Autoantibody status, neuroradiological and clinical findings in children with acute cerebellitis.

BACKGROUND: Acute cerebellitis (AC) in children and adolescents is an inflammatory disease of the cerebellum due to viral or bacterial infections but also autoimmune-mediated processes. OBJECTIVE: To investigate the frequency of autoantibodies in serum and CSF as well as the neuroradiological features in children with AC. MATERIAL AND METHODS: Children presenting with symptoms suggestive of AC defined as acute/subacute onset of cerebellar symptoms and MRI evidence of cerebellar inflammation or additional CSF pleocytosis, positive oligoclonal bands (OCBs), and/or presence of autoantibodies in case of negative cerebellar MRI. Children fulfilling the above-mentioned criteria and a complete data set including clinical presentation, CSF studies, testing for neuronal/cerebellar and MOG antibodies as well as MRI scans performed at disease onset were eligible for this retrospective multicenter study. RESULTS: 36 patients fulfilled the inclusion criteria for AC (f:m = 14:22, median age 5.5 years). Ataxia was the most common cerebellar symptom present in 30/36 (83 %) in addition to dysmetria (15/36) or dysarthria (13/36). A substantial number of children (21/36) also had signs of encephalitis such as somnolence or seizures. In 10/36 (28 %) children the following autoantibodies (abs) were found: MOG-abs (n = 5) in serum, GFAPα-abs (n = 1) in CSF, GlyR-abs (n = 1) in CSF, mGluR1-abs (n = 1) in CSF and serum. In two further children, antibodies were detected only in serum (GlyR-abs, n = 1; GFAPα-abs, n = 1). MRI signal alterations in cerebellum were found in 30/36 children (83 %). Additional supra- and/or infratentorial lesions were present in 12/36 children, including all five children with MOG-abs. Outcome after a median follow-up of 3 months (range: 1 a 75) was favorable with an mRS ≤2 in 24/36 (67 %) after therapy. Antibody (ab)-positive children were significantly more likely to have a better outcome than ab-negative children (p = .022). CONCLUSION: In nearly 30 % of children in our study with AC, a range of abs was found, underscoring that autoantibody testing in serum and CSF should be included in the work-up of a child with suspected AC. The detection of MOG-abs in AC does expand the MOGAD spectrum.

Psychosocial stress and longitudinally measured gestational weight gain throughout pregnancy: The Ulm SPATZ Health Study.

Psychosocial stress is thought to influence gestational weight gain (GWG), but results are inconsistent. We investigated the relationship of questionnaire-based maternal stress and related constructs assessed at childbirth with maternal weight measured throughout pregnancy. Data were derived from the Ulm SPATZ Health Study, a birth cohort recruited from the general population (04/2012-05/2013, Ulm, Germany). Adjusted generalized estimating equations were performed. Regression coefficients (b) and 95% confidence intervals, each highest versus lowest tertile of stress or related constructs, are presented. In 748 women, we observed positive associations for maternal chronic stress (b = 4.36 kg (1.77; 6.95)), depressive symptoms (b = 2.50 kg (0.14; 4.86)), anxiety symptoms (b = 3.26 kg (0.62, 5.89)), and hair cortisol (b = 3.35 kg (0.86; 5.83)) with maternal weight at the first gestational month. GWG was considerably lower in mothers with higher chronic stress. Pregnancy-related anxiety was positively related to weight at first month (b = 4.16 kg (1.74; 6.58)) and overall GWG. In contrast, no association was observed between anxiety symptoms and GWG. Odds ratios for association with inadequate weight gain according to Institute of Medicine recommended cutoffs differed from the results presented obove. There is evidence of an association between stress and weight gain lying beyond the recommended cut-offs, which however needs further corroboration.

The association of potential stressors with hair steroids in parents with small children: The Ulm SPATZ health study.

Previous studies have reported weak associations between questionnaire-based stress measurements and hair steroids. A stronger relationship may exist in highly stressed subpopulations or with stress brought up by novel or unpredictable situations. In the Ulm SPATZ Health Study, conducted in Ulm, Germany, baseline recruitment 04/2012 to 05/2013, we analyzed data of families enrolled shortly after childbirth. Mothers completed standardized questionnaires assessing sociodemographic, health- and family-life-related factors, and the Screening Scale of the Trier Inventory of Chronic Stress (TICS) at 6 months (T2) and 12 months postpartum (T3). Their current partners completed SSCS-TICS and an Effort-Reward Imbalance (ERI) Questionnaire obtained at 6 weeks postpartum (T1). Partners (n = 375 at T1) and mothers (n = 654 at T2 or T3) provided a 2 to 3-cm hair segment for hair analysis. Adjusted linear and cubic spline regressions were used to analyze (non-)linear relationships between potential stressors and hair cortisol (hairF) and hair cortisone (hairE) concentrations as well as the respective change scores between 12 months and 6 months. Lacking social recognition and high paternal work overload were significantly associated with paternal hairF in cubic spline models (test for overall association, chi2 = 8.24, p = 0.041, chi2 = 8.41, p = 0.038) but not in linear models. However, the association between ERI and hairF (chi2 = 7.54, p = 0.059) was marginally significant. Maternal education was related to maternal hairF and hairE at T2. No association was observed between maternal postpartum employment and hair steroids at T2 or T3. Conversely, we could show a relationship between some change scores of stress and hairE in mothers. Considering non-linearity and family-related stressors, there are few associations between questionnaire-based stress measurements and hairF or hairE. Novelty of stressors was not shown to be a relevant factor.

Targeting the actin cytoskeleton: selective antitumor action via trapping PKCɛ.

Targeting the actin cytoskeleton (CSK) of cancer cells offers a valuable strategy in cancer therapy. There are a number of natural compounds that interfere with the actin CSK, but the mode of their cytotoxic action and, moreover, their tumor-specific mechanisms are quite elusive. We used the myxobacterial compound Chondramide as a tool to first elucidate the mechanisms of cytotoxicity of actin targeting in breast cancer cells (MCF7, MDA-MB-231). Chondramide inhibits cellular actin filament dynamics shown by a fluorescence-based analysis (fluorescence recovery after photobleaching (FRAP)) and leads to apoptosis characterized by phosphatidylserine exposure, release of cytochrome C from mitochondria and finally activation of caspases. Chondramide enhances the occurrence of mitochondrial permeability transition (MPT) by affecting known MPT modulators: Hexokinase II bound to the voltage-dependent anion channel (VDAC) translocated from the outer mitochondrial membrane to the cytosol and the proapoptotic protein Bad were recruited to the mitochondria. Importantly, protein kinase C-ɛ (PKCɛ), a prosurvival kinase possessing an actin-binding site and known to regulate the hexokinase/VDAC interaction as well as Bad phosphorylation was identified as the link between actin CSK and apoptosis induction. PKCɛ, which was found overexpressed in breast cancer cells, accumulated in actin bundles induced by Chondramide and lost its activity. Our second goal was to characterize the potential tumor-specific action of actin-binding agents. As the nontumor breast epithelial cell line MCF-10A in fact shows resistance to Chondramide-induced apoptosis and notably express low level of PKCɛ, we suggest that trapping PKCɛ via Chondramide-induced actin hyperpolymerization displays tumor cell specificity. Our work provides a link between targeting the ubiquitously occurring actin CSK and selective inhibition of pro-tumorigenic PKCɛ, thus setting the stage for actin-stabilizing agents as innovative cancer drugs. This is moreover supported by the in vivo efficacy of Chondramide triggered by abrogation of PKCɛ signaling shown in a xenograft breast cancer model.

Pretubulysin: a new option for the treatment of metastatic cancer.

Tubulin-binding agents such as taxol, vincristine or vinblastine are well-established drugs in clinical treatment of metastatic cancer. However, because of their highly complex chemical structures, the synthesis and hence the supply issues are still quite challenging. Here we set on stage pretubulysin, a chemically accessible precursor of tubulysin that was identified as a potent microtubule-binding agent produced by myxobacteria. Although much simpler in chemical structure, pretubulysin abrogates proliferation and long-term survival as well as anchorage-independent growth, and also induces anoikis and apoptosis in invasive tumor cells equally potent to tubulysin. Moreover, pretubulysin posseses in vivo efficacy shown in a chicken chorioallantoic membrane (CAM) model with T24 bladder tumor cells, in a mouse xenograft model using MDA-MB-231 mammary cancer cells and finally in a model of lung metastasis induced by 4T1 mouse breast cancer cells. Pretubulysin induces cell death via the intrinsic apoptosis pathway by abrogating the expression of pivotal antiapoptotic proteins, namely Mcl-1 and Bcl-xL, and shows distinct chemosensitizing properties in combination with TRAIL in two- and three-dimensional cell culture models. Unraveling the underlying signaling pathways provides novel information: pretubulysin induces proteasomal degradation of Mcl-1 by activation of mitogen-activated protein kinase (especially JNK (c-Jun N-terminal kinase)) and phosphorylation of Mcl-1, which is then targeted by the SCF(Fbw7) E3 ubiquitin ligase complex for ubiquitination and degradation. In sum, we designate the microtubule-destabilizing compound pretubulysin as a highly promising novel agent for mono treatment and combinatory treatment of invasive cancer.

Death inducer-obliterator 1 (Dido1) is a BMP target gene and promotes BMP-induced melanoma progression.

Bone morphogenetic proteins (BMPs) are known to play an important role in melanoma development and progression. However, the downstream targets of BMPs have not been investigated thus far. Therefore, we treated melanoma cell lines with the Smad-specific BMP inhibitor Dorsomorphin and performed a cDNA microarray. We identified death inducer-obliterator 1 (Dido1) as a BMP-specific Smad-regulated target gene, which was confirmed by qRT-PCR, immunofluorescence staining and electrophoretic mobility shift assay experiments. An analysis of Dido1 expression revealed an upregulation of Dido1 levels in melanoma cell lines and tissues compared with normal melanocytes. Colony-formation assays showed that siDido1-transfected cells formed significantly smaller colonies when grown in soft agar compared with control cells. In addition, fluorescence-activated cell sorting and western blot experiments revealed that transfection of melanoma cells with Dido1 small interfering RNAs led to an upregulation of apoptosis. Furthermore, cell migratory and invasive potentials were strongly reduced in siDido1-transfected cells compared with control cells. Finally, we demonstrated that Dido1 induces the expression of Integrin αV, thereby promoting the attachment, migration, invasion and apoptosis resistance of melanoma cells.

CTGF is overexpressed in malignant melanoma and promotes cell invasion and migration.

BACKGROUND: Malignant melanoma cells are known to have altered expression of growth factors compared with normal human melanocytes. These changes most likely favour tumour growth and progression, and influence tumour environment. The induction of transforming growth factor beta1, 2 and 3 as well as BMP4 and BMP7 expression in malignant melanoma has been reported before, whereas the expression of an important modulator of these molecules, connective tissue growth factor (CTGF), has not been investigated in melanomas until now. METHODS: Expression of CTGF was analysed in melanoma cell lines and tissue samples by qRT-PCR and immunohistochemistry. To determine the regulation of CTGF expression in malignant melanoma, specific siRNA was used. Additionally, migration, invasion and attachment assays were carried out. RESULTS: We were able to demonstrate that CTGF expression is upregulated in nine melanoma cell lines and in primary and metastatic melanoma in situ. The transcription factor HIF-1α was revealed as a positive regulator for CTGF expression. Melanoma cells, in which CTGF expression is diminished, show a strong reduction of migratory and invasive properties when compared with controls. Further, treatment of normal human epidermal melanocytes with recombinant CTGF leads to an increase of migratory and invasive behaviour of these cells. CONCLUSION: These results suggest that CTGF promotes melanoma cell invasion and migration and, therefore, has an important role in the progression of malignant melanoma.

[Clinical management of genital herpes: what can be done in pregnancy?]. / Prise en charge pratique de l'herpès génital: que faire en cas de grossesse?

Neonatal herpes infection is the major complication of genital herpes even if it occurs in less than 1/10,000 births. A great number of recent studies illustrates the natural history of genital herpes. The importance of viral transmission by asymptomatic shedding is now well established. The widespread use of viral diagnosis strategies is the prerequisite to efficient genital herpes prevention in order to eradicate viral mother-to-child transmission. This starts with the detection of at-risk situations such as primary infection in late pregnancy. Once the at-risk situation is known there should be concern about the adaptation of treatment strategies including antiviral therapy. The following work proposes different strategies facing each at-risk situation in order to discuss the efficiency of new diagnostic and treatment tools.

[Therapeutic strategies for genital herpes]. / Stratégies thérapeutiques face à l'herpès génital.

Genital herpes, usually a benign infection, has nevertheless an important psychological impact by its recurrent character. The clinical management needs first well done patient counseling, and second, the biological documentation of the virus excretion. When this is achieved, different treatment strategies may be proposed targeting mainly acute crisis. There is, however, a strong trend towards the prevention of recurrences using suppressive antiviral treatment or modulating the immune system (vaccines, immunomodulators). Indeed, there is a hope that these new approaches may lead to the reduction of disease transmission by diminishing the viral shedding.

[Genital herpes: practical impact of the 2001 consensus conference?]. / Herpès génital: que faut-il retenir de la conférence de consensus 2001?

Genital herpes, usually a benign infection, has nevertheless an important psychological impact by its recurrent character. The clinical management needs first a well done patient counseling, and second, the biological documentation of the virus excretion. When this is achieved, different treatment strategies may be proposed aiming mainly acute crisis. There is, however, a strong trend towards the prevention of recurrences using suppressive antiviral treatment or modulating the immune system (vaccines, immunomodulators). Indeed, there is a hope that these new approaches may lead to the reduction of disease transmission by diminishing the viral shedding.

Acyclovir prophylaxis in late pregnancy prevents recurrent genital herpes and viral shedding.

Neonatal herpes affects about 1 in 15,000 newborns and the prognosis for disseminated disease with encephalitis is poor. We investigated whether acyclovir prophylaxis in late pregnancy effectively reduces the risk of viral shedding and, hence, of mother-to-child transmission at delivery. A prospective study was conducted. Pregnant women who had at least one episode of genital herpes during pregnancy were randomly assigned to two groups: group 1 (n=167) received oral acyclovir from 36 weeks of gestation to term; group 2 (n=121) received no treatment. Group 3 (n=201) comprised women not given prophylaxis who had a history of genital herpes, but no active episodes during pregnancy. No specific instruction were set up for obstetrical management except for cesarean section in case of a suspected herpes lesion at the time of labor. The rate of Cesarean section was 8.4% in group 1, 16.5% in group 2, and 9.9% in group 3 (p<0.001). 75% of cesareans in group 2 and 10% in group 3 were done for genital herpes. Percentage of viral shedding was, respectively, 0% (group1), 5% (group2), and 0.5%(group3) (p<0.05). These findings underline the value of antiviral prophylaxis in late pregnancy for women with a known history of genital herpes. Such prophylaxis only partly prevents neonatal herpes infection, because it is not applicable to patients with no known clinical history but may excrete the virus.

Fetal fibronectin in the cervical secretion predicts accurately the onset of labor at term.

OBJECTIVE: The objective of our study was to check if presence of fetal fibronectin in the cervical secretion of full term patient predicts accurately the onset of labour at term. STUDY DESIGN: 78 women in the term period were included in the study, serial samples for fetal fibronectin were assessed, each patient underwent spontaneous labour, delay between last sample and delivery were analysed. RESULTS: Patient with positive fetal fibronectin delivered within 3 +/- 1.9 days where as patient with negative fetal fibronectin delivered within 5.7 +/- 3.9 days (P = 0.01). CONCLUSION: Presence of fetal fibronectin in cervical secretions seems to be a powerful tool to predict in a short delay the onset of labour at term, it should be used in conjunction with clinical and fetal assessment data.

[Agenesia of the canal of Arantius. A case report]. / Agénésie du canal d'Arantius. A propos d'un cas.

Looking for the etiology of hydramnios which became symptomatic at 21 weeks' gestation ultrasonography revealed a hepatic vascular abnormality without other symptoms. The suspected diagnosis was agenesis of the ductus venosus with creation of a high grade arteriovenous shunt between the umbilical vein and the inferior vena cava. Agenesis of the ductus venosus may be one expression of the different possible systemic-portal-umbilical abnormalities. Physiological consequences vary according to the type of substitutive anastomoses.

[Amnioinfusion: indications and results]. / Amnioinfusion: indications et résultats.

Amnioinfusion is a recent procedure introduced for routine obstetrical care fifteen years ago. The most widely recognized indication for amnioinfusion is in labor, to reduce fetal distress due to variable decceleration associated with oligohydramnios and probable presence of thick meconium stained amniotic fluid. During pregnancy, amnioinfusion can help in the diagnosis and morphologic evaluation in case of anamnios. The indication for amnioinfusion in the management of oligohydramnios at term before labour remains controversial. As a new procedure amnioinfusion must be managed with extreme caution.

Zeolithe A--A phosphate substitute for detergents: toxicological investigation.

Tests on Zeolithe A, a sodium aluminium silicate developed as a substitute for phosphates in detergents, were designed to investigate the safety of exposure to the material, or to detergents containing it, either under industrial conditions encountered during manufacturing processes or as a consequence of domestic use. The test programme included oral studies (acute, subchronic and long-term carcinogenicity tests and absorption measurements), and dermal, ocular and inhalation studies on the silicate alone and on appropriate detergent formulations, as well as studies of possible silicogenic activity and metal-complexing potential and measurements of dust generation and particle-size distribution. These studies did not produce any evidence to suggest that levels of domestic and industrial exposure resulting from the projected use of Zeolithe A in detergents would present any hazard to health. Zeolithe A did not induce silicotic tissue reactions and when incorporated into detergent formulations did not increase the liberation of fine dusts.

Mutanten des hüllproteins (b-protein) des bakteriophagen fd.

Spontaneous mutants of the bacteriophage fd and mutants resulting from fd-infected cultures of E. coli grown in the presence of 2.7-diaminofluoren and proflavin were isolated by means of free flow electrophoresis.The amino acid analyses of the mutant coat proteins (B-proteins) show significant differences in comparison with the amino acid analyses of wild type coat protein.