drugs and has been used to treat advanced ovarian and breast cancers. This study examined the effect of olaparib on the cytotoxicity of anticancer drugs in ESCC cell lines. MATERIALS AND METHODS: ESCC KYSE70 and KYSE140 cells were grown in Dulbecco's modified Eagle's medium and treated with 5-fluorouracil (5-FU), cisplatin, docetaxel, doxorubicin, SN-38, or temozolomide without or with olaparib. RESULTS: Olaparib enhanced the cytotoxicity of all tested anticancer drugs and increased the effects of cisplatin, doxorubicin, SN-38, and temozolomide synergistically. These anticancer drugs caused the accumulation of phospho-histone H2AX Ser139 (γH2AX), a biomarker of DNA damage, and olaparib increased this accumulation. CONCLUSION: PARP inhibitors may potentiate the anticancer activity of DNA-damaging agents in ESCC patients synergistically.

Astrocyte-neuron lactate shuttle sensitizes nociceptive transmission in the spinal cord.

Astrocytes play a key role in the maintenance of synaptic transmission by producing L-lactate via the astrocyte-neuron lactate shuttle (ANLS). Astrocyte activation in the spinal cord is involved in the expression of neuropathic pain. We investigated the role of the ANLS in the spinal cord on hyperalgesia in neuropathic pain in mice. Specific activation of dorsal horn astrocytes induced mechanical hyperalgesia, which was attenuated by α-cyano-4-hydroxycinnamate (4-CIN), an inhibitor of monocarboxylate transporters that deliver L-lactate from astrocytes to neurons. Intrathecal L-lactate administration lowered the mechanical nociceptive threshold, which was attenuated by pretreatment with 4-CIN and isosafrole (a lactate dehydrogenase inhibitor), but not gliotoxin. Intrathecal L-lactate administration significantly upregulated c-Fos and cofilin phosphorylation, which was reversed by 4-CIN. The lowered mechanical nociceptive threshold was significantly attenuated by intrathecal fluorocitrate (an astrocyte-specific Krebs cycle inhibitor), 4-CIN, and isosafrole treatment. Thus, these results suggested that, in neuropathic pain, mechanical hyperalgesia was maintained by excessive L-lactate supplied by activated astrocytes via an aberrant ANLS.

Role of microglia in mechanical allodynia in the anterior cingulate cortex.

Plastic changes that increase nociceptive transmission are observed in several brain regions under conditions of chronic pain. Synaptic plasticity in the anterior cingulate cortex (ACC) is particularly associated with neuropathic pain. Glial cells are considered candidates for the modulation of neural plastic changes in the central nervous system. In this study, we aimed to investigate the role of ACC glial cells in the development of neuropathic pain. First, we examined the expression of glial cells in the ACC of nerve-ligated mice. The expression of astrocytes and microglia was increased in the ACC of nerve-ligated mice, which was reversed by intracerebroventricular (i.c.v) treatment with the microglia inhibitor minocycline. Then, we examined the effect of minocycline on mechanical allodynia in nerve-ligated mice. I.c.v. and intra-ACC treatment with minocycline partially inhibited mechanical allodynia in the nerve-ligated mice. The expression of phosphorylated alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor GluR1 subunit at Ser831, but not at Ser845, was increased in the ACC of the nerve-ligated mice compared to sham-operated mice, which was attenuated by minocycline administration. These results suggest that the activation of microglia in the ACC is involved in the development of hyperalgesia in mice with neuropathic pain.

The hypnotic bromovalerylurea ameliorates 6-hydroxydopamine-induced dopaminergic neuron loss while suppressing expression of interferon regulatory factors by microglia.

The low molecular weight organic compound bromovalerylurea (BU) has long been used as a hypnotic/sedative. In the present study, we found that BU suppressed mRNA expression of proinflammatory factors and nitric oxide release in lipopolysaccharide (LPS)-treated rat primary microglial cell cultures. BU prevented neuronal degeneration in LPS-treated neuron-microglia cocultures. The anti-inflammatory effects of BU were as strong as those of a synthetic glucocorticoid, dexamethasone. A rat hemi-Parkinsonian model was prepared by injecting 6-hydroxydopamine into the right striatum. BU was orally administered to these rats for 7 days, which ameliorated the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and alleviated motor deficits. BU suppressed the expression of mRNAs for interferon regulatory factors (IRFs) 1, 7 and 8 in the right (lesioned) ventral midbrain as well as those for proinflammatory mediators. BU increased mRNA expression of various neuroprotective factors, including platelet-derived growth factor and hepatocyte growth factor, but it did not increase expression of alternative activation (M2) markers. In microglial culture, BU suppressed the LPS-induced increase in expression of IRFs 1 and 8, and it reduced LPS-induced phosphorylation of JAK1 and STATs 1 and 3. Knockdown of IRFs 1 and 8 suppressed LPS-induced NO release by microglial cells. These results suggest that suppression of microglial IRF expression by BU prevents neuronal cell death in the injured brain region, where microglial activation occurs. Because many Parkinsonian patients suffer from sleep disorders, BU administration before sleep may effectively ameliorate neurological symptoms and alleviate sleep dysfunction.

Processed aconite root and its active ingredient neoline may alleviate oxaliplatin-induced peripheral neuropathic pain.

ETHNOPHARMACOLOGICAL RELEVANCE: Processed aconite root (PA, the root of Aconitum carmichaeli, Ranunculaceae) is a crude drug used in traditional Chinese or Japanese kampo medicine to generate heat in the body and to treat pain associated with coldness. Oxaliplatin (L-OHP) is a platinum-based anticancer drug that frequently causes acute and chronic peripheral neuropathies, including cold and mechanical hyperalgesia. AIM OF THE STUDY: We investigated the effects of PA on L-OHP-induced peripheral neuropathies and identified the active ingredient within PA extract. MATERIALS AND METHODS: L-OHP was intraperitoneally injected into mice, and PA boiled water extract was orally administered. Cold and mechanical hyperalgesia were evaluated using the acetone test and the von Frey filament method, respectively. Dorsal root ganglion (DRG) neurons were isolated from normal mice and cultured with L-OHP with or without PA extract. Cell viability and neurite elongation were evaluated. RESULTS: PA extract significantly attenuated cold and mechanical hyperalgesia induced by L-OHP in mice. In cultured DRG neurons, L-OHP reduced cell viability and neurite elongation in a dose-dependent manner. Treatment with PA extract significantly alleviated the L-OHP-induced reduction of neurite elongation, while the cytotoxicity of L-OHP was not affected. Using activity-guided fractionation, we isolated neoline from PA extract as the active ingredient. Neoline significantly alleviated L-OHP-induced reduction of neurite elongation in cultured DRG neurons in a concentration-dependent manner. Moreover, subcutaneous injection of neoline attenuated cold and mechanical hyperalgesia in L-OHP-treated mice. PA extract and neoline did not show sedation and motor impairment. CONCLUSIONS: The present study indicates that PA and its active ingredient neoline are promising agents to alleviate L-OHP-induced neuropathic pain.

Streptococcus agalactiae mural infective endocarditis in a structurally normal heart.

A 38-year-old Caucasian man with uncontrolled diabetes mellitus type 2 was admitted with a 1-week duration of fevers, chills, and a non-productive cough. He had a left ischiorectal abscess 1 month prior to admission. Physical examination revealed caries on a left upper molar and a well-healed scar on the left buttock, but no heart murmur or evidence of micro-emboli. Blood cultures grew Streptococcus agalactiae. A transesophageal echocardiogram revealed a mobile mass in the right ventricle that attached to chordae tendineae without valvular disease or dysfunction. A computed tomography (CT) with contrast revealed the mass within the right ventricle, a left lung cavitary lesion, and a splenic infarction. He was initially treated with penicillin G for a week. Subsequently, ceftriaxone was continued for a total of 8 weeks. A follow-up CT showed no evidence of right ventricular mass 8 weeks after discharge. This is the first reported case of S. agalactiae mural infective endocarditis in a structurally normal heart.

Nonbacterial thrombotic endocarditis leading to acute heart failure due to aortic stenosis in a patient with lung cancer.

We herein report an autopsied case of a patient with adenocarcinoma of the lungs who developed nonbacterial thrombotic endocarditis (NBTE) that caused acute heart failure (AHF) due to acute aortic stenosis (AS). A 37-year-old man was admitted to our hospital due to chest pain and fever. He was diagnosed as having Stage IV lung cancer. Following the administration of chemotherapy, the patient presented with acute onset of dyspnea. He was diagnosed with having AHF based on his clinical course and physical findings, and ultimately he died without responding to treatment. The autopsy revealed that NBTE caused acute AS leading to AHF.

[Strategy for marginally resectable lung cancer].

Lung cancer accounts for the largest number of new cases of cancer deaths annually. The treatment of locally advanced non-small-cell lung cancer(NSCLC)will continue to be a problem for many years. In particular, the border-zone subset of stage III A(N2)patients, which lies between the generally resectable stage I and II tumors and the unresectable stage III B patients, has been the subject of a wide variety of clinical trials incorporating various combinations of chemotherapy, radiotherapy, and surgery.What is the ideal therapy for stage III A(N2)patients ? is a controversial question, and the role of surgery is not clearly defined because of its heterogeneous nature. Most importantly, treatment decisions for these patients should be dictated by the stage of the patients' disease and the patients' performance status, medical comorbidities, and preferences. At our hospital, therefore, all of these patients' data are discussed at our cancer-board conference, incorporating the options of thoracic surgeons, medical oncologists, and radiation oncologists to determine the optimal prospective treatment strategies for the patients. We focused on a treatment strategy for the patients with the so called marginally resectable' lung cancer in this article.

Carbon black nanoparticles enhance bleomycin-induced lung inflammatory and fibrotic changes in mice.

With the recent increasing use of nanoparticles, there is concern that they may become an environmental risk factor as airborne particles. However, the impact of these particles on susceptible subjects with predisposing lung disease have not been sufficiently elucidated. In the present study, we investigated the effects of nanoparticles on pulmonary inflammatory and fibrotic changes induced by intratracheal bleomycin (BLM) challenge in mice. Mice were intratracheally administered either vehicle, 14-nm carbon black nanoparticles (CBNPs), BLM or BLM plus CBNP. First, we assessed lung collagen content, lung compliance and fibrotic changes in histopathology on day 21 after instillation. Then, to elucidate how CBNP contributes to the development of BLM-induced fibrosis, we collected bronchoalveolar lavage (BAL) fluid on days 2, 7, 14 and 21 and determined the total and differential cell counts and concentrations of two proinflammatory cytokines (keratinocyte chemoattractant [KC] and interleukin [IL]-6) and two fibrogenic mediators (CC chemokine ligand 2 [CCL2] and transforming growth factor-ß(1) [TGF-ß(1)]). Expression of nitrotyrosine, an indicator of oxidant injury, was also evaluated on days 7 and 21. CBNP, when combined with BLM, significantly enhanced BLM-induced increase in lung collagen content, decrease in lung compliance, and fibrotic changes in histopathology. CBNP significantly augmented BLM-induced increase in the numbers of inflammatory cells in BAL fluid on days 2 and 7 and levels of KC and IL-6 on day 2. In addition, CBNP administered in combination with BLM significantly elevated the levels of CCL2 on days 2, 7 and 14, and TGF-ß(1) on day 14 in BAL fluid as compared with BLM alone. Nitrotyrosine expression was also increased by BLM plus CBNP compared with BLM alone. In contrast, CBNP did not exert any significant effect on these parameters by itself. These results indicate that CBNP can exaggerate BLM-induced inflammatory and fibrotic changes in the lung, suggesting the potential impact of nanoparticles on lung inflammation and fibrosis.