Differential magnetic field effects on heart rate and nociception in anosmic pigeons

Several studies have shown that exposure to altered magnetic fields affects nociception by suppressing stress‐induced hypoalgesia, and that this effect is reduced or abolished if the treatment is performed in the absence of light. This raises the question as to whether other sources of sensory stimuli may also modulate these magnetic effects. We investigated the possible role of olfaction in the magnetically induced effects on sensitivity to nociceptive stimuli and heart rate (HR) in restraint‐stressed homing pigeons exposed to an Earth‐strength, irregularly varying (<1 Hz) magnetic field. The magnetic treatment decreased the nociceptive threshold in normally smelling birds and an opposite effect was observed in birds made anosmic by nostril plugging. Conversely, no differential effect of olfactory deprivation was observed on HR, which was reduced by the magnetic treatment both in smelling and anosmic pigeons. The findings highlight an important role of olfactory environmental information in the mediation of magnetic effects on nociception, although the data cannot be interpreted unambiguously because of the lack of an additional control group of olfactory‐deprived, non‐magnetically exposed pigeons. The differential effects on a pigeon's sensitivity to nociceptive stimulus and HR additionally indicate that the magnetic stimuli affect nociception and the cardiovascular system in different ways. Bioelectromagnetics 33:309–319, 2012. © 2011 Wiley Periodicals, Inc.     

CD80+Gr-1+ myeloid cells inhibit development of antifungal Th1 immunity in mice with candidiasis

To find out whether polymorphonuclear neutrophils (PMN), abundantly recruited in disseminated Candida albicans infection, could directly affect the activation of Th cells we addressed the issues as to whether murine PMN, like their human counterparts, express costimulatory molecules and the functional consequence of this expression in terms of antifungal immune resistance. To this purpose, we assessed 1) the expression of CD80 (B7-1) and CD86 (B7-2) molecules on peripheral, splenic, and inflammatory murine Gr-1+ PMN; 2) its modulation upon interaction with C. albicans in vitro, in vivo, and in human PMN; 3) the effect of Candida exposure on the ability of murine PMN to affect CD4+ Th1 cell proliferation and cytokine production; and 4) the mechanism responsible for this effect. Murine PMN constitutively expressed CD80 molecules on both the surface and intracellularly; however, in both murine and human PMN, CD80 expression was differentially modulated upon interaction with Candida yeasts or hyphae in vitro as well as in infected mice. The expression of the CD86 molecule was neither constitutive nor inducible upon exposure to the fungus. In vitro, Gr-1+ PMN were found to inhibit the activation of IFN-gamma-producing CD4+ T cells and to induce apoptosis through a CD80/CD28-dependent mechanism. A population of CD80+Gr-1+ myeloid cells was found to be expanded in conventional as well as in bone marrow-transplanted mice with disseminated candidiasis, but its depletion increased the IFN-gamma-mediated antifungal resistance. These data indicate that alternatively activated PMN expressing CD80 may adversely affect Th1-dependent resistance in fungal infections.     

Sequence plasticity in the antigen-binding site of a therapeutic anti-HER2 antibody

We have examined the plasticity of the antigen-combining site of a high-affinity antibody. In phage-displayed Fab libraries, selected CDR positions and one FR position of the humanized anti-Her2 antibody hu4D5 were substituted with all 20 amino acids. Antigen-binding selections were used to enrich for high-affinity variants, and a large number of sequences were obtained prior to convergence of the selected pool to a small set of clones. As expected, sequence variability of the antigen-binding site is overall diminished compared to known IgG sequences; however, certain positions retain much higher variability than others. The sequence variability map of the hu4D5 binding site is compared with a map derived from previous alanine-scanning of the antibody. Affinities of soluble Fab fragments for antigen confirm that multiple variants were selected with high affinity for antigen, including one variant with a single point mutation that was about threefold improved in affinity compared to the parental hu4D5. Interestingly, this mutation is one of the most radical in terms of changing side-chain chemistry (Trp for Asp) and occurs at the most plastic site as calculated by the Wu-Kabat variability coefficient. Thus variability mapping yields information about the antibody-antigen interaction that is useful and complementary to that obtained by alanine scanning mutagenesis.     

A Missense Mutation in KCTD17 Causes Autosomal Dominant Myoclonus-Dystonia

Myoclonus-dystonia (M-D) is a rare movement disorder characterized by a combination of non-epileptic myoclonic jerks and dystonia. SGCE mutations represent a major cause for familial M-D being responsible for 30%–50% of cases. After excluding SGCE mutations, we identified through a combination of linkage analysis and whole-exome sequencing KCTD17 c.434 G>A p.(Arg145His) as the only segregating variant in a dominant British pedigree with seven subjects affected by M-D. A subsequent screening in a cohort of M-D cases without mutations in SGCE revealed the same KCTD17 variant in a German family. The clinical presentation of the KCTD17-mutated cases was distinct from the phenotype usually observed in M-D due to SGCE mutations. All cases initially presented with mild myoclonus affecting the upper limbs. Dystonia showed a progressive course, with increasing severity of symptoms and spreading from the cranio-cervical region to other sites. KCTD17 is abundantly expressed in all brain regions with the highest expression in the putamen. Weighted gene co-expression network analysis, based on mRNA expression profile of brain samples from neuropathologically healthy individuals, showed that KCTD17 is part of a putamen gene network, which is significantly enriched for dystonia genes. Functional annotation of the network showed an over-representation of genes involved in post-synaptic dopaminergic transmission. Functional studies in mutation bearing fibroblasts demonstrated abnormalities in endoplasmic reticulum-dependent calcium signaling. In conclusion, we demonstrate that the KCTD17 c.434 G>A p.(Arg145His) mutation causes autosomal dominant M-D. Further functional studies are warranted to further characterize the nature of KCTD17 contribution to the molecular pathogenesis of M-D.     

Neurodevelopmental outcome in children with periventricular leukomalacia

The purpose of this study was to question the correlation of different grades of periventricular leukomalacia (PVL) and subsequent neurodevelopmental outcome. In a prospective study we followed 52 preterm infants. Infants were divided into three groups according to their cranial ultrasound findings of PVL (De Vries classification). Seventeen children had PVL 1, 20 children had PVL 2, and 15 children had PVL 3. All 15 (100%) children with PVL 3 developed cerebral palsy with additional visual perceptual dysfunctions and epilepsy. Children with PVL 1 had high frequency of mild neuromotoric delay and visual impairment. PVL 2 and 3 have great predictive value for subsequent severe neurodevelopmental disorder which refers to cerebral palsy, different cognitive deficits, vision impairment and epilepsy. We have determined that due to high frequency of visual impairment and epilepsy we need to include neurophysiologic examinations very early in children with PVL lesions.     

West syndrome with periventricular leukomalacia: ten-year clinical study

The aim of the study was to evaluate magnetic resonance imaging (MRI) findings in infants with periventricular leukomalacia (PVL) and West syndrome (WS) and determine the neurodevelopmental outcome in children with West syndrome and PVL. Ultrasound and brain MRI were performed in 37 infants with recognized PVL. PVL was categorized according to De Vries, whereas West syndrome was categorized according to International League Against Epilepsy 1989. West syndrome in our patients developed during the first 2 years of life. The most common interictal abnormality was hypsarrhythmia. All, except two patients had delayed development and various degrees of mental retardation. The most characteristic neuroimaging findings were major reduction in cerebral cortical gray matter volume, reduction in the volume of brain myelin, and delayed myelination. These findings may explain the anatomical association between the West syndrome onset and PVL and intellectual and cognitive deficit in premature infants with PVL.     

A diagnosis of pneumococcal peritonitis secondary to pyo-salpinx in a young healthy female by culturing peritoneal pus

Pneumococcal intra-abdominal infections of female genital tract origin are rare. A 33-year-old woman with peritonitis due to Streptococcus pneumoniae serotype 3 was reported. The patient did not have any of the known predisposing conditions for intra-abdominal pneumococcal infection. The clinical presentation included signs of multiorgan failure. Peritoneal toilette, bilateral salpingectomy and antibiotic treatment were promptly administered. The patient remained febrile, developed respiratory failure and required a repeated laparotomy and a prolonged antimicrobial treatment. Penicillin susceptible S. pneumoniae was isolated from the pus collected at surgery. Thus, culturing of intra-operative specimens should never be neglected to establish the correct microbiologic diagnosis.