HE4 suppresses the expression of osteopontin in mononuclear cells and compromises their cytotoxicity against ovarian cancer cells.

Ovarian cancers are known to evade immunosurveillance and to orchestrate a suppressive immune microenvironment. Here we examine the role of human epididymis protein 4 (HE4), an ovarian cancer biomarker, in immune evasion. Through modified subtractive hybridization analyses we have characterized the gene targets of HE4 in human peripheral blood mononuclear cells (PBMCs), and established a preliminary mechanism for HE4-mediated immune failure in ovarian tumours. Upon exposure of purified PMBCs to HE4, osteopontin (OPN) and dual-specificity phosphatase 6 (DUSP6) emerged as the most suppressed and up-regulated genes, respectively. SKOV3 and OVCAR8, human ovarian carcinoma cell lines, exhibited enhanced proliferation in conditioned media from HE4-exposed PBMCs, an effect that was attenuated by the addition of recombinant OPN or OPN-inducible cytokines [interleukin (IL)-12 and interferon (IFN)-Ɣ]. Additionally, upon co-culture with PBMCs, HE4-silenced SKOV3 cells were found to be more susceptible to cytotoxic cell death. The relationship between HE4 and OPN was reinforced further through the analysis of serous ovarian cancer patient samples. In these biopsy specimens, the number of OPN+ T cells correlated positively with progression free survival (PFS) and inversely with serum HE4 level. Taken together, these findings show that HE4 enhances ovarian cancer tumorigenesis by compromising OPN-mediated T cell activation.

Status Epilepticus Impairs Synaptic Plasticity in Rat Hippocampus and Is Followed by Changes in Expression of NMDA Receptors.

Cognitive deficits and memory loss are frequent in patients with temporal lobe epilepsy. Persistent changes in synaptic efficacy are considered as a cellular substrate underlying memory processes. Electrophysiological studies have shown that the properties of short-term and long-term synaptic plasticity in the cortex and hippocampus may undergo substantial changes after seizures. However, the neural mechanisms responsible for these changes are not clear. In this study, we investigated the properties of short-term and long-term synaptic plasticity in rat hippocampal slices 24 h after pentylenetetrazole (PTZ)-induced status epilepticus. We found that the induction of long-term potentiation (LTP) in CA1 pyramidal cells is reduced compared to the control, while short-term facilitation is increased. The experimental results do not support the hypothesis that status epilepticus leads to background potentiation of hippocampal synapses and further LTP induction becomes weaker due to occlusion, as the dependence of synaptic responses on the strength of input stimulation was not different in the control and experimental animals. The decrease in LTP can be caused by impairment of molecular mechanisms of neuronal plasticity, including those associated with NMDA receptors and/or changes in their subunit composition. Real-time PCR demonstrated significant increases in the expression of GluN1 and GluN2A subunits 3 h after PTZ-induced status epilepticus. The overexpression of obligate GluN1 subunit suggests an increase in the total number of NMDA receptors in the hippocampus. A 3-fold increase in the expression of the GluN2B subunit observed 24 h after PTZ-induced status epilepticus might be indicative of an increase in the proportion of GluN2B-containing NMDA receptors. Increased expression of the GluN2B subunit may be a cause for reducing the magnitude of LTP at hippocampal synapses after status epilepticus.

Characteristic MRI findings in hyperglycaemia-induced seizures: diagnostic value of contrast-enhanced fluid-attenuated inversion recovery imaging.

AIM: To describe characteristic magnetic resonance imaging (MRI) abnormalities in hyperglycaemia-induced seizures, and evaluate the diagnostic value of contrast-enhanced fluid-attenuated inversion recovery (FLAIR) imaging. Possible underlying mechanisms of this condition are also discussed. MATERIALS AND METHODS: Eleven patients with hyperglycaemia-induced seizures and MRI abnormalities were retrospectively studied. Clinical manifestations, laboratory findings, MRI findings, and clinical outcomes were analysed. RESULTS: All patients, except one, presented with focal seizures, simple or complex partial seizures, or negative motor seizures. All patients had long-standing uncontrolled diabetes mellitus. The MRI abnormalities observed acutely were focal subcortical hypointensities on T2-weighted imaging and FLAIR imaging in all patients with overlying cortical gyral T2 hyperintensities in five. Focal overlying cortical or leptomeningeal enhancement on contrast-enhanced T1-weighted imaging or contrast-enhanced FLAIR imaging was observed in all patients. Contrast-enhanced FLAIR imaging was superior to contrast-enhanced T1-weighted imaging for detecting characteristic cortical or leptomeningeal enhancement. Diffusion-weighted imaging showed mildly restricted diffusion in four of five patients with cortical gyral T2 hyperintensity. In nine patients, the lesions were localised in the parietal or parieto-occipital lobes. The other two patients showed localised precentral gyral lesions. After treatment, the neurological symptoms, including the seizures, improved in all patients. On clinical recovery, the subcortical T2 hypointensity, gyral or leptomeningeal enhancement, and overlying cortical T2 hyperintensities resolved. CONCLUSION: Recognition of these radiological abnormalities in patients with hyperglycaemia-induced seizures is important in restricting unwarranted investigations and initiating early therapy. These patients generally have a good prognosis.

A case of spinal cord infarction caused by polycythemia vera.

STUDY DESIGN: This is a case report. OBJECTIVE: The objective of this study was to report on a 66-year-old woman with a confirmed diagnosis of polycythemia vera who presented with acute spinal cord infarction. SETTING: A 66-year-old woman was previously diagnosed with polycythemia vera and presented with acute paraparesis and urinary retention. RESULTS: The patient's platelet count was 847,000 platelets per µl. T2- and diffusion-weighted magnetic resonance imaging revealed hyperintensity at the T12-L1 spinal cord. Computed tomography of the abdominal aorta further revealed multiple thrombi filling the aortic lumen. CONCLUSIONS: Polycythemia vera creates a high risk of systemic thrombosis due to hyperviscosity and platelet activation. Although acute infarction in the spinal cord is a rare complication of this myeloproliferative disease, it should be considered in all affected patients.

Associations between the GNB3 C825T polymorphism and obesity-related metabolic risk factors in Korean obese women.

PURPOSE: It is important to identify a 'metabolically unhealthy obese' subset with higher cardiovascular risk among obese individuals. We investigated the associations between the GNB3 C825T polymorphism and obesity-related metabolic risk factors among Korean obese women. METHODS: This study was a sub-investigation of a double-blind randomized controlled trial that examined the additive effect of or list at on weight loss with sibutramine. A sample of 111 obese women were divided into T-carriers (CT/TT) or a homozygous CC group, according to the presence of the 825T allele at GNB3. These groups were compared to determine their associations with obesity-related metabolic risk factors, i.e., fasting plasma glucose, serum lipids, serum insulin/insulin resistance, and abdominal fat amounts. RESULTS: The allele frequencies of the GNB3 polymorphism were C allele = 59.5% and T allele = 40.5%. The T allele was found to be significantly associated with greater visceral fat and higher serum lipids, and these significances remained robust after adjusting for potential covariates. CONCLUSIONS: The GNB3 825T polymorphism is significantly associated with greater visceral fat and higher serum lipids in Korean obese women and it suggests that the GNB3 C825T is a determinant of obesity-related metabolic traits in this population.

Quality indicators for initial licensure and discipline in nursing laws in South Korea and North Carolina.

BACKGROUND: The Korean regulatory framework of nursing licensure reflects that of the USA, but its content differs in some of the powers related to quality assurance. AIM: This article compares regulatory quality indicators and describes core standards in nursing regulations that are related to both initial licensure and discipline for three groups: the National Council of State Boards of Nursing, the North Carolina and the South of Korea. METHODS: A descriptive, comparative law design is used to examine the differences and similarities in the quality indicators and core standards found in three documents: the National Council of State Boards of Nursing Model Act, the North Carolina Nursing Practice Act and the Korean Medical Service Act for registered nurses. RESULTS: The findings indicate that ten quality indicators and two standards appear in study objects. Although most of the quality indicators are common to all documents, some differences are found in terms of the scope of criminal background checks and the range of grounds for disciplinary action. LIMITATIONS: These findings cannot be generalized in the USA because although the North Carolina nursing act was selected as an example of US nursing laws, nursing laws differ somewhat across states. CONCLUSIONS: This comparative study shows a clear opportunity to develop indicators that acknowledge the important areas of competence and good moral character and how they can improve patient safety in Korea. IMPLICATIONS FOR NURSING AND HEALTH POLICY: This study provides recommendations for Korean nursing legislative redesign and pointers for other jurisdictions to consider.

A guide to facilitate the early treatment of patients with idiopathic demyelinating disease (multiple sclerosis and neuromyelitis optica).

Definite diagnosis of inflammatory demyelinating disease (multiple sclerosis (MS) and neuromyelitis optica (NMO)) may require time, but early treatment offers the opportunity to maximize patient outcomes. The purpose of this report is to provide guidance to facilitate early treatment decisions for patients with inflammatory demyelinating disease, before definitive diagnosis. Neurology experts reviewed the existing literature and clinical evidence. A treatment decision pathway was developed, defining patients for whom first-line MS disease-modifying therapies (a) are unlikely to be effective, (b) may be effective but require careful monitoring and (c) are likely to provide benefit. This algorithm seeks to ensure that patients, particularly those in Asia, receive appropriate treatment early in inflammatory demyelinating disease.

Effect of the G-protein ß3 subunit 825T allele on the change of body adiposity in obese female.

No clinical studies on the lipolytic effect of guanine nucleotide-binding protein ß3 subunit gene (GNB3) 825T polymorphism have been performed. This study was a subinvestigation of a 12-week randomized controlled trial (NCT01184560) for the additive effect of orlistat on sibutramine treatment. The analysis involved 101 obese females aged 18-49 years, genotyped at the GNB3 825 locus. To exclude any influence from potential confounders, we used an analysis of covariance model. After the intervention, fat mass proportion in total weight loss was significantly lower in subjects with a T allele than in those without a T allele (p = 0.034). GNB3 825T allele was associated with blunted fat mass reduction in obese females.

Specific mechanism of use-dependent channel block of calcium-permeable AMPA receptors provides activity-dependent inhibition of glutamatergic neurotransmission.

This study examined the blocking action of the selective channel blocker of calcium-permeable (CP) AMPA receptors, N1-(1-phenylcyclohexyl)pentane-1,5-diaminium bromide (IEM-1925), on excitatory postsynaptic currents in rat neostriatal and cortical neurons and in fly neuromuscular junctions. In both preparations, the blocking of CP-AMPA receptor currents increased along with the stimulation frequency. The continuous presence of kainate, which activates AMPA receptors, in the external solution also caused an enhanced blocking effect. Likewise, decrease of the synaptic release by lowering calcium concentration resulted in significant reduction of the blocking action. The activity dependence of the block is explained using the guarded receptor model. The drug molecule can only bind if the channel is open. After the channel has closed, the drug molecule remains trapped inside. However, the trapped molecule slowly egresses from closed channels to the cytoplasm. The total block effect is determined by the equilibrium between accumulation of the drug in the open channels and relief from the closed channels. Therefore, the conditions that favour the open state result in enhanced inhibition. This significant finding reveals a new way to modulate CP-AMPAR-mediated transmission using a physiologically relevant approach. Moreover, it allows the involvement of CP-AMPARs in the physiological and pathological processes ­ such as high-frequency synaptic activity or increase of the steady-state glutamate concentration ­ to be examined.

Structure of the mouse pore-forming protein (perforin) gene: analysis of transcription initiation site, 5' flanking sequence, and alternative splicing of 5' untranslated regions.

We studied the 5' untranslated regions (UTRs) of the mouse lymphocyte pore-forming protein (PFP, perforin, and cytolysin). 5' UTRs were determined by primer extension analysis, sequencing PFP cDNA clone PFP-7, ribonuclease protection assays, and amplification of poly(A)+ RNA of cytolytic T lymphocyte using polymerase chain reaction (PCR). Two alternatively spliced 5' UTRs, designated type I and type II, of 222 and 115 bp, respectively, were found associated with PFP. Type II is identical to type I, except for being 107 bp shorter in the second exon. This deletion was generated by the use of alternative acceptor splice sites. The mouse PFP gene (Pfp) encodes three exons, is separated by two small introns, and spans a chromosomal region of approximately 7 kb. The first exon contains 79 bp of 5' UTR, the second exon contains 143 or 36 bp of 5' UTR (type I or type II UTR, respectively) plus the NH2-terminal region of the mouse PFP, and the third exon contains the rest of the COOH-terminal mouse PFP. The organization of the mouse Pfp is similar to that of the human gene. Moreover, the 5' flanking sequence of the mouse Pfp is highly homologous to that of the human Pfp. In contrast to the human sequence, the more immediate 5' flanking sequence of mouse Pfp contains two tandem "TATA" box-related elements and a GC box, but lacks a typical CAAT box-related sequence. Several other enhancer elements were found further upstream, including cAMP-, phorbol ester-, interferon-gamma-, and UV-responsive elements, and PU box-like and NFkB binding site-like elements. In addition, we found a nuclear inhibitory protein-like element, a transcriptional silencer, and a pair of purine-rich sequence motifs that were found in other T cell-specific genes, and three repeats of GGCCTG that may be a variation of a highly repetitious GCCCTG consensus sequence found in human Pfp.

Population structure of the olive flounder (Paralichthys olivaceus) in Korea inferred from microsatellite marker analysis.

The population structure of olive flounder Paralichthys olivaceus was estimated using nine polymorphic microsatellite (MS) loci in 459 individuals collected from eight populations, including five wild and three hatchery populations in Korea. Genetic variation in hatchery (mean number of alleles per locus, A = 10.2-12.1; allelic richness, A(R) = 9.3-10.1; observed heterozygosity, H(O) = 0.766-0.805) and wild (mean number of alleles per locus, A = 11.8-19.6; allelic richness, A(R) = 10.9-16.1; observed heterozygosity, H(O) = 0.820-0.888) samples did not differ significantly, suggesting a sufficient level of genetic variation in these well-managed hatchery populations, which have not lost a substantial amount of genetic diversity. Neighbour-joining tree and principal component analyses showed that genetic separation between eastern and pooled western and southern wild populations in Korea was probably influenced by restricted gene flow between regional populations due to the barrier effects of sea currents. The pooled western and southern populations are genetically close, perhaps because larval dispersal may depend on warm currents. One wild population (sample from Wando) was genetically divergent from the main distribution, but it was genetically close to hatchery populations, indicating that the genetic composition of the studied populations may be affected by hydrographic conditions and the release of fish stocks. The estimated genetic population structure and potential applications of MS markers may aid in the proper management of P. olivaceus populations.

KITENIN recruits Dishevelled/PKC delta to form a functional complex and controls the migration and invasiveness of colorectal cancer cells.

BACKGROUND AND AIMS: KITENIN was previously reported to promote metastasis in mouse colon tumour models; however, the signalling mechanism of KITENIN at the cellular level was unknown. Here the functional role of KITENIN with respect to colorectal cancer (CRC) cell invasion and its expression in CRC tissues were investigated. METHODS: The effect of KITENIN on cell motility was analysed in a migration and invasion assay upon its overexpression and knockdown. Immunoprecipitation was used to elucidate binding partners, and immunohistochemistry was used to study expression levels. RESULTS: KITENIN overexpression enhanced the migration of rat intestinal epithelial cells, whereas a loss of invasiveness was observed in CRC cells after KITENIN knockdown. Mechanically, KITENIN served as a scaffolding molecule that simultaneously recruited both Dishevelled (Dvl) and protein kinase C delta (PKC delta) through the membrane-spanning C-terminal region to form a complex that stimulated extracellular signal-regulated kinase (ERK)/activating protein-1 (AP-1) via a PKC delta component but also organised the actin filament via a Dvl component. The KITENIN complex controlled the invasiveness of CRC cells aetiologically harbouring various mutations in APC, beta-catenin or K-ras, in which AP-1 activation is redundant but the organisation of the actin filament is indispensable for cell motility. Clinically, KITENIN expression was significantly higher in colon cancer tissues from advanced stage (III, IV) than that of stage I CRC and also in corresponding metastatic tissues. CONCLUSIONS: The functional KITENIN complex acts as an executor with regard to cell motility and thereby controls CRC cell invasion, which may contribute to promoting metastasis.

Subconjunctival gene delivery of the transcription factor GA-binding protein delays corneal neovascularization in a mouse model.

Corneal neovascularization can reduce visual acuity. GA-binding protein (GABP) is a transcription factor that regulates the expression of target genes including vascular endothelial growth factor (VEGF) and roundabout4 (Robo4), which participate in pathologic angiogenesis. We assessed whether intraocular injection of the GABP gene affects the growth of new corneal blood vessels in a mouse ocular neovascularization model. Transfection of human GABPalpha and GABPbeta gene (GABPalpha/beta) into human conjunctival epithelial cells resulted in decreased VEGF and Robo4 expression. Three groups of mice underwent chemical and mechanical denudation of the corneal epithelium. Subsequently, two groups were administered subconjunctival injection of lipoplexes carrying plasmid DNA encoding for human GABPalpha/beta or an empty plasmid DNA at 1-week intervals. The third group served as an experimental control. In vivo delivery of human GABPalpha/beta into mouse neovascularized cornea reduced VEGF and Robo4 gene expression. Biomicroscopic examination showed that, at 1 week after one or two injections, GABPalpha/beta-treated eyes had significantly less neovascularized corneal area than did eyes treated with the empty vector. Histologic examination showed significantly less vascularized area and fewer blood vessels in the GABP-treated group at 1 week after injections. However, these angiosuppressive effects were weakened at 2 weeks after injections. Our results indicate that subconjunctival GABP gene delivery delays corneal neovascularization for up to 2 weeks in a mouse model of deliberate corneal injury.

Cloning of profilin (FcPFN) from the shrimp Fenneropenaeus chinensis, a highly expressed protein in white spot syndrome virus (WSSV)-infected shrimp.

We isolated and characterized the profilin (FcPFN) cDNA from hemocytes of Fenneropenaeus chinensis, a unique shrimp species from the Yellow Sea. The FcPFN cDNA consists of 830 bp and encodes a polypeptide of 125 amino acids, having a predicted isoelectric point of 5.06. The deduced amino acid sequence of FcPFN shows 36% and 90% amino acid sequence identity to the profilin genes of Pacific white shrimp Litopenaeus vannamei and black tiger shrimp Penaeus monodon, respectively. The FcPFN mRNA was highly expressed in hemocytes and hepatopancreas and moderately in muscle of normal shrimp. The higher expression of FcPFN mRNA is observed in shrimp infected with the white spot syndrome virus (WSSV), which is a major concern in all shrimp-growing regions of the world. These results suggest a potential role for FcPFN in viral host defense mechanisms.

Isothiocyanate NB7M causes selective cytotoxicity, pro-apoptotic signalling and cell-cycle regression in ovarian cancer cells.

The present report identifies indole-3-ethyl isothiocyanate NB7M as a potent cytotoxic agent with selective activity against cell lines derived from various tumour types. Ovarian cancer cell lines showed sensitivity to NB7M (60-70% cytotoxicity at 2.5 microM), in contrast to control cells (TCL-1 and HTR-8; IC(50) approximately 15 microM). In a screen performed by the National Cancer Institute (NCI) (NCI(60) cancer cell-line assay) NB7M (NSC746077) reduced growth up to 100% with an IC(50) between 0.1 and 10 microM depending on the cell line studied. Using SKOV-3 ovarian cancer cells as a model, mechanisms of cytotoxicity were analysed. NB7M caused hallmarks of apoptosis such as PARP-1 deactivation, chromatin condensation, DNA nicks, activation of caspases-9, -8, -3, loss of mitochondrial transmembrane depolarisation potential and upregulation of pro-apoptotic mitogen activated protein kinases (p38, SAP/JNK). NB7M downregulated phosphorylation of prosurvival kinases (PI-3K, AKT, IKK alpha), transcription factor NF-kappaB, and expression of DNA-Pk and AXL receptor tyrosine kinase. Subcytotoxic doses of NB7M inhibited DNA synthesis, caused G1-phase cell-cycle arrest and upregulated p27 expression. The present report suggests that NB7M is a selective cytotoxic agent in vitro for cell lines derived from ovarian and certain other tumours. In addition, NB7M acts as a growth/cell-cycle-suppressing agent and may be developed as a potential therapeutic drug to treat ovarian cancer.

Bilateral cerebral hemispheric infarction associated with sildenafil citrate (Viagra) use.

Sildenafil citrate (Viagra) is one of the frequently prescribed drugs for men with erectile dysfunction. We describe a 52-year-old man with bilateral middle cerebral artery (MCA) territory infarction after sildenafil use. He ingested 100 mg of sildenafil and about 1 h later, he complained of chest discomfort, palpitation and dizziness followed by mental obtundation, global aphasia and left hemiparesis. Brain magnetic resonance imaging documented acute bilateral hemispheric infarction, and cerebral angiography showed occluded bilateral MCA. Despite significant bilateral MCA stenosis and cerebral infarction, systemic hypotension persisted for a day. We presume that cerebral infarction was caused by cardioembolism with sildenafil use.

Diagnostic Performance of Multidetector Computerized Tomography in the Detection of Abdominal Complications Early and Late After Liver Transplantation: A 10-Year Experience.

BACKGROUND: Multidetector computerized tomography (MDCT) is considered to be a fast noninvasive diagnostic technique for the evaluation of postoperative complications in patients with liver transplantation (LT). However, its role has not been fully established in the diagnosis for detecting complications after liver transplantation. The aim of this work was to evaluate the diagnostic performance of MDCT for detecting abdominal complications in the early and late periods after LT. METHODS: We retrospectively enrolled 75 patients who had undergone LT from March 2006 to January 2010, followed by MDCT from March 2006 to November 2017. Patients were divided into 2 groups according to the timing after LT: within the first 3 months (early period) or ≥3 months after LT (late period). We evaluated vascular, biliary, and other complications on MDCT. Angiography, endoscopic retrograde cholangiography, and percutaneous transhepatic cholangiography were used as reference standards. RESULTS: We initially found 77 complications in 45 patients (60.0%) with the use of MDCT. After comparison with the reference standards, 83 complications were diagnosed in 49 patients (65.3%). Forty-seven complications (34 vascular, 10 biliary, 3 other complications) were diagnosed in 33 patients (44.0%) during the early period, and 36 complications (6 vascular, 20 biliary, 10 other complications) were detected in 27 patients (36.0%) in the late period. The sensitivity, specificity, and diagnostic accuracy of MDCT for diagnosing overall complications were, respectively, 93.6%, 90.2%, and 92.0% in the early period (for vascular complications: 97.1%, 92.6%, and 94.3%,; for biliary complications: 80.0%, 100%, and 97.7%) and 77.8%, 98.1%, and 89.8% in the late period (for vascular complications: 83.3%, 100%, and 98.9%; for biliary complications: 65.0%, 98.6%, and 90.9%). CONCLUSIONS: Although MDCT in the late period should be interpreted with caution in patients with suspected biliary complication, MDCT is a reliable diagnostic technique for the identification of early and late abdominal complications after LT.

Cyclin D1 overexpression promotes cardiomyocyte DNA synthesis and multinucleation in transgenic mice.

D-type cyclin/cyclin-dependent kinase (CDK) complexes regulate transit through the restriction point of the cell cycle, and thus are required for the initiation of DNA synthesis. Transgenic mice which overexpress cyclin D1 in the heart were produced to determine if D-type cyclin deregulation would alter myocardial development. Cyclin D1 overexpression resulted in a concomitant increase in CDK4 levels in the adult myocardium, as well as modest increases in proliferating cell nuclear antigen and CDK2 levels. Flow cytometric and morphologic analyses of dispersed cell preparations indicated that the adult transgenic cardiomyocytes had abnormal patterns of multinucleation. Histochemical analyses confirmed a marked increase in number of cardiomyocyte nuclei in sections prepared from the transgenic mice as compared with those from control animals. Tritiated thymidine incorporation analyses revealed sustained cardiomyocyte DNA synthesis in adult transgenic hearts.

Selective blockade of Ca2+ permeable AMPA receptors in CA1 area of rat hippocampus.

Using whole cell patch-clamp recording from pyramidal cells and interneurons in the CA1 area of hippocampal slices, the effect of IEM-1460, a selective channel blocker of Ca2+ permeable AMPA receptors (AMPARs), on postsynaptic currents (PSCs) was studied. Excitatory postsynaptic currents (EPSCs) were evoked by stimulation of Schaffer collaterals (SCs) in the presence of APV and bicuculline to pharmacologically isolate the EPSCs mediated by AMPAR activation. IEM-1460 (50 microM) did not affect the amplitude of EPSCs in CA1 pyramidal cells but reversibly decreased their amplitude in interneurons of pyramidal layer (15 cells), radiatum (37 cells) and border radiatum-lacunosum-moleculare (R-LM) (55 cells) layers. The ability of IEM-1460 to decrease EPSC amplitude correlated with EPSC rectification properties in CA1 interneurons, providing evidence for synaptic localization of Ca2+ permeable AMPARs at the SC synaptic input. Independent of their localization, the majority of interneurons studied exhibited only modest sensitivity to IEM-1460 (EPSC amplitude decreased by less than 30%), while in 15% of interneurons IEM-1460 induced more than 50% reduction in EPSC amplitude. To reveal possible afferent-specific localization of Ca2+ permeable AMPARs on R-LM interneurons, the effect of IEM-1460 on EPSCs evoked by stimulation of SC was compared with that of perforant path (PP). Although average sensitivities did not differ significantly, in 61% of R-LM layer interneurons, the SC-evoked EPSCs exhibited higher sensitivity to IEM-1460 than the PP-evoked EPSCs. Moreover, in 54% of R-LM layer interneurons the EPSCs evoked by SC stimulation were complex, having an initial peak followed by one or several late components. Kinetics, latency distribution and reversal potential of late components suggest di- and polysynaptic origin of the late components. Late EPSCs were strongly and reversibly inhibited by IEM-1460 indicating that Ca2+ permeable AMPARs are involved in the indirect excitation of R-LM layer interneurons. Despite the ability to decrease the excitatory synaptic input to interneurons, IEM-1460 did not affect interneuron-mediated inhibitory postsynaptic currents (IPSCs) evoked in pyramidal neurons by SC stimulation. These data suggest that interneurons with a synaptic input highly sensitive to IEM-1460 do not contribute specifically to the feed-forward inhibition of hippocampal pyramidal neurons.

Obesity: a chronic relapsing progressive disease process. A position statement of the World Obesity Federation.

This paper considers the argument for obesity as a chronic relapsing disease process. Obesity is viewed from an epidemiological model, with an agent affecting the host and producing disease. Food is the primary agent, particularly foods that are high in energy density such as fat, or in sugar-sweetened beverages. An abundance of food, low physical activity and several other environmental factors interact with the genetic susceptibility of the host to produce positive energy balance. The majority of this excess energy is stored as fat in enlarged, and often more numerous fat cells, but some lipid may infiltrate other organs such as the liver (ectopic fat). The enlarged fat cells and ectopic fat produce and secrete a variety of metabolic, hormonal and inflammatory products that produce damage in organs such as the arteries, heart, liver, muscle and pancreas. The magnitude of the obesity and its adverse effects in individuals may relate to the virulence or toxicity of the environment and its interaction with the host. Thus, obesity fits the epidemiological model of a disease process except that the toxic or pathological agent is food rather than a microbe. Reversing obesity will prevent most of its detrimental effects.