Induction of atypical EAE mediated by transgenic production of IL‐6 in astrocytes in the absence of systemic IL‐6

Interleukin (IL)‐6 is crucial for the induction of many murine models of autoimmunity including experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. While IL‐6‐deficient mice (IL‐6 KO) are resistant to EAE, we showed previously that in transgenic mice with astrocyte‐targeted production of IL‐6‐restricted to the cerebellum (GFAP‐IL6), EAE induced with MOG_35–55 was redirected away from the spinal cord to the cerebellum. To further establish the importance of IL‐6 produced in the central nervous system, we have generated mice producing IL‐6 essentially only in the brain by crossing the GFAP‐IL6 mice with IL‐6 KO mice. Interestingly, GFAP‐IL6‐IL‐6 KO mice showed a milder but almost identical phenotype as the GFAP‐IL6 mice, which correlated with a lower load of inflammatory cells and decreased microglial reactivity. These results indicate that not only is cerebellar IL‐6 production and eventual leakage into the peripheral compartment the dominating factor controlling this type of EAE but that it can also facilitate induction of autoimmunity in the absence of normal systemic IL‐6 production. © 2013 Wiley Periodicals, Inc.     

Neonatal oxytocin manipulations have long-lasting, sexually dimorphic effects on vasopressin receptors

Developmental exposure to oxytocin (OT) or oxytocin antagonists (OTAs) has been shown to cause long-lasting and often sexually dimorphic effects on social behaviors in prairie voles (Microtus ochrogaster). Because regulation of social behavior in monogamous mammals involves central receptors for OT, arginine vasopressin (AVP), and dopamine, we examined the hypothesis that the long-lasting, developmental effects of exposure to neonatal OT or OTA might reflect changes in the expression of receptors for these peptides. On postnatal day 1, prairie voles were injected intraperitoneally with either OT (1 mg/kg), an OTA (0.1 mg/kg), saline vehicle, or were handled only. At approximately 60 days of age, vasopressin V1a receptors, OT receptors (OTR) and dopamine D2 receptor binding were quantified using receptor autoradiography in brain tissue taken from males and females. Significant treatment effects on V1a binding were found in the bed nucleus of the stria terminalis (BNST), cingulate cortex (CgCtx), mediodorsal thalamus (MdThal), medial preoptic area of the hypothalamus (MPOA), and lateral septum (LS). The CgCtx, MPOA, ventral pallidum, and LS also showed significant sex by treatment interactions on V1a binding. No significant treatment or sex differences were observed for D2 receptor binding. No significant treatment difference was observed for OTR receptor binding, and only a marginal sex difference. Changes in the neuropeptide receptor expression, especially the V1a receptor, may help to explain sexually dimorphic changes in behavior that follow comparable neonatal manipulations.     

Gain of multiple copies of the CBFB gene: a new genetic aberration in a case of granulocytic sarcoma

Granulocytic sarcomas (GS) are tumor masses of immature myeloid cells presenting at an extramedullary site, mainly the skin, bone, and lymph node. They are often associated with acute myeloid leukemia (AML) with monoblastic or myelomonocytic differentiation, including either AML M2 with t(8;21)(q22;q22) or AML M4Eo with inv(16)(p13q22). We present a case diagnosed with GS associated with AML M4 that presented a normal karyotype with conventional cytogenetic analysis. Although the myeloblasts did not show the inv(16)(p13q22) (CBFB/MYH11), a gain of multiple copies of the CBFB gene was detected with fluorescence in situ hybridization analysis. To our knowledge, no cases with this rare genetic anomaly have been previously described.     

Molecular cloning and characterisation of Ts8B1, Ts8B2 and Ts8B3, three new members of the Taenia solium metacestode 8 kDa diagnostic antigen family

Antibody screening of a lambdaZAP-XR Taenia solium metacestode cDNA library yielded a clone (Ts8B1), with an insert of 345 bp, and an open reading frame of 258 bp, that coded for a protein with 85 amino acid residues. Alignment of the predicted amino acid sequence with sequences from SWISSPROT revealed an 88% identity with TcA5.5, a 10 kDa immunodiagnostic antigen of T. crassiceps, 75% identity with CyDA a T. solium metacestode antigen, 40-50% identity with several variants of the 8 kDa subunit of antigen B of Echinococcus spp. and with members of the T. solium metacestode 8 kDa antigen family. Two other Ts8B1 related molecules, Ts8B2 and Ts8B3, were identified in the metacestode cDNA library by PCR, coding for 85 and 66 amino acid polypeptides, respectively. Both Ts8B1 and Ts8B2 were characterized as E/S antigens through their subcellular localisation in the secretory membrane system when expressed in NRK cells. The three cDNA inserts were expressed, purified and probed in enzyme-linked immunosorbent assays (ELISA) with sera and cerebro-spinal fluid from patients with confirmed neurocysticercosis, and with sera from pigs infected with T. solium. The most promising antigen, Ts8B2, performed with a sensitivity of 96.8% and specificity of 93.1% in the detection of active NCC when using serum samples in the assay and performed similarly in the porcine system. The implications of these findings are discussed.     

Induction of virus-neutralizing antibodies by immunization with Rachiplusia nu per os infected with a recombinant baculovirus expressing the E2 glycoprotein of bovine viral diarrhea virus

This work describes the development of a novel protein expression system based on Rachiplusia nu larvae for the production of the recombinant E2 protein to be used as a vaccine candidate against bovine viral diarrhea virus (BVDV). A recombinant baculovirus (Ac-E2pol+) bearing the E2 glycoprotein coding sequence of BVDV was obtained. Fourth-instar R. nu larvae were infected orally with recombinant polyhedra and the expression of E2 protein was confirmed by immunoblot. In order to test the recombinant product as a vaccine candidate, an immunization assay was performed and the neutralizing humoral immune response against BVDV NADL strain was evaluated. Mice vaccinated with Ac-E2pol+ extracts of per os infected larvae developed a neutralizing antibody titer of 3.16 after the administration of three doses of the immunogen. This report demonstrates the efficacy of per os infected larval extracts as a BVDV recombinant immunogen, which constitutes an easier and economic approach for producing recombinant antigens.     

Health-related quality of life in allergic rhinitis: comparing the short form ESPRINT-15 and MiniRQLQ questionnaires

BACKGROUND: We compared the psychometric properties of the ESPRINT-15, the short form of a new Spanish instrument to measure health-related quality of life in allergic rhinitis (AR) patients, with those of the Mini-Rhinoconjunctivitis Quality of Life Questionnaire (MiniRQLQ). METHODS: The questionnaires were compared in Spanish patients with intermittent allergic rhinitis (IAR) or persistent AR in a prospective, observational study. Floor and ceiling effects, internal consistency (Cronbach's alpha), test-retest reliability (intraclass correlation coefficient; ICC), convergent and known groups validity, and sensitivity to change (standardized response means; SRMs) were compared. RESULTS: In terms of content, while the MiniRQLQ has a dimension covering practical problems and places more emphasis on symptoms, the ESPRINT-15 has two dimensions (Sleep and Psychological impact) which are not included in the MiniRQLQ. In the validation study, 400 patients were included and 59% of the sample had persistent AR. There were no significant floor or ceiling effects on any dimension on either questionnaire. Cronbach's alpha values for the ESPRINT-15 and MiniRQLQ overall scores were 0.92 and 0.90, respectively. In 48 clinically stable patients, ICCs were 0.80 and 0.77, respectively. Both instruments discriminated between patients with IAR and persistent AR. Correlations with symptom scores and generic measures were moderate to strong. SRMs for overall scores and individual dimensions on the two questionnaires in the 197 patients reporting a change in health status ranged from 0.7 to 1.3. CONCLUSIONS: Both questionnaires performed well in psychometric terms. The ESPRINT-15 is particularly recommended for use in Spanish-speaking populations.     

Head-to-head comparison between the EQ-5D-5L and the EQ-5D-3L in general population health surveys

Background

The EQ-5D has been frequently used in national health surveys. This study is a head-to-head comparison to assess how expanding the number of levels from three (EQ-5D-3L) to five in the new EQ-5D-5L version has improved its distribution, discriminatory power, and validity in the general population.

Methods

A representative sample (N?=?7554) from the Catalan Health Interview Survey 2011–2012, aged ≥18, answered both EQ-5D versions, and we evaluated the response redistribution and inconsistencies between them. To assess validity of this redistribution, we calculated the mean of the Visual Analogue Scale (VAS), which measures perceived health. The discriminatory power was examined with Shannon Indices, calculated for each dimension separately. Spanish preference value sets were applied to obtain utility indices, examining their distribution with statistics of central tendency and dispersion. We estimated the proportion of individuals reporting the best health state in EQ-5D-5L and EQ-5D-3L within groups of specific chronic conditions and their VAS mean.

Results

A very small reduction in the percentage of individuals with the best health state was observed, from 61.8% in EQ-5D-3L to 60.8% in EQ-5D-5L. In contrast, a large proportion of individuals reporting extreme problems in the 3 L version moved to severe problems (level 4) in the 5 L version, particularly for pain/discomfort (75.5%) and anxiety/depression (66.4%). The average proportion of inconsistencies was 0.9%. The pattern of the perceived health VAS mean confirmed the hypothesis established a priori, supporting the validity of the observed redistribution. Shannon index showed that absolute informativity was higher in the 5 L version for all dimensions. The means (SD) of the Spanish EQ-5D-3L and EQ-5D-5L indices were 0.87 (0.25) and 0.89 (0.22). The proportion of individuals with the best health state within each specific chronic condition was very similar, regardless of the EQ-5D version (≤?30% in half of the 28 chronic conditions).

Conclusion

Although the proportion of individuals with the best possible health state is still very high, our findings support that the increase of levels provided by the EQ-5D-5L contributed to the validity and discriminatory power of this new version to measure health in general population, as in the national health surveys.

     

Dexamethasone decreases contraction to electrical field stimulation in mesenteric arteries from spontaneously hypertensive rats through decreases in thromboxane A2 release

Glucocorticoids play a role in the control of vascular smooth muscle tone through the alteration of vasoconstrictor and vasodilator factor production. We studied the effect of dexamethasone on vasoconstriction induced by electrical field stimulation (EFS) in rat mesenteric arteries (MAs) and the role of hypertension in this effect. Endothelium-denuded MAs were obtained from Wistar-Kyoto rats and spontaneously hypertensive rats (SHRs). EFS response was analyzed by isometric tension recordings and cyclooxygenase (COX-1 and COX-2) expression by Western blot. Noradrenaline (NA) release was evaluated in segments incubated with [(3)H]NA. Dexamethasone (0.1 and 1 microM; 2-8 h) reduced vasoconstriction to EFS (200 mA, 0.3 ms, 1-16 Hz), in a dose- and time-dependent manner only in SHRs. However, the EFS-induced release of [(3)H]NA was increased in SHR arteries preincubated with dexamethasone (1 microM; 6 h). The thromboxane A(2) (TxA(2)) synthase inhibitor furegrelate (10 microM), the selective COX-2 inhibitor NS-398 (N-[2-cyclohexyloxy-4-nitrophenyl] methanesulfonamide; 10 microM), or the TxA(2) receptor antagonist SQ 29548 (1 microM), reduced EFS and NA induced vasoconstrictor responses. However, the effect of these drugs was abolished in arteries preincubated with dexamethasone. Both dexamethasone and phentolamine (1 microM) inhibited the increased thromboxane B(2) levels observed after EFS. COX-2 protein expression was reduced by dexamethasone in SHR arteries. Results suggest that dexamethasone reduces vasoconstriction to EFS in MAs from SHRs by decreasing COX-2 expression, thereby decreasing the smooth muscle TXA(2) release induced by alpha-adrenoceptor activation. The undetectable COX-2 expression in MAs from normotensive animals explains the noneffect of dexamethasone in their arteries.     

Gingival neurofibroma in a neurofibromatosis type 1 patient

Neurofibroma is a benign peripheral nerve sheath tumour. It is one of the most frequent tumours of neural origin and its presence is one of the clinical criteria for the diagnosis of type 1 neurofibromatosis (NF-I). Neurofibromatosis type 1 is an autosomal dominantly inherited disease due to an alteration in the long arm of chromosome 17. About 50% of NF-I patients have no family history of the disease. NF-I patients have skin lesions (cafe au lait spots and neurofibromas) as well as bone malformations and central nervous system tumours. Diagnosis is based on a series of clinical criteria. Gingival neurofibroma in NF-I is uncommon. Treatment of neurofibromas is surgical resection. The aim of this paper is to report a case of NF-I with gingival involvement and to review the literature.