Personality traits in patients with juvenile myoclonic epilepsy

There is evidence of personality disorders in patients with juvenile myoclonic epilepsy (JME). To date, there have been no published quantitative studies on personality traits in JME. The aim of the work described here was to study a group of patients with JME and quantitatively measure personality traits. We evaluated 42 patients (mean age: 26.57 years, SD: 8.38) and 42 controls (mean age: 26.96, SD: 8.48) using a validated personality inventory, the Temperament and Character Inventory (TCI). We applied two scores, one for the Beck Depression Inventory and one for the State-Trait-Anxiety Inventory, as depression and anxiety may impact the performance of these patients on the TCI. We compared both groups on TCI scales using analysis of covariance with Beck Depression Inventory and State-Trait-Anxiety Inventory scores as covariates. Patients with JME obtained significantly higher scores on Novelty Seeking (P=0.001) and Harm Avoidance (P=0.002) and significantly lower scores on Self-Directedness (P=0.001). Patients with JME have a higher expression of impulsive personality traits that demand early recognition to avoid further consequences and facilitate social insertion, consequently avoiding future stigma. (C) 2011 Elsevier Inc. All rights reserved.

Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection in children and adolescents

Background & Aims: This multi-center study aimed to prospectively evaluate the safety and efficacy of a genotype-based Pegylated Interferon alfa-2a/Ribavirin therapy in treatment-naive hepatitis C virus (HCV), positive HCV serology, and quantifiable HCV RNA, infected children. Methods: Eighteen children with genotypes 2 and 3 patients (group A) were assigned to medication for 24 weeks, and 47 children with genotypes 1, 4, 5 and 6 patients (group B) for 48 weeks. Results: Early response at week 12 was observed in 83% of group A patients and in 57% of group B patients (p <0.05). End of treatment response was achieved in 94% of patients in group A and in 57% in group B (p <0.001). Sustained virologic response was maintained in 89% of patients in group A and in 57% of patients in group B (p <0.01). Ten patients stopped prematurely the treatment, 2 for serious adverse event (acute hepatitis and thyrotoxicosis), and 8 because of no virologic response at week 24. Peginterferon alfa-2a and Ribavirin dose was adjusted in 15 patients (23%), 11 for neutropenia (17%), and 3 patients (5%), for anemia, respectively. Treatment-related adverse events included fever and flu-like symptoms (54%), irritability depression change of mood (34%), vomiting (23%), abdominal pain (38%), loss of appetite (21.5%) and dermatitis (29%). No influence on height growth was observed. Conclusions: Pegylated inteferon alfa-2a and Ribavirin treatment allowed to achieve SVR in 57% of pediatric patients with genotypes 1, 4, 5 and 6, and in 94% of genotypes 2 and 3. These results show an improved SVR as compared to reference series in adults with similar regimen. (c) 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Estrogen receptor-positive breast carcinomas in younger women are different from those of older women: A pathological and immunohistochemical study

The higher frequency of triple-negative and HER-2-positive tumors detected in younger patients has been suggested as an explanation for the more aggressive tumor types observed in this age group. However, estrogen receptor (ER)-positive tumors are the most frequent subtype of breast carcinomas identified, even in younger patients. In this retrospective study, the morphological and immunohistochemical profiles of ER-positive breast carcinomas from women 35 yrs and younger that were diagnosed between 1997 and 2007 were evaluated. From these cases, 213 were selected based on the availability of pathology reports and paraffin blocks. For comparison, 117 consecutive cases of breast carcinomas diagnosed in patients >60 yrs from 2006 were included. Paraffin-embedded tumors were stained for expression of ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER-2). Ki-67 antigen, epidermal growth factor receptor (EGFR), cytokeratin 5/6, p53, vimentin, CD117, and p63 using tissue microarrays. ER-positive carcinomas were diagnosed in 120 (56.1%) samples of the younger patient group and in 92 (78.6%) samples of the older patient group. Of these ER-positive carcinomas, 48 (40%) from the younger patient group presented the subtype luminal A, compared with 53 (57.6%) from the older patient group (p=0.01). Tumors from the younger patient group were also associated with increased vascular involvement, co-expression of HER-2, and decreased expression of CD117. These results highlight differences in expression markers and the pathology of ER-positive tumors detected in younger women, with a notable characteristic being co-expression of HER-2. (C) 2010 Elsevier Ltd. All rights reserved.

Quetiapine versus clomipramine in the augmentation of selective serotonin reuptake inhibitors for the treatment of obsessive-compulsive disorder: a randomized, open-label trial

After 12 weeks of selective serotonin reuptake inhibitor (SSRI) monotherapy with inadequate response, 10 patients received clomipramine and 11 received quetiapine as augmentation agents of the SSRI. The primary outcome measure was the difference between initial and final scores of the YaleBrown Obsessive-Compulsive Scale (Y-BOCS), rated in a blinded fashion, and the score of clinical global improvement (CGI-I). Statistical analyses were performed using nonparametric tests to evaluate treatment efficacy and the difference between treatment groups. Percentile plots were constructed with YBOCS scores from the clomipramine and quetiapine groups. Considering response a >= 35% reduction in the initial Y-BOCS score plus a rating of `much improved` or `very much improved` on CGI-I, four of eleven quetiapine patients and one out of ten clomipramine patients were classified as responders. The mean final Y-BOCS score was significantly lower than baseline in the quetiapine augmentation group (P = 0.023), but not in the clomipramine augmentation group (P = 0.503). The difference between groups showed a trend towards significance only at week 4, the mean Y-BOCS score being lower for those receiving quetiapine (P = 0.052). A difference between groups was also observed at week 4 according to percentile plots. These results corroborate previous findings of quetiapine augmentation efficacy in obsessive-compulsive disorder (OCD). Clomipramine augmentation did not produce a significant reduction in Y-BOCS scores. Higher target maximum dosages might have yielded different results.

Vitamin D Receptor and Calcium-Sensing Receptor Gene Polymorphisms in Hypercalciuric Stone-Forming Patients

Background/Aim: Some studies have identified an association of kidney stone formation with vitamin D receptor (VDR) or calcium-sensing receptor (CaSR) polymorphisms. We aimed to evaluate the association between these polymorphisms with urinary calcium excretion (uCa) in calcium-stone-forming patients. Methods: VDR polymorphism, detected by BsmI digestion, and 3 CaSR polymorphisms (G/T at codon 986, G/A at codon 990 and C/G at codon 1011), detected by direct sequencing, were evaluated in 100 hypercalciuric (HCa) and 101 normocalciuric (NCa) calcium-stone-forming patients. Results: The total allelic frequency of VDR polymorphism was: 16% BB, 49% Bb and 35% bb. The prevalence of bb genotype was significantly higher in the HCa when compared to the NCa group (43 vs. 27%). With respect to CaSR polymorphisms, 986S, 990G and 1011E variant alleles were detected, respectively, in 5, 4 and 3% of the whole sample and 5 CaSR haplotypes were identified: 94% ARQ (wildtype), 3% SRQ, 1.5% AGQ, 1.0% ARE and 0.5% AGE. No statistical differences have been observed between NCa and HCa with respect to these CaSR haplotypes. Conclusions: The present study suggested that bb homozygous for VDR polymorphism was overrepresented in hypercalciuric stone formers. Urinary calcium excretion was not associated with CaSR polymorphism in the present sample. Copyright (C) 2009 S. Karger AG, Basel

Serotonin and Sensitivity to Trauma-Related Exposure in Selective Serotonin Reuptake Inhibitors-Recovered Posttraumatic Stress Disorder

Background: Selective serotonin reuptake inhibitors (SSRIs) are first-line treatments for posttraumatic stress disorder (PTSD). Serotonergic (5HT) attenuation of stress sensitivity is postulated from SSRIs` effects in other anxiety disorders, and we studied this in PTSD. Methods: Ten patients with PTSD fully recovered on SSRIs (Clinical Global Impression Scale-I 1 and 2) were enrolled in the study. Patients were tested on two occasions I week apart; in each session, they received a drink containing large neutral amino acids (LNAAs) either with (sham tryptophan depletion [STD], control) or without (acute tryptophan depletion [ATD]) tryptophan. At 5.5 hours after the drink, subjects were exposed to a trauma-related exposure challenge. Self-reports of PTSD (visual analogue scales [VAS] and the Davidson Trauma Scale [DTSI), anxiety (Spielberger State Inventory [STAI] Form Y-1), and mood (Profile of Mood States [POMS]) were obtained. Heart rate (HR), systolic (SBP) and diastolic (DBP) blood pressure were also measured. Results: The trauma-related exposure challenge induced anxiety on both days, with more marked responses on the ATD day according to VAS, DTS, POMS, and DBP (p < .05). A trend of significance (.1 > p >.05) was observed for STAI Form Y-1, HR, and SBP. Conclusions: These data demonstrate that ATD accentuates responses to trauma-related stimuli in SSRI-recovered PTSD. They also suggest that SSRI-induced increases in serotonin function restrain PTSD symptoms, especially under provocation, supporting a role for serotonin in mediating stress resilience.

Antidepressants, suicidality and rebound effect: evidence of similitude?

Background: Samuel Hahnemann noticed that palliative treatments for the symptoms of chronic diseases, after an initial improvement, provoked symptoms similar but stronger symptoms to those initially suppressed. He regarded this as a consequence of the vital reaction of the organism: an automatic and instinctive capacity to return to the initial health condition altered by medicines. Using this homeostatic conception of the organism as a treatment rationale, Hahnemann proposed the therapy of similarity, administering to the patients medicines capable of causing, in healthy individuals, similar symptoms to the natural disease. Based on experimental observations, he proposed that the primary action of the drug was followed by the secondary and opposite action of the organism, inaugurating homeopathic pharmacology, and alerting to the harmful consequences of palliative medicines in susceptible individuals. Such liatrogenic events can be observed in contemporary medicine, after the withdrawal of modern enantiopathic medicines, according to the study of the rebound effect or paradoxical reaction of the organism. Method. This study reviews the recent studies which describe suicidallity after the suspension or discontinuation of second generation antidepressants according to the hypothesis of the paradoxical reaction of the organism. Conclusions: Rebound and withdrawal effects, including suicidality occur with antidepressant drugs. They are relatively rare but more intense than the primary action of the drug. The probability of such effects is influenced by patient factors including age and diagnosis, and drug factors including half-life. Homeopathy (2009) 98, 114-121.

Toll-like receptor activity in Recurrent Aphthous Ulceration

Toll-like receptors (TLR) are membrane proteins that recognize conserved molecules derived from bacterial, virus, fungal or host tissues. Activation of TLRs causes the production of cytokines that mediate inflammatory responses and drive T helper (Th) 1 and 2 cell development. As an exaggerated Th1 immune response is supposed to be involved in pathogenesis of Recurrent Aphthous Ulceration (RAU), we suggest that RAU patients may have an imbalance in TLR pathways. To study the function of TLR activation ex vivo, peripheral blood mononuclear cells (PBMCs) from RAU patients (n = 17) and controls (n = 17) were exposed to TLR2 [lipoteichoic acid (LTA), heat-killed Listeria monocytogenes (HKLM) and PamC3CSK4], TLR3 [Poly(I:C)], TLR4 [lipopolysaccharide (LPS)], TLR5 (flagellin) and TLR7 (imiquimod) ligands, and the time course of supernatant tumor necrosis factor-alpha (TNF-alpha) levels was quantified by enzyme-linked immunosorbent assay. In addition, serological and salivary TNF-alpha and soluble CD14 levels were quantified. The TNF-alpha produced by PBMCs in contact with each TLR ligand and autologous serum or saliva at the same time was also investigated. The data were analyzed by statistical multivariate tests. The control group had a higher response to LTA, whereas RAU had a higher response to HKLM. LTA and LPS interfered with the salivary stimulation of the RAU PBMC and HKLM with the stimulation of the control. Autologous serum was capable of inhibiting TLR2 responsiveness to LTA and enhancing LPS stimulation. Salivary and serological levels of sCD14 and TNF-alpha were not significantly different. Recurrent Aphthous Ulceration patients have an anomalous activity of the TLR2 pathway that probably influences the stimulation of an abnormal Th1 immune response.

Expression profiles of the glucose-dependent insulinotropic peptide receptor and LHCGR in sporadic adrenocortical tumors

Glucose-dependent insulinotropic peptide receptor (GIPR) and LHCGR are G-protein-coupled receptors with a wide tissue expression pattern. Aberrant expression of these receptors has rarely been demonstrated in adult sporadic adrenocortical tumors with a lack of data on pediatric tumors. We quantified the GIPR and LHCGR expression in a large cohort of 55 patients (25 children and 30 adults) with functioning and non-functioning sporadic adrenocortical tumors. Thirty-eight tumors were classified as adenomas whereas 17 were carcinomas. GIPR, and LHCGR expression were analyzed by real-time PCR and normal human pancreatic and testicular tissue samples were used as positive controls. Mean expression values were determined by fold increase in comparison with a normal adrenal pool. GIPR mRNA levels were significantly higher in adrenocortical carcinomas than in adenomas from both pediatric and adult groups. LHCGR expression was similar in both carcinomas and adenomas from the pediatric group but significantly lower in carcinomas than in adenomas from the adult group (median 0.06 and 2.3 respectively, P<0.001). GIPR was detected by immunohistochemistry in both pediatric and adult tumors. Staining and real-time PCR results correlated positively only when GIPR in RN A levels were increased at least two-fold in comparison with normal adrenal expression levels. In Conclusion, GIPR overexpression was observed in pediatric and adult adrenocortical tumors and very low levels of LHCGR expression were found in all adult adrenocortical carcinomas.

Topical interleukin-1 receptor antagonist inhibits inflammatory cell infiltration into the cornea

Interleukin (IL)-1 alpha and beta are important modulators of many functions of corneal epithelial and stromal cells that occur following injury to the cornea, including the influx of bone marrow-derived inflammatory cells into the stroma attracted by chemokines released from the stroma and epithelium. In this study, we examined the effect of topical soluble IL-1 receptor antagonist on bone marrow-derived cell influx following corneal epithelial scrape injury in a mouse model. C57BL/6 mice underwent corneal epithelial scrape followed by application of IL-1 receptor antagonist (Amgen, Thousand Oaks, CA) at a concentration of 20 mg/ml or vehicle for 24 h prior to immunocytochemical detection of marker CD11b-positive cells into the stroma. In two experiments, topical IL-1 receptor antagonist had a marked effect in blocking cell influx. For example, in experiment 1, topical IL-1 receptor antagonist markedly reduced detectible CD11b-positive cells into the corneal stroma at 24 It after epithelial injury compared with the vehicle control (3.5 +/- 0.5 (standard error of the mean) cells/400x field and 13.9 +/- 1.2 cells/400x field, respectively, p < 0.01). A second experiment with a different observer performing cell counting had the same result. Thus, the data demonstrate conclusively that topical IL-1 receptor antagonist markedly down-regulates CD-11b-positive monocytic cell appearance in the corneal stroma. Topical IL-1 receptor antagonist could be an effective adjuvant for clinical treatment of corneal conditions in which unwanted inflammation has a role in the pathophysiology of the disorder. (c) 2008 Elsevier Ltd. All rights reserved.

Candidate-Gene Approach in Posttraumatic Stress Disorder After Urban Violence: Association Analysis of the Genes Encoding Serotonin Transporter, Dopamine Transporter, and BDNF

Posttraumatic stress disorder (PTSD) is a prevalent, disabling anxiety disorder marked by behavioral and physiologic alterations which commonly follows a chronic course. Exposure to a traumatic event constitutes a necessary, but not sufficient, factor. There is evidence from twin studies supporting a significant genetic predisposition to PTSD. However, the precise genetic loci still remain unclear. The objective of the present study was to identify, in a case-control study, whether the brain-derived neurotrophic factor (BDNF) val66met polymorphism (rs6265), the dopamine transporter (DAT1) three prime untranslated region (3`UTR) variable number of tandem repeats (VNTR), and the serotonin transporter (5-HTTPRL) short/long variants are associated with the development of PTSD in a group of victims of urban violence. All polymorphisms were genotyped in 65 PTSD patients as well as in 34 victims of violence without PTSD and in a community control group (n = 335). We did not find a statistical significant difference between the BDNF val66met and 5-HTTPRL polymorphism and the traumatic phenotype. However, a statistical association was found between DAT1 3`UTR VNTR nine repeats and PTSD (OR = 1.82; 95% CI, 1.20-2.76). This preliminary result confirms previous reports supporting a susceptibility role for allele 9 and PTSD.

Novel inactivating mutations in the GH secretagogue receptor gene in patients with constitutional delay of growth and puberty

Background: A limited number of mutations in the GH secretagogue receptor gene (GHSR) have been described in patients with short stature. Objective: To analyze GHSR in idiopathic short stature (ISS) children including a subgroup of constitutional delay of growth and puberty (CDGP) patients. Subjects and methods: The GHSR coding region was directly sequenced in 96 independent patients with ISS, 31 of them with CDGP, in 150 adults, and in 197 children with normal stature. The pharmacological consequences of GHSR non-synonymous variations were established using in vitro cell-based assays. Results: Five different heterozygous point variations in GHSR were identified (c.-6 G>C, c.251G>T (p.Ser84Ile), c.505G>A (p.Ala169Thr), c.545 T>C (p.Val182Ala), and c.1072G>A (p.Ala358Thr)), all in patients with CDGP. Neither these allelic variants nor any other mutations were found in 694 alleles from controls. Functional studies revealed that two of these variations (p.Ser84Ile and p. Val182Ala) result in a decrease in basal activity that was in part explained by a reduction in cell surface expression. The p.Ser84Ile mutation was also associated with a defect in ghrelin potency. These mutations were identified in two female patients with CDGP (at the age of 13 years, their height SDS were -2.4 and -2.3). Both patients had normal progression of puberty and reached normal adult height (height SDS of -0.7 and -1.4) without treatment. Conclusion: This is the first report of GHSR mutations in patients with CDGP. Our data raise the intriguing possibility that abnormalities in ghrelin receptor function may influence the phenotype of individuals with CDGP.

Mouse Leydig cells express multiple P2X receptor subunits

ATP acts on cellular membranes by interacting with P2X (ionotropic) and P2Y (metabotropic) receptors. Seven homomeric P2X receptors (P2X(1)-P2X(7)) and seven heteromeric receptors (P2X(1/2), P2X(1/4), P2X(1/5), P2X(2/3), P2X(2/6), P2X(4/6), P2X(4/7)) have been described. ATP treatment of Leydig cells leads to an increase in [Ca(2+)](i) and testosterone secretion, supporting the hypothesis that Ca(2+) signaling through purinergic receptors contributes to the process of testosterone secretion in these cells. Mouse Leydig cells have P2X receptors with a pharmacological and biophysical profile resembling P2X(2). In this work, we describe the presence of several P2X receptor subunits in mouse Leydig cells. Western blot experiments showed the presence of P2X(2), P2X(4), P2X(6), and P2X(7) subunits. These results were confirmed by immunofluorescence. Functional results support the hypothesis that heteromeric receptors are present in these cells since 0.5 mu M ivermectin induced an increase (131.2 +/- 5.9%) and 3 mu M ivermectin a decrease (64.2 +/- 4.8%) in the whole-cell currents evoked by ATP. These results indicate the presence of functional P2X(4) subunits. P2X(7) receptors were also present, but they were non-functional under the present conditions because dye uptake experiments with Lucifer yellow and ethidium bromide were negative. We conclude that a heteromeric channel, possibly P2X(2/4/6), is present in Leydig cells, but with an electrophysiological and pharmacological phenotype characteristic of the P2X(2) subunit.

Two allelic isoforms of the serotonin transporter from Schistosoma mansoni display electrogenic transport and high selectivity for serotonin

The human blood fluke Schistosoma mansoni is the primary cause of schistosomiasis, a debilitating disease that affects 200 million individuals in over 70 countries. The biogenic amine serotonin is essential for the survival of the parasite and serotonergic proteins are potential novel drug targets for treating schistosomiasis. Here we characterize two novel serotonin transporter gene transcripts, SmSERT-A and SmSERT-B, from S. mansoni. Southern blot analysis shows that the two mRNAs are the products of different alleles of a single SmSERT gene locus. The two SmSERT forms differ in three amino acid positions near the N-terminus of the protein. Both SmSERTs are expressed in the adult form and in the sporocyst form (infected snails) of the parasite, but are absent from all other stages of the parasite`s complex life cycle. Heterologous expression of the two cDNAs in mammalian cells resulted in saturable, sodium-dependent serotonin transport activity with an apparent affinity for serotonin comparable to that of the human serotonin transporter. Although the two SmSERTs are pharmacologically indistinguishable from each other, efflux experiments reveal notably higher substrate selectivity for serotonin compared with their mammalian counterparts. Several well-established substrates for human SERT including (+/-)MDMA, S-(+)amphetamine, RU 24969, and m-CPP are not transported by SmSERTs, underscoring the higher selectivity of the schistosomal isoforms. Voltage-clamp recordings of SmSERT substrate-elicited currents confirm the substrate selectivity observed in efflux experiments and suggest that it may be possible to exploit the electrogenic nature of SmSERT to screen for compounds that target the parasite in vivo. (C) 2009 Elsevier B.V. All rights reserved.

CCR2 receptor is essential to activate microbicidal mechanisms to control Toxoplasma gondii infection in the central nervous system

Chemokines comprise a structurally related family of cytokines that regulate leukocyte trafficking. Because infection with Toxoplasma gondii can induce an important inflammatory reaction that, if left uncontrolled, can lead to death, we investigated the role of the chemokine receptor CCR2 in T gondii infection. We orally infected CCR2(-/-) mice with five ME-49 T gondii cysts and monitored morbidity, survival, and immune response thereafter. The CCR2(-/-) mice displayed higher susceptibility to infection as all mice died on day 28 after infection. Despite similar Th1 responses, a more evident anti-inflammatory response was induced in the peripheral organs of CCR2(-/-) mice compared with wild-type C57BL/6 mice. Additionally, CCR2-/- mice presented greater parasitism and a milder inflammatory reaction in their peripheral organs with lesser CD4(+) and MAC-1(+) and greater CD8(+) cell migration. The parasite load decreased in these organs in CCR2(-/-) mice but remained uncontrolled in the central nervous system. Additionally, we observed down-regulated inducible nitric oxide synthase expression in peripheral organs from CCR2(-/-) mice that was associated with a small nitric oxide production by spleen macrophages. In conclusion, in the absence of CCR2, another mechanism is activated to control tissue parasitism in peripheral organs. Nevertheless, CCR2 is essential for the activation of microbicidal mediators that control T gondii replication in the central nervous system.