Changes in Management Strategies After Spontaneous Migration of a Retained Intraorbital Metallic Foreign Body

Purpose: Because of the controversial biologic tolerance and management, retained intraorbital metallic foreign body (RIMFb) poses a formidable challenge to surgeons. Besides location of the foreign body, indications for surgical management include neurologic injury, mechanical restriction of the eye movement, and development of local infection or draining fistula. The authors describe an unusual case of spontaneous migration of a RIMFb. Methods: A 26-year-old man had a gunshot injury on the left orbit. The patient was initially managed conservatively because of the posterior position of the bullet fragment. Thereafter, because of the clinical impairments and anterior migration of projectile, surgical treatment was considered. Results: Spontaneous anterior migration has led to mechanical disturbances and inflammatory complications that comprise explicit surgical indications for removal. The patient underwent surgery with complete relief of symptoms. We suppose that extrinsic ocular muscles might play a role in shifting large RIMFb over time, leading to change in the management strategies. Conclusions: Spontaneous migration of RIMFb is a rare clinical situation that can lead to pain, local deformity, as well as changes in the management strategies of the affected patients even in the late phase of follow-up.

Abnormal Left and Right Amygdala-Orbitofrontal Cortical Functional Connectivity to Emotional Faces: State Versus Trait Vulnerability Markers of Depression in Bipolar Disorder

Background: Amygdala-orbitofrontal cortical (OFC) functional connectivity (FC) to emotional stimuli and relationships with white matter remain little examined in bipolar disorder individuals (BD). Methods: Thirty-one BD (type 1; n = 17 remitted; n = 14 depressed) and 24 age- and gender-ratio-matched healthy individuals (HC) viewed neutral, mild, and intense happy or sad emotional faces in two experiments. The FC was computed as linear and nonlinear dependence measures between amygdala and OFC time series. Effects of group, laterality, and emotion intensity upon amygdala-OFC FC and amygdala-OFC FC white matter fractional anisotropy (FA) relationships were examined. Results: The BD versus HC showed significantly greater right amygdala-OFC FC (p <= .001) in the sad experiment and significantly reduced bilateral amygdala-OFC FC (p = .007) in the happy experiment. Depressed but not remitted female BD versus female HC showed significantly greater left amygdala-OFC FC (p = .001) to all faces in the sad experiment and reduced bilateral amygdala-OFC FC to intense happy faces (p = .01). There was a significant nonlinear relationship (p = .001) between left amygdala-OFC FC to sad faces and FA in HC. In BD, antidepressants were associated with significantly reduced left amygdala-OFC FC to mild sad faces (p = .001). Conclusions: In BD, abnormally elevated right amygdala-OFC FC to sad stimuli might represent a trait vulnerability for depression, whereas abnormally elevated left amygdala-OFC FC to sad stimuli and abnormally reduced amygdala-OFC FC to intense happy stimuli might represent a depression state marker. Abnormal FC measures might normalize with antidepressant medications in BD. Nonlinear amygdala-OFC FC-FA relationships in BID and HC require further study.

Abnormal Amygdala-Prefrontal Effective Connectivity to Happy Faces Differentiates Bipolar from Major Depression

Background: Bipolar disorder is frequently misdiagnosed as major depressive disorder, delaying appropriate treatment and worsening outcome for many bipolar individuals. Emotion dysregulation is a core feature of bipolar disorder. Measures of dysfunction in neural systems supporting emotion regulation might therefore help discriminate bipolar from major depressive disorder. Methods: Thirty-one depressed individuals-15 bipolar depressed (BD) and 16 major depressed (MDD), DSM-IV diagnostic criteria, ages 18-55 years, matched for age, age of illness onset, illness duration, and depression severity-and 16 age- and gender-matched healthy control subjects performed two event-related paradigms: labeling the emotional intensity of happy and sad faces, respectively. We employed dynamic causal modeling to examine significant among-group alterations in effective connectivity (EC) between right- and left-sided neural regions supporting emotion regulation: amygdala and orbitomedial prefrontal cortex (OMPFC). Results: During classification of happy faces, we found profound and asymmetrical differences in EC between the OMPFC and amygdala. Left-sided differences involved top-down connections and discriminated between depressed and control subjects. Furthermore, greater medication load was associated with an amelioration of this abnormal top-down EC. Conversely, on the right side the abnormality was in bottom-up EC that was specific to bipolar disorder. These effects replicated when we considered only female subjects. Conclusions: Abnormal, left-sided, top-down OMPFC-amygdala and right-sided, bottom-up, amygdala-OMPFC EC during happy labeling distinguish BD and MDD, suggesting different pathophysiological mechanisms associated with the two types of depression.

Abnormal methylation at the KvDMR1 imprinting control region in clinically normal children conceived by assisted reproductive technologies

Genomic imprinting alterations have been shown to be associated with assisted reproductive technologies (ARTs) in animals. At present, data obtained in humans are inconclusive; however, some epidemiological studies have demonstrated an increased incidence of imprinting disorders in children conceived by ARTs. In the present study, we focused on the effect of ARTs [IVF and intracytoplasmic sperm injection (ICSI)] on the epigenetic reprogramming of the maternally methylated imprinting control region KvDMR1 in clinically normal children. Qualitative and quantitative methylation at KvDMR1 were assessed by the methylation-specific PCR approach and by the methylation-sensitive enzymatic digestion associated with real-time PCR method, respectively. DNA was obtained from peripheral blood of 12/18 and umbilical cord blood and placenta of 6/18 children conceived by IVF or ICSI. The methylation patterns observed in this group were compared with the patterns observed in 30 clinically normal naturally conceived children (negative controls) and in 3 naturally conceived Beckwith-Wiedemann syndrome patients (positive controls). Hypomethylation at KvDMR1 was observed in 3/18 clinically normal children conceived by ARTs (2 conceived by IVF and 1 by ICSI). A discordant methylation pattern was observed in the three corresponding dizygotic twins. Our findings corroborate the hypothesis of vulnerability of maternal imprinting to ARTs. Furthermore, the discordant methylation at KvDMR1 observed between dizygotic twins could be consequent to one of the following possibilities: (i) a differential vulnerability of maternal imprints among different embryos; or (ii) epimutations that occurred during gametogenesis resulting in the production of oocytes without the correct primary imprint at KvDMR1.

Abnormal corpus callosum myelination in pediatric bipolar patients

Background: Decreased signal intensity in the corpus callosum, reported in adult bipolar disorder patients, has been regarded as an indicator of abnormalities in myelination. Here we compared the callosal signal intensity of children and adolescents with bipolar disorder to that of matched healthy subjects, to investigate the hypothesis that callosal myelination is abnormal in pediatric bipolar patients. Methods: Children and adolescents with DSM-lV bipolar disorder (n=16, mean age +/- S.D. = 15.5 +/- 3.4 y) and matched healthy comparison subjects (n=21, mean age +/- S.D.=16.9 3.8 y) underwent a 1.5 T MRI brain scan. Corpus callosuin signal intensity was measured using an Apple Power Mac G4 running NIH Image 1.62 software. Results: Bipolar children and adolescents had significantly lower corpus callosum signal intensity for all callosal sub-regions (genu, anterior body, posterior body, isthmus and splenium) compared to healthy subjects (ANCOVA, all p < 0.05, age and gender as covariates). Limitations: Relatively small sample size. Conclusions: Abnormalities in corpus callosum, probably due to altered myelination during neurodevelopment, may play a role in the pathophysiology of bipolar disorder among children and adolescents. (c) 2007 Elsevier B.V All rights reserved.

Abnormal Methylation of Histone Deacetylase Genes: Implications on Etiology and Epigenetic Therapy of Astrocytomas

Background: A growing body of evidence has revealed, the involvement of epigenetic alterations in the etiology of astrocytomas. In the present study, we aimed to evaluate the association of DNA methylation of histone deacetylase genes (HDAC) with the etiology of astrocytoma, and the implications for epigenetic therapy. Materials and Methods: Methylation of the HDAC4, HDAC5 and HDAC6 genes was assessed in 29 tumor samples (astrocytomas grades I, III, and IV) and in the glioblastoma cell lines U87, U251, U343, SF188, and T98G by methylation-specific quantitative PCR (MSED-qPCR). Results: Significantly increased methylation of the HDAC5 gene was observed in astrocytomas when compared to non-neoplastic brain samples (p=0.0007) and to glioblastomas cell lines (p=0.001). A heterogenic methylation pattern was evidenced when compared to the glioblastoma cell lines. Distinct effects on methylation and gene expression were observed after in vitro treatment of the different cell lines with decitabine. Conclusion: Our results suggest that abnormal methylation of HDAC genes is involved in the etiology of astrocytomas and indicate that loci-specific epigenetic interindividualities might be associated to the differential responses to treatment with decitabine.

Interictal hyperemia correlates with epileptogenicity in polymicrogyric cortex

Objective: To investigate pathophysiological factors underlying the presence of interictal hyper-perfusion within the limits of the polymicrogyric (PMG) cortex in epileptic patients. Methods: Retrospective observational study on interictal perfusion by Single Photon Emission Computed Tomography (SPECT) in 16 patients with PMG and its correlations with a number of clinical and neurophysiological variables. Patients underwent video-EEG monitoring, neurological and psychiatric assessments, invasive EEG, and the interictal SPECT coregistered to Magnetic Resonance Imaging (MRI). Results: Patients with interictal hyperperfusion within the PMG cortex had a significantly higher spike rate on interictal EEG than patients with normal perfusion. Interictal hyperperfusion was not correlated to sex, age at epilepsy onset, age at evaluation, number of seizures per month, presence of initial precipitating insult (IPI), abnormal neurological examination, EEG findings, ictal serniology, and seizure outcome. The high interictal spike rate did not correlate to a high frequency of seizures per month. Conclusions: Our work provides further evidences for an intrinsic epileptogenesis of the PMG cortex during the interictal state, which accounts for the major rote of PMG tissue in seizure generation. These results might help to increase our understanding about epileptogenesis related to the PMG cortex, providing new toots for more tailored epilepsy surgery in PMG patients. (c) 2008 Elsevier B.V. All rights reserved.

Abnormal cell-cycle expression of the proteins p27, mdm2 and cathepsin B in oral squamous-cell carcinoma infected with human papillomavirus

Since the role of human papillomavirus (HPV) infection in oral carcinogenesis is still unclear, the purpose of this study was to verify the association between the expression of p27, mdm2 and cathepsin B and by HPV-related oral lesions. Fifty-five oral biopsies were studied and HPV detection and typing (6/11, 16, 18, 31 and 33) were performed using polymerase chain reaction techniques. The distribution p27, mdm2 and cathepsin B was determined by immunohistochemistry. Twenty-one (38%) out of the 55 oral lesions tested positive for HPV, of which 6(33%) were HPV 6/11, 1 (5%) was HPV 16,14 (72%) were HPV 18 and none was HPV 33/31. Among the 55 biopsies, immunopostivity for p27, mdm2 and cathepsin B was observed in 17 (30.9%), 37 (67.2%) and 37 (67.2%), respectively. Among 21 HPV-positive oral lesions, immunopostivity of mdm2, p27 and cathepsin B was found, respectively, in 6 (33%) out of 18 benign lesions (BL), 4(22%) out of 18 potential malignant epithelial lesions (PMEL) and 11(57.9%) out of 19 malignant lesions (ML). High-risk HPV types may be associated with oral carcinoma, by cell-cycle control dysregulation, contributing to oral carcinogenesis and the overexpression of mdm2, p27 and cathepsin B. (C) 2009 Elsevier GmbH. All rights reserved.

Prostaglandin mediates IL-23/IL-17-induced neutrophil migration in inflammation by inhibiting IL-12 and IFN gamma production

IL-23/IL-17-induced neutrophil recruitment plays a pivotal role in rheumatoid arthritis (RA). However, the mechanism of the neutrophil recruitment is obscure. Here we report that prostaglandin enhances the IL-23/IL-17-induced neutrophil migration in a murine model of RA by inhibiting IL-12 and IFN gamma production. Methylated BSA (mBSA) and IL-23-induced neutrophil migration was inhibited by anti-IL-23 and anti-IL-17 antibodies, COX inhibitors, IL-12, or IFN gamma but was enhanced by prostaglandin E(2) (PGE(2)). IL-23-induced IL-17 production was increased by PGE(2) and suppressed by COX-inhibition or IL-12. Furthermore, COX inhibition failed to reduce IL-23-induced neutrophil migration in IL-12- or IFN gamma-deficient mice. IL-17-induced neutrophil migration was not affected by COX inhibitors, IL-12, or IFN gamma but was inhibited by MK886 (a leukotriene synthesis inhibitor), anti-TNF alpha, anti-CXCL1, and anti-CXCL5 antibodies and by repertaxin (a CXCR1/2 antagonist). These treatments all inhibited mBSA- or IL-23-induced neutrophil migration. IL-17 induced neutrophil chemotaxis through a CXC chemokines-dependent pathway. Our results suggest that prostaglandin plays an important role in IL-23-induced neutrophil migration in arthritis by enhancing IL-17 synthesis and by inhibiting IL-12 and IFN gamma production. We thus provide a mechanism for the pathogenic role of the IL-23/IL-17 axis in RA and also suggest an additional mechanism of action for nonsteroidal anti-inflammatory drugs.

Regulation of chemokine receptor by Toll-like receptor 2 is critical to neutrophil migration and resistance to polymicrobial sepsis

Patients with sepsis have a marked defect in neutrophil migration. Here we identify a key role of Toll-like receptor 2 (TLR2) in the regulation of neutrophil migration and resistance during polymicrobial sepsis. We found that the expression of the chemokine receptor CXCR2 was dramatically down-regulated in circulating neutrophils from WT mice with severe sepsis, which correlates with reduced chemotaxis to CXCL2 in vitro and impaired migration into an infectious focus in vivo. TLR2 deficiency prevented the down-regulation of CXCR2 and failure of neutrophil migration. Moreover, TLR2(-/-) mice exhibited higher bacterial clearance, lower serum inflammatory cytokines, and improved survival rate during severe sepsis compared with WT mice. In vitro, the TLR2 agonist lipoteichoic acid (LTA) down-regulated CXCR2 expression and markedly inhibited the neutrophil chemotaxis and actin polymerization induced by CXCL2. Moreover, neutrophils activated ex vivo by LTA and adoptively transferred into naive WT recipient mice displayed a significantly reduced competence to migrate toward thioglycolate-induced peritonitis. Finally, LTA enhanced the expression of G protein-coupled receptor kinases 2 (GRK2) in neutrophils; increased expression of GRK2 was seen in blood neutrophils from WT mice, but not TLR2(-/-) mice, with severe sepsis. Our findings identify an unexpected detrimental role of TLR2 in polymicrobial sepsis and suggest that inhibition of TLR2 signaling may improve survival from sepsis.

Targeting endothelin ET(A) and ET(B) receptors inhibits antigen-induced neutrophil migration and mechanical hypernociception in mice

Endothelin may contribute to the development of inflammatory events such as leukocyte recruitment and nociception. Herein, we investigated whether endothelin-mediated mechanical hypernociception (decreased nociceptive threshold, evaluated by electronic pressure-meter) and neutrophil migration (myeloperoxidase activity) are inter-dependent in antigen challenge-induced Th1-driven hind-paw inflammation. In antigen challenge-induced inflammation, endothelin (ET) ET(A) and ET(B) receptor antagonism inhibited both hypernociception and neutrophil migration. Interestingly, ET-1 peptide-induced hypernociception was not altered by inhibiting neutrophil migration or endothelin ET(B) receptor antagonism, but rather by endothelin ET(A) receptor antagonism. Furthermore, endothelin ET(A), but not ET(B), receptor antagonism inhibited antigen-induced PGE(2) production, whereas either selective or combined blockade of endothelin ET(A) and/or ET(B) receptors reduced hypernociception and neutrophil recruitment caused by antigen challenge. Concluding, this study advances knowledge into the role for endothelin in inflammatory mechanisms and further supports the potential of endothelin receptor antagonists in controlling inflammation.

Hydrogen sulfide augments neutrophil migration through enhancement of adhesion molecule expression and prevention of CXCR2 internalization: Role of ATP-sensitive potassium channels

In this study, we have addressed the role of H2S in modulating neutrophil migration in either innate (LPS-challenged naive mice) or adaptive (methylated BSA (mBSA)-challenged immunized mice) immune responses. Treatment of mice with H S synthesis inhibitors, DL-propargylglycine (PAG) or beta-cyanoalanine, reduced neutrophil migration induced by LPS or methylated BSA (mBSA) into the peritoneal cavity and by mBSA into the femur/tibial joint of immunized mice. This effect was associated with decreased leukocyte rolling, adhesion, and P-selectin and ICAM-1 expression on endothelium. Predictably, treatment of animals with the H2S donors, NaHS or Lawesson`s reagent, enhanced these parameters. Moreover, the NaHS enhancement of neutrophil migration was not observed in ICAM-1-deficient mice. Neither PAG nor NaHS treatment changed LPS-induced CD18 expression on neutrophils, nor did the LPS- and mBSA-induced release of neutrophil chemoattractant mediators TNF-alpha, keratinocyte-derived chemokine, and LTB4. Furthermore, in vitro MIP-2-induced neutrophil chemotaxis was inhibited by PAG and enhanced by NaHS treatments. Accordingly, MIP-2-induced CXCR2 internalization was enhanced by PAG and inhibited by NaHS treatments. Moreover, NaHS prevented MIP-2-induced CXCR2 desensitization. The PAG and NaHS effects correlated, respectively, with the enhancement and inhibition of MIP-2-induced G protein-coupled receptor kinase 2 expression. The effects of NaHS on neutrophil migration both in vivo and in vitro, together with CXCR2 internalization and G protein-coupled receptor kinase 2 expression were prevented by the ATP-sensitive potassium (K-ATP(+)) channel blocker, glybenclamide. Conversely, diazoxide, a K-ATP(+) channel opener, increased neutrophil migration in vivo. Together, our data suggest that during the inflammatory response, H`S augments neutrophil adhesion and locomotion, by a mechanism dependent on K-ATP(+) channels.

Phlebotomine salivas inhibit immune inflammation-induced neutrophil migration via an autocrine DC-derived PGE(2)/IL-10 sequential pathway

In the present study, we investigated whether saliva from Phlebotomus papatasi and Phlebotomus duboscqi inhibited antigen-induced neutrophil migration and the mechanisms involved in these effects. The pretreatment of immunized mice with salivary gland extracts (SGE) of both phlebotomines inhibited OVA challenge-induced neutrophil migration and release of the neutrophil chemotactic mediators, MIP-1 alpha, TNF-alpha, and leukotriene B-4 (LTB4). Furthermore, SGE treatment enhanced the production of anti-inflammatory mediators, IL-10 and PGE(2). SGE treatments failed to inhibit neutrophil migration and MIP-1 alpha and LTB4 production in IL-10(-/-) mice, also failing in mice treated with nonselective (indomethacin) or selective (rofecoxibe) cyclooxygenase (COX) inhibitors. COX inhibition resulted in diminished SGE-induced IL-10 production, and PGE(2) release triggered by SGE remained increased in IL-10(-/-) mice, suggesting that prostanoids are acting through an IL-10-dependent mechanism. SGE treatments in vivo reduced the OVA-induced lymphoproliferation of spleen-derived cells. Further, the in vitro incubation of bone marrow-derived dendritic cells (DC) with SGE inhibited the proliferation of CD4(+) T cells from OVA-immunized mice, which was reversed by indomethacin and anti-IL-10 antibody treatments. Supporting these results, SGE induced the production of PGE(2) and IL-10 by DC, which were blocked by COX inhibition. These effects were associated with the reduction of DC-membrane expression of MHC-II and CD86 by SGE treatment. Altogether, the results showed that Phlebotomine saliva inhibits immune inflammation-induced neutrophil migration by an autocrine DC sequential production of PGE(2)/IL-10, suggesting that the saliva constituents might be promising therapeutic molecules to target immune inflammatory diseases.

Neutrophil migration induced by IL-1 beta depends upon LTB4 released by macrophages and upon TNF-alpha and IL-1 beta released by mast cells

In the present study, we investigate whether mast cells and macrophages are involved in the control of IL-1 beta-induced neutrophil migration, as well as the participation of chemotactic mediators. IL-1 beta induced a dose-dependent neutrophil migration to the peritoneal cavity of rats which depends on LTB4, PAF and cytokines, since the animal treatment with inhibitors of these mediators (MK 886, PCA 4248 and dexamethasone respectively) inhibited IL-1 beta-induced neutrophil migration. The neutrophil migration induced by IL-1 beta is dependent on mast cells and macrophages, since depletion of mast cells reduced the process whereas the increase of macrophage population enhanced the migration. Moreover, mast cells or macrophages stimulated with IL-1 beta released a neutrophil chemotactic factor, which mimicked the neutrophil migration induced by IL-1 beta. The chemotactic activity of the supernatant of IL-1 beta-stimulated macrophages is due to the presence of LTB4, since MK 886 inhibited its release. Moreover, the chemotactic activity of IL-1 beta-stimulated mast cells supernatant is due to the presence of IL-1 beta and TNF-alpha, since antibodies against these cytokines inhibited its activity. Furthermore, significant amounts of these cytokines were detected in the supernatant. In conclusion, our results suggest that neutrophil migration induced by IL-1 beta depends upon LTB4 released by macrophages and upon IL-1 beta and TNF alpha released by mast cells.