Chimeric Singleton Placenta Comprising Placental Mesenchymal Dysplasia and Complete Hydatidiform Mole with Live Birth and Postpartum Diagnosis of Gestational Trophoblastic Neoplasia.

INTRODUCTION: Placental mesenchymal dysplasia (PMD) is a benign lesion that is often misdiagnosed as complete (CHM) or partial hydatidiform mole. PMD usually results in live birth but can be associated with several fetal defects. Herein, we report PMD with CHM in a singleton placenta with live birth. CASE PRESENTATION: A 34-year-old gravida 2, para 1, living 1 (G2P1L1) woman was referred on suspicion of a molar pregnancy in the first trimester. Maternal serum human chorionic gonadotrophin levels were increased during early pregnancy, with multicystic lesions and placentomegaly observed on ultrasonography. Levels decreased to normal with no fetal structural abnormalities observed. A healthy male infant was delivered at 34 gestational weeks. Placental p57KIP2 immunostaining and short tandem repeat analysis revealed three distinct histologies and genetic features: normal infant and placenta, PMD, and CHM. Gestational trophoblastic neoplasia was diagnosed and up to fourth-line chemotherapy administered. CONCLUSION: Distinguishing PMD from hydatidiform moles is critical for avoiding unnecessary termination of pregnancy. CHM coexisting with a live fetus rarely occurs. This case is unique in that a healthy male infant was born from a singleton placenta with PMD and CHM.

Cochlin produced by follicular dendritic cells promotes antibacterial innate immunity.

Cochlin, an extracellular matrix protein, shares homologies with the Factor C, a serine protease found in horseshoe crabs, which is critical for antibacterial responses. Mutations in the COCH gene are responsible for human DFNA9 syndrome, a disorder characterized by neurodegeneration of the inner ear that leads to hearing loss and vestibular impairments. The physiological function of cochlin, however, is unknown. Here, we report that cochlin is specifically expressed by follicular dendritic cells and selectively localized in the fine extracellular network of conduits in the spleen and lymph nodes. During inflammation, cochlin was cleaved by aggrecanases and secreted into blood circulation. In models of lung infection with Pseudomonas aeruginosa and Staphylococcus aureus, Coch(-/-) mice show reduced survival linked to defects in local cytokine production, recruitment of immune effector cells, and bacterial clearance. By producing cochlin, FDCs thus contribute to the innate immune response in defense against bacteria.

Deubiquitination of NLRP3 by BRCC3 critically regulates inflammasome activity.

NLRP3 is an important pattern recognition receptor involved in mediating inflammasome activation in response to viral and bacterial infections as well as various proinflammatory stimuli associated with tissue damage or malfunction. Upon activation, NLRP3 assembles a multimeric inflammasome complex comprising the adaptor ASC and the effector pro-caspase-1 to mediate the activation of caspase-1. Although NLRP3 expression is induced by the NF-κB pathway, the posttranscriptional molecular mechanism controlling the activation of NLRP3 remains elusive. Using both pharmacological and molecular approaches, we show that the activation of NLRP3 inflammasome is regulated by a deubiquitination mechanism. We further identify the deubiquitinating enzyme, BRCC3, as a critical regulator of NLRP3 activity by promoting its deubiquitination and characterizing NLRP3 as a substrate for the cytosolic BRCC3-containing BRISC complex. Our results elucidate a regulatory mechanism involving BRCC3-dependent NLRP3 regulation and highlight NLRP3 ubiquitination as a potential therapeutic target for inflammatory diseases.

Association of baseline histopathology and kidney donor risk index with graft outcomes in deceased donor kidney transplantation
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BACKGROUND: Donor organ quality is a key determinant of graft outcomes in deceased donor kidney transplantation (DDKT). The predictive values of baseline histopathology and several clinical scoring systems for long-term graft outcomes have been evaluated, but the results remain controversial. MATERIALS AND METHODS: We screened 167 patients who underwent DDKT at Ulsan University Hospital from April 2003 to June 2016. Among them, 66 patients who underwent baseline kidney biopsy and whose kidney donor risk index (KDRI) was available were included in this analysis. All baseline biopsies were rescored according to the updated Banff classification. RESULTS: Median follow-up was 22 months. Mean age of recipients and donors was 51.4 and 44.7 years, respectively. Mean KDRI was 1.40 ± 0.44. During follow-up, delayed graft function and biopsy-proven acute rejection (BPAR) developed in 7 and 11 patients, respectively. Graft failure occurred in 2 patients. In Cox regression analysis, interstitial fibrosis/tubular atrophy (IFTA) (hazard ratio (HR) = 3.59; p = 0.049) was a significant risk factor for BPAR. In multivariate linear regression, age (standardized ß (SB) = -0.282; p = 0.002), BPAR (SB = -0.406; p < 0.001), KDRI (SB = -0.277; p = 0.003), and IFTA (SB = -0.298; p = 0.001) were significant predictors of last-visit estimated glomerular filtration rate (eGFR). CONCLUSION: Several clinical and pathologic parameters, such as KDRI and IFTA, may be helpful for predicting long-term graft outcomes, including BPAR and last-visit eGFR, in DDKT.
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Genetic Determinants of Circulating Lipoproteins in Nonalcoholic Fatty Liver Disease.

BACKGROUND: Recent genome-wide association studies have identified 2 genetic polymorphisms in association with nonalcoholic fatty liver disease (NAFLD): patatin-like phospholipase domain containing 3 (PNPLA3) and transmembrane 6 superfamily member 2 (TM6SF2), both of which appear to influence the production of very low density lipoprotein (VLDL). The impact of these genetic variations on lipoprotein metabolism in the setting of nonalcoholic steatohepatitis and liver fibrosis are not fully characterized. MATERIALS AND METHODS: We measured comprehensive lipoprotein profiles by nuclear magnetic resonance among 170 serially recruited patients in an NAFLD registry, and determined their relationships with PNPLA3 and TM6SF2 genotypes. RESULTS: In this cohort, 72% patients had at least 1 allele of either PNPLA3 I148M or TM6SF2 E167K, and 30% carried 2 alleles. In multivariate models adjusting for histologic features of nonalcoholic steatohepatitis and liver fibrosis, PNPLA3 I148M is associated with a decrease in VLDL particle size. Both PNPLA3 I148M and TM6SF2 E167K genotypes were associated with increases in the size of low density lipoprotein (LDL) and high density lipoprotein particles, phenotypes considered atheroprotective. When adjusted for both genotypes, NAFLD activity score, in particular the degree of hepatic steatosis was strongly associated with increases in the size of VLDL particles, the concentration of LDL, especially small LDL particles, and a decrease in the size of high density lipoprotein particles, all of which are linked with a proatherogenic phenotype. CONCLUSIONS: PNPLA3 and TM6SF2 are common genetic variants among NAFLD patients and impact lipoprotein profiles in slightly different ways. The interactions between genotypes, hepatic steatosis, and lipoprotein metabolism shed lights on the pathophysiology of NAFLD, and provide opportunities for personalized treatment in the era of emerging NAFLD therapeutics.

Clear Cell Hidradenoma: Characteristic Imaging Features on Ultrasonography, Computed Tomography, and Magnetic Resonance Imaging.

OBJECTIVES: The purpose of this study was to evaluate the imaging features of clear cell hidradenoma on ultrasonography (US), computed tomography (CT), and magnetic resonance imaging (MRI). METHODS: The radiologic and pathologic databases at 2 medical institutions were searched retrospectively from 2004 to 2016 to identify patients with a diagnosis of clear cell hidradenoma. Ultrasonographic, CT, and MRI features were described, and pathologic specimens were reviewed. RESULTS: There were 5 female and 4 male patients. The mean patient age was 48.9 years (range, 28-70 years). Five patients underwent only US; 2 patients underwent only CT; 1 patient underwent both US and CT; and 1 patient underwent US and MRI. Most of the tumors were located primarily in the subcutaneous fat layer. The mean tumor size was 18.4 mm. On US, 6 masses had a heterogeneous echo texture, including an anechoic portion with protruding echogenic portions. Two masses had multiple septa in the anechoic portion. On color Doppler US, blood flow was both central and peripheral in 5 patients. All 3 cases seen on CT presented as a low-attenuation mass with an enhanced solid internal nodule. On MRI, the mass showed heterogeneous signal intensity on T2-weighted images and enhancement of the peripheral wall and internal solid component on contrast-enhanced T1-weighted images. CONCLUSIONS: Clear cell hidradenoma is usually located in the subcutaneous fat layer, has a well-defined margin, appears as a cystic mass with an internal solid nodule, and occasionally has multiple septa on US, CT, and MRI.

Dietary inflammatory index and its relationship with high-sensitivity C-reactive protein in Korean: data from the health examinee cohort.

Inflammation is associated with chronic disease. High-sensitivity C-reactive protein (hs-CRP) is a predictor of chronic disease. The dietary inflammatory index (DII) is used to determine the overall inflammatory potential of diet. A cross-sectional analysis of Health Examinee cohort data (2012-2014) from Korea was performed. Subjects were 40-79 years of age (8,332 males; 19,754 females). The DII was used to analyze the relationship between subject characteristics, nutrient intake, and the hs-CRP. Additionally, the relationship between DII and hs-CRP as a predictor of chronic disease was examined. The DII was divided into 4 quartile: Q1 = -7.21 to -1.88 (median: -3.020), Q2 = -1.87 to -0.02 (median: -0.410), Q3 = -0.01 to 1.87 (median = 0.870) and Q4 = 1.88 to 7.34 (median = 3.040). For each group, the carbohydrate/protein/fat intake ratio was Q1 = 66.7:16.6:19.2, Q2 = 67.2:15.6:18.7, Q3 = 67.3:15.1:18.4 and Q4 = 67.3:14.0:17.9. The odds of elevated hs-CRP were 1.241 times higher in participants with the most proinflammatory diets than those with the most anti-inflammatory diets [hs-CRP; odds ratio (95% confidence interval) for Q4 vs Q1: 1.241 (1.071, 1.438); p for trend = 0.002]. An association was found between a high DII and high levels of hs-CRP. The DII may be applied to measure the association between diet and chronic diseases.

Expression of programmed cell death 1 and programmed cell death ligand 1 in extranodal NK/T-cell lymphoma, nasal type.

Programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) are new therapeutic targets in cancer immunotherapy. The aim of this study was to investigate the clinicopathological characteristics of PD-1 and PD-L1 expression in extranodal natural killer/T­cell lymphoma, nasal type (ENKTL). We performed PD-1 and PD-L1 immunostaining in 79 ENKTL biopsy samples and retrospectively analyzed medical records of all 79 patients from four tertiary referral hospitals. The expression of PD-1 and PD-L1 by tumor cells and/or infiltrating immune cells was evaluated. The expression rates of PD-L1 in tumor cells and infiltrating immune cells were 79.7 and 78.5 %, respectively, whereas PD-1 in tumor cells and infiltrating immune cells were 1.3 and 11.4 %. The PD-L1 positivity in tumor cells and infiltrating immune cells was significantly associated with low international prognostic index (IPI) (P = 0.044 and 0.037, respectively). Patients with normal range of serum lactate dehydrogenase demonstrated a significantly higher PD-L1 positivity in tumor cells (P = 0.020). PD-L1-positive patients had a trend toward better overall survival compared with that in patients with PD-L1-negative in tumor cells and infiltrating immune cells (P = 0.498 and 0.435, respectively). The expression rate of PD-L1 was up to 79.7 % in ENKTL, while PD-1 expression rate was very low. This is the first report describing the clinicopathological features and survival outcome according to expression of PD-1 and PD-L1 in ENKTL.

Clinicopathologic and prognostic associations of KRAS and BRAF mutations in small intestinal adenocarcinoma.

Activating KRAS and/or BRAF mutations have been identified as predictors of resistance to anti-epidermal growth factor receptor (EGFR) chemotherapy in colorectal cancer. But the status of KRAS and BRAF mutations and their clinicopathologic and prognostic significance has not been extensively evaluated in small intestinal adenocarcinomas. In this work, the KRAS and BRAF genes in 190 surgically resected small intestinal adenocarcinoma cases were sequenced and their association with various clinicopathologic variables, including survival of the patients, was analyzed. KRAS or BRAF mutations were observed in 63 (33%) cases. Sixty-one cases had KRAS mutations and 2 had BRAF mutations and the two types of mutation were mutually exclusive. The majority of KRAS mutations were G>A transition (43/61 cases, 71%) or p.G12D (31/61 cases, 51%). The patients with mutant KRAS tended to have higher pT classifications (P=0.034) and more frequent pancreatic invasion (P=0.020) than those with wild-type KRAS. Multivariate logistic regression analysis showed that certain mutated KRAS subtypes (G>A transitions and G12D mutations) were significantly correlated with higher pT classification (P=0.015 and 0.004, respectively) than wild-type KRAS and other KRAS mutations. The patients with KRAS or BRAF mutation had a tendency to shorter overall survival than those with wild-type KRAS and BRAF (P=0.148), but subgroup analysis demonstrated the patients with KRAS mutations showed worse survival (median, 46.0 months; P=0.046) than those with wild-type KRAS (85.4 months) in lower pT classification (pT1-pT3) group. In summary, KRAS and, infrequently, BRAF mutations are observed in a subset of small intestinal adenocarcinomas, and are associated with higher pT classification and more frequent pancreatic invasion. KRAS mutation is a poor prognostic predictor in patients with lower pT classification tumors. Anti-EGFR targeted therapy could be applied to about two-thirds of small intestinal adenocarcinoma patients, namely those with wild-type KRAS and BRAF if they have metastatic disease, similar to colorectal cancer patients.

Steatohepatitis and liver fibrosis are predicted by the characteristics of very low density lipoprotein in nonalcoholic fatty liver disease.

BACKGROUND & AIMS: A major challenge in the management of nonalcoholic fatty liver disease (NAFLD) is to identify patients with nonalcoholic steatohepatitis (NASH) and early liver fibrosis. The progression of NAFLD is accompanied by distinctive changes in very low density lipoprotein (VLDL), a lipoprotein particle produced exclusively in the liver. Herein, we sought to determine the characteristics of VLDL profiles associated with NASH and liver fibrosis. METHODS: We evaluated VLDL profiles of 128 patients from a single centre NAFLD registry, and examined VLDL size, total and subclass VLDL concentrations in relation to NAFLD activity score (NAS), steatohepatitis and liver fibrosis as determined by liver biopsy. RESULTS: A near linear relationship was observed between mean VLDL particle size and NAFLD activity score (NAS). In multivariate models, VLDL particle size was significantly associated with both NAS and NASH, after adjustment for BMI and diabetes. A decrease in small VLDL particle concentration was associated with more advanced liver fibrosis. In receiver operative characteristic analyses, mean VLDL size performed similarly to cytokeratin 18 in predicting NASH, whereas small VLDL particle concentration had similar performance to NAFLD fibrosis score in predicting stage 2 or above liver fibrosis. CONCLUSIONS: The increase in mean VLDL size in NASH and decrease in small VLDL particle concentration in liver fibrosis likely reflect changes in the number and state of hepatocytes associated with NASH and fibrosis. In addition to its value in risk stratification of cardiovascular diseases, circulating VLDL profile may provide information for the staging of NAFLD disease severity.

Periosteal chondroma with spinal cord compression in the thoracic spinal canal: a case report.

Periosteal chondroma is a very unusual cartilaginous neoplasm of the spinal canal. We herein report a case of periosteal chondroma in a 41-year-old male who presented with gait disturbance and paresthesia of both lower extremities. Magnetic resonance (MR) images showed an extradural mass which caused compression of the spinal cord at the T5/6 level. The mass showed iso-signal intensity on T1-weighted images, high signal intensity on T2-weighted images, and nodular and peripheral rim enhancement on post-contrast T1-weighted images. Computed tomography (CT) images showed a mass with punctate calcifications and extension into the left T5/6 neural foramen. MR and CT images showed extrinsic cortical bone erosion of the posterior inferior body of T5 and superior pedicle of T6, bone remodeling with overhanging margins, and sclerosis adjacent to the tumor. The patient underwent a complete excision of the mass by left T5/6 hemi-laminectomy and exhibited complete resolution of his symptoms. Histopathologic examination revealed periosteal chondroma. Tumor recurrence was not recorded during the 18-month follow-up period.

Src is a novel potential off-target of RXR agonists, 9-cis-UAB30 and Targretin, in human breast cancer cells.

9-cis-UAB30 (UAB30) and Targretin are well-known retinoid X receptor (RXR) agonists. They were highly effective in decreasing the incidence of methylnitrosourea (MNU)-induced mammary cancers. However, whether the anti-mammary cancer effects of UAB30 or Targretin originate from the activation of RXR is unclear. In the present study, we hypothesized that UAB30 and Targretin not only affect RXR, but likely influence one or more off-target proteins. Virtual screening results suggest that Src is a potential target for UAB30 and Targretin that regulates extracellular matrix (ECM) molecules and cell motility and invasiveness. In vitro kinase assay data revealed that UAB30 or Targretin interacted with Src and attenuated its kinase activity. We found that UAB30 or Targretin substantially inhibited invasiveness and migration of MCF-7 and SK-BR-3 human breast cancer cells. We examined the effects of UAB30 and Targretin on the expression of matrix metalloproteinases (MMP)-9, which are known to play an essential role in tumor invasion. We show that activity and expression of MMP-9 were decreased by UAB30 or Targretin. Western blot data showed that UAB30 or Targretin decreased AKT and its substrate molecule p70(s6k), which are downstream of Src in MCF-7 and SK-BR-3 cells. Moreover, knocking down the expression of Src effectively reduced the sensitivity of SK-BR-3 cells to the inhibitory effects of UAB30 and Targretin on invasiveness. Taken together, our results demonstrate that UAB30 and Targretin each inhibit invasion and migration by targeting Src in human breast cancer cells.

Heterotopic pancreas of the jejunum: associations between CT and pathology features.

PURPOSE: To investigate the computed tomography (CT) features of heterotopic pancreas of the jejunum (HPJ) and to assess their associations with HPJ pathology features. METHODS: In this retrospective series analysis, two radiologists reviewed the CT images of 17 patients with surgically proven HPJ in order to determine in consensus the location, long diameter, margin, shape, contour, and growth pattern of the lesions, the presence of a duct-like structure, the lesion enhancement patterns, including the homogeneity, and the degree of contrast enhancement compared with that of the main pancreas. The pathology features of the surgical specimens were reviewed and their associations with the CT features were assessed. RESULTS: On CT, the HPJs typically appeared as a small (<3 cm), well-defined, ovoid or flat-shaped mass in the proximal jejunum with multiple and tiny lobulations. The growth pattern varied and the duct-like structure was rarely visible. The HPJs mostly appeared to be homogeneous and exhibited hyper- or isoattenuation compared to the main pancreas in the arterial and portal phases. However, these enhancement patterns varied slightly depending on the microscopic composition of the lesions (i.e., acinar vs. ductal predominance). Most HPJs comprised histologically of large acini, some ducts, and small islet cells, and had ductal communication with the jejunum. CONCLUSIONS: HPJs typically manifested as small, well-defined, ovoid or flat-shaped, homogeneous, and well-enhancing masses with a microlobulated contour in the proximal jejunum on CT, and their enhancement patterns associated with their microscopic composition. The pathology features of HPJs generally mimic those of the normal pancreas.

Dietary intake of vitamin K in relation to bone mineral density in Korea adults: The Korea National Health and Nutrition Examination Survey (2010-2011).

Low vitamin K nutritional status has been associated with increased risk of fracture, however inconsistent results exist to support the role of vitamin K on bone mineral density depending on ethnic difference and gender. Our objective was to determine vitamin K intake in Korean adults, examine correlation between vitamin K intake and bone mineral density. This study analyzed raw data from the fifth Korea National Health and Nutrition Examination Survey for adults (2,785 men, 4,307 women) aged over 19 years. Cross-sectional analyses showed only positive association between vitamin K intake and femur bone mineral density in men after adjusting bone-related factors. However, women in high tertiles of vitamin K intake had a significantly higher bone mineral density both in femur and lumber as compared to women in lowest tertiles (p<0.05). The risk for osteoporosis was decreased as vitamin K intake increased in women, but this effect was not persisted after adjusting factors. The findings of this study indicate that low dietary vitamin K intake was associated with low bone mineral density in subjects. From these results we may suggest an increase in dietary vitamin K intakes for maintaining bone mineral density. (2010-02CON-21-C, 2011-02CON-06-C).

Comparison between arthroscopic findings and 1.5-T and 3-T MRI of oblique coronal and sagittal planes of the knee for evaluation of selective bundle injury of the anterior cruciate ligament.

OBJECTIVE: The purpose of this study was to evaluate the diagnostic usefulness of combining oblique sagittal and oblique coronal MRI views of the anterior cruciate ligament (ACL) with traditional orthogonal views for the evaluation of selective-bundle ACL injury and to evaluate whether there is a statistical difference in diagnostic ability between 1.5-T and 3-T MRI. MATERIALS AND METHODS: This retrospective study included 114 patients who underwent knee MRI (46 on 1.5 T and 68 on 3 T) and arthroscopy at our institution. Two radiologists evaluated orthogonal views and ACL views on 1.5-T and 3-T MRI in variable combinations. They diagnosed ACL views as normal, entire ligament tear, anteromedial bundle tear, or posterolateral bundle tear. The surgeon then confirmed tears in the anteromedial or posterolateral bundle of the ACL arthroscopically if a selective-bundle tear did exist. The arthroscopically confirmed diagnoses were used as the reference standard. The values were statistically analyzed. RESULTS: Sixty-seven percent of patients showed an ACL tear on arthroscopy, and 33% had a selective bundle tear; of these, 75% were anteromedial bundle tears and 25% were posterolateral bundle tears. On 1.5-T MRI, specificities of each view and combined views were the same (80%). The sensitivities and accuracies of the combined views were higher than the individual views; differences between individual views ranged from 4% to 15%. Reader 1 saw statistically significant differences between the oblique coronal and combined views. Although the performances of reader 2 showed similar results, the p values exceeded the critical value of statistical significance (0.063). On 3-T MRI, differences in specificities between the orthogonal and combined views and between the orthogonal and oblique coronal views were statistically significant (p, 0.016 and 0.008 for readers 1 and 2, respectively). There were no significant differences in the diagnostic performance of 1.5-T and 3-T MRI. CONCLUSION: The oblique coronal view and the combination of the orthogonal view and both additional ACL views provide better diagnostic information with an improvement in specificity on 3-T MRI compared with orthogonal views alone in the diagnosis of selective-bundle tears. Although diagnostic performance was not improved with the addition of the oblique views over orthogonal views on 1.5-T imaging, diagnostic performance was improved on 3-T MRI. Accuracies for individual imaging planes were not significantly different when comparing 1.5-T and 3-T MRI.

The usefulness of the oblique coronal plane in knee MRI on the evaluation of the posterior cruciate ligament.

BACKGROUND: Imaging findings of posterior cruciate ligament (PCL) injury may be equivocal, particularly when the patient has suffered a partial ligament tear. Some PCLs are positioned more horizontally, making it difficult to diagnose injury based on routine imaging planes alone due to partial volume artifact. PURPOSE: To evaluate the diagnostic accuracy of combining oblique coronal imaging (PCL view) with traditional orthogonal views for PCL evaluation. MATERIAL AND METHODS: This retrospective study included 20 patients with PCL injury and 43 patients with intact PCL who underwent PCL view imaging. Anatomic identification of PCL pathology on the orthogonal magnetic resonance imaging (MRI) sequences and PCL views was evaluated. Subjective scoring of the PCL was performed by two radiologists who assessed the possibility of a PCL tear based on an entire length view, an entire width view, and margin sharpness according to a 4-point scale. Diagnostic accuracy using these two views was evaluated by calculating the sensitivity, specificity, and accuracy. Arthroscopic and clinical findings were used as the reference standard. RESULTS: Total scores for the PCL view were higher than those of orthogonal views (P < 0.001). Both readers found that anatomic identification using the full width view and sharp margin to be superior using the PCL view compared with the orthogonal views (P < 0.001). The specificities and accuracies were higher in cases where an additional PCL view was provided, but did not show statistical significance. CONCLUSION: PCL view provides better anatomic evaluation of the PCL and mild improvement in the specificity and accuracy.

Metabolic remodeling in cancer and senescence and its therapeutic implications.

Cellular metabolism is a flexible and plastic network that often dictates physiological and pathological states of the cell, including differentiation, cancer, and aging. Recent advances in cancer metabolism represent a tremendous opportunity to treat cancer by targeting its altered metabolism. Interestingly, despite their stable growth arrest, senescent cells - a critical component of the aging process - undergo metabolic changes similar to cancer metabolism. A deeper understanding of the similarities and differences between these disparate pathological conditions will help identify which metabolic reprogramming is most relevant to the therapeutic liabilities of senescence. Here, we compare and contrast cancer and senescence metabolism and discuss how metabolic therapies can be established as a new modality of senotherapy for healthy aging.

An essential role for histone deacetylase 4 in synaptic plasticity and memory formation.

Histone deacetylases (HDACs), a family of enzymes involved in epigenetic regulation, have been implicated in the control of synaptic plasticity, as well as learning and memory. Previous work has demonstrated administration of pharmacological HDAC inhibitors, primarily those targeted to class I HDACs, enhance learning and memory as well as long-term potentiation. However, a detailed understanding of the role of class II HDACs in these processes remains elusive. Here, we show that selective loss of Hdac4 in brain results in impairments in hippocampal-dependent learning and memory and long-term synaptic plasticity. In contrast, loss of Hdac5 does not impact learning and memory demonstrating unique roles in brain for individual class II HDACs. These findings suggest that HDAC4 is a crucial positive regulator of learning and memory, both behaviorally and at the cellular level, and that inhibition of Hdac4 activity may have unexpected detrimental effects to these processes.

Functional and mechanistic exploration of an adult neurogenesis-promoting small molecule.

Adult neurogenesis occurs throughout life in the mammalian hippocampus and is essential for memory and mood control. There is significant interest in identifying ways to promote neurogenesis and ensure maintenance of these hippocampal functions. Previous work with a synthetic small molecule, isoxazole 9 (Isx-9), highlighted its neuronal-differentiating properties in vitro. However, the ability of Isx-9 to drive neurogenesis in vivo or improve hippocampal function was unknown. Here we show that Isx-9 promotes neurogenesis in vivo, enhancing the proliferation and differentiation of hippocampal subgranular zone (SGZ) neuroblasts, and the dendritic arborization of adult-generated dentate gyrus neurons. Isx-9 also improves hippocampal function, enhancing memory in the Morris water maze. Notably, Isx-9 enhances neurogenesis and memory without detectable increases in cellular or animal activity or vascularization. Molecular exploration of Isx-9-induced regulation of neurogenesis (via FACS and microarray of SGZ stem and progenitor cells) suggested the involvement of the myocyte-enhancer family of proteins (Mef2). Indeed, transgenic-mediated inducible knockout of all brain-enriched Mef2 isoforms (Mef2a/c/d) specifically from neural stem cells and their progeny confirmed Mef2's requirement for Isx-9-induced increase in hippocampal neurogenesis. Thus, Isx-9 enhances hippocampal neurogenesis and memory in vivo, and its effects are reliant on Mef2, revealing a novel cell-intrinsic molecular pathway regulating adult neurogenesis.

The effect of rifaximin on gut flora and Staphylococcus resistance.

AIM: Rifaximin is a non-absorbed antibiotic relative of rifampicin. The location of effect and staphylococcal resistance are two recent potential concerns with rifaximin. In this study we evaluate the location of effect of rifaximin as well as the development of staphylococcal rifampicin resistance. METHODS: Rats were divided into three groups. Group 1 gavaged for 10 days with PBS, group 2 gavaged with rifaximin for 10 days, and group 3 gavaged with rifaximin for 10 days and housed for 30 days. In each group, stool was collected daily for quantitative culture of Staphylococcus spp. and coliforms. After euthanasia luminal bacterial counts were determined at multiple gut locations by qPCR. Rifampicin susceptibility was tested on Staphylococcus pre and post rifaximin. RESULTS: At baseline, rats had a median of 2.90 × 10(6) cfu/ml Staphylococcus spp. in stool. After 10 days of rifaximin, this dropped to 1.20 × 10(5) cfu/ml (P < 0.01). With coliform counts, rats had a median of 1.86 × 10(4) cfu/ml at baseline which dropped to 2.2 × 10(3) cfu/ml (P < 0.01) after rifaximin. After cessation of rifaximin, coliform counts recovered within 3 days. When examining the total bacterial counts by qPCR, rifaximin reduced small bowel bacterial levels, but not colon. This reduction was sustained for 30 days. No colonies of Staphylococcus became resistant and only one colony was intermediate. The mean inhibitory concentration for rifampicin was not different before and after rifaximin. CONCLUSION: Staphylococcal spp. fail to demonstrate resistance to rifampicin after rifaximin. The transient reductions in stool coliform counts recover while rifaximin appears to produce durable reductions in duodenal bacteria.