Hypothetical LOC387715 is a second major susceptibility gene for age-related macular degeneration, contributing independently of complement factor H to disease risk

Age-related macular degeneration (AMD) is a multifactorial disease and a prevalent cause of visual impairment in developed countries. Risk factors include environmental components and genetic determinants. The complement factor H (CFH) has been the first major susceptibility gene for AMD identified within 1q32. Here, we focused on a second region of interest in 10q26 where a recent meta-analysis revealed strongest evidence for linkage to AMD at a genome-wide significance level. Within an interval of 22 Mb, we have analyzed 93 single nucleotide polymorphisms for allelic association with AMD in two independent case-control cohorts of German origin (AMD(combined) n=1166; controls(combined) n=945). Significant association was found across a 60 kb region of high linkage disequilibrium harboring two genes PLEKHA1 and hypothetical LOC387715. The strongest association (P=10(-34)) centered over a frequent coding polymorphism, Ala69Ser, at LOC387715, strongly implicating this gene in the pathogenesis of AMD. Besides abundant expression in placenta, we demonstrate weak expression of LOC387715 in the human retina. At present, however, there is no functional information on this gene, which appears to have evolved recently within the primate lineage. The joint contribution of the common risk allele at LOC387715, Ala69Ser, and at CFH, Tyr402His, was assessed in our case-control population, which suggests an additive model indicating an independent contribution of the two gene loci to disease risk. Our data show a disease odds ratio of 57.6 (95% CI: 37.2, 89.0) conferred by homozygosity for risk alleles at both CFH and LOC387715 when compared with the baseline non-risk genotype.     

Histamine release during induction of anaesthesia and preparation for operation in patients undergoing general surgery: Incidence and clinically severe cases

Histamine release events were shown in a prospective randomized controlled trial in patients undergoing elective general surgery with an extraordinarily high incidence: 73 per cent. This high incidence was explained by several factors: — the sample size which was much greater than in previous studies — the improved plasma histamine assay — the precise definition of histamine release in clinical conditions and its measurement at the top of Bateman functions — the standardized induction of anaesthesia and preparation of the surgical patient — and finally the considerable number of cancer patients since more than 60% of the reactions >5 ng/ml occurred in this group which comprised only 20% of the study population.

Two cases of life-threatening anaphylactoid reactions occurred in this trial corresponding to an incidence of 1 per cent. This was — again — very high compared to previous epidemiological studies. Both cases were again cancer patients and occurred in the placebo group — information given by the external study advisory group for further treatment of the individual patient.

The data on the high incidence of histamine release including the high incidence of life-threatening reactions favourrationally a preoperative H₁ ⁻+H₂-prophylaxis with the drugs used in this study: dimetindene and cimetidine. The question of the incidence was one of the unsettled problems which led to this trial. Analysis of the first 180 patients already answered this question more than we had ever expected.

     

Influence of extracellur Ca2+ on endogenous Cl− channels in Xenopus oocytes

Removal of Ca²⁺ from the external bath solution evoked marked depolarization and large currents (up to several microamperes) in voltage-clamped defolliculated oocytes of Xenopus laevis. The resulting current was not carried by a cation influx but was due to a huge Cl^– efflux, which could be strongly inhibited by the Cl^– channel blockers flufenamic acid and niflumic acid. Removal of Mg²⁺ or Ba²⁺ from the solutions had the same effects as removing Ca²⁺. The reversal potential of –12 mV also indicated that Cl^– channels were responsible for the large currents. Patch-clamp studies revealed a single-channel slope conductance of 90 pS. During oocyte maturation these channels remained active. The half-maximal Ca²⁺ concentration of about 20 M showed that quite low doses of extracellular Ca²⁺ profoundly influence the electrical properties of the oocyte membrane.     

Mosaic genes and mosaic chromosomes: intra- and interspecies genomic variation of Streptococcus pneumoniae

Streptococcus pneumoniae remains a major causative agent of serious human diseases. The worldwide increase of antibiotic resistant strains revealed the importance of horizontal gene transfer in this pathogen, a scenario that results in the modulation of the species-specific gene pool. We investigated genomic variation in 20 S. pneumoniae isolates representing major antibiotic-resistant clones and 10 different capsular serotypes. Variation was scored as decreased hybridization signals visualized on a high-density oligonucleotide array representing 1,968 genes of the type 4 reference strain KNR.7/87. Up to 10% of the genes appeared altered between individual isolates and the reference strain; variability within clones was below 2.1%. Ten gene clusters covering 160 kb account for half of the variable genes. Most of them are associated with transposases and are assumed to be part of a flexible gene pool within the bacterial population; other variable loci include mosaic genes encoding antibiotic resistance determinants and gene clusters related to bacteriocin production. Genomic comparison between S. pneumoniae and commensal Streptococcus mitis and Streptococcus oralis strains indicates distinct antigenic profiles and suggests a smooth transition between these species, supporting the validity of the microarray system as an epidemiological and diagnostic tool.     

Giant ragweed specific immunotherapy is not effective in a proportion of patients sensitized to short ragweed: analysis of the allergenic differences between short and giant ragweed

BACKGROUND: Short ragweed and giant ragweed pollen allergens are considered largely cross-reactive, and it is generally believed that 1 species is sufficient for skin testing and immunotherapy. However, in the area north of Milan (a zone widely invaded only by short ragweed), about 50% of patients submitted to injection specific immunotherapy with giant ragweed showed little or no clinical response, but showed an excellent outcome if they were shifted to short ragweed specific immunotherapy. OBJECTIVE: To investigate allergenic differences between short and giant ragweed. METHODS: IgE reactivity to short ragweed of sera from 16 patients allergic to ragweed was assessed by immunoblot before and after absorption with short and giant ragweed. Moreover, 41 ragweed-monosensitive patients underwent skin prick test with both ragweed species. RESULTS: In several cases, preabsorption of sera with giant ragweed extract was unable to inhibit IgE reactivity fully against both a 43-kd allergen and other allergens at different molecular weights in short ragweed. On skin prick test, short ragweed induced larger wheals than giant ragweed in the majority of patients, and 6 of 41 (15%) patients were strongly short ragweed-positive but giant ragweed-negative. The immunoblot with the serum from 1 of these subjects showed a strong IgE reactivity to short ragweed at about 43 kd in the absence of any reactivity to giant ragweed. CONCLUSION: Short and giant ragweed are not allergenically equivalent. Allergenic differences involve both the major allergens Amb a 1-2/Amb t 1-2 and some minor allergens. In patients allergic to ragweed, both diagnosis in vivo and immunotherapy should always be performed by using the ragweed species present in that specific geographic area.     

Immunological properties of the human Goodpasture target antigen.

IgE rheumatoid factor activity was found to be significantly elevated (P less than 0.01) using an ELISA assay when paired synovial fluid and sera from 13 patients with active RA were compared to ten control samples. Synovial fluid IgE RF activity was higher than predicted by diffusion alone in 7/11 (64%) of the RA synovial fluids studied when coefficients of diffusion were determined. The specificity of IgE RF activity as measured by the ELISA was confirmed using immunoaffinity chromatography. Mast cells, obtained by enzymatic dispersion of rheumatoid synovial tissue, were sensitized with sera containing either IgE antibodies directed against ragweed or IgE with RF activity. Histamine was released upon challenge with anti-IgE antibodies (33.2% +/- 11), ragweed antigen E (34.6% +/- 11), or aggregated gamma globulin (47.6% +/- 17.9). No histamine release was observed if antigen challenge occurred in the absence of appropriate sensitization, with C3 anaphylatoxin, or after immunoadsorption of IgE from sera containing IgE RF activity.     

Cytochemische Untersuchungen an Merozoiten von Babesia ovis und Babesia bigemina (Piroplasmidea) in der Zeckenhämolymphe

Zusammenfassung An Merozoiten von Babesia ovis in der Hämolymphe von Rhipicephalus bursa und Merozoiten von Babesia bigemina in der Hämolymphe von Boophilus microplus und Boophilus decoloratus wurden cytochemische Tests auf DNS, RNS, Lipide und Polysaccharide durchgeführt. Der Merozoitenkern ist feulgenpositiv. Die den Kern undifferenzierter Merozoiten kompakt ausfüllende DNS konzentriert sich in differenzierten Formen an der Kernperipherie. Im Cytoplasma ist kein feulgenpositives Material nachzuweisen. RNS ist im gesamten Cytoplasma der undifferenzierten Merozoiten reichlich vorhanden. In differenzierten Merozoiten akkumuliert die hauptsächliche Masse der RNS in Kernnähe und bildet besonders bei B. ovis intensiv pyroninophile perinukleäre Konzentrationen. Nukleoläre RNS war nicht nachzuweisen. In einem Teil der Merozoiten sind Lipide in geringer Menge vorhanden. PAS-positives Material (Glykogen) scheint in den untersuchten Formen zu fehlen.

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A cytochemical study on merozoites of babesia ovis and babesia bigemina (piroplasmidea) in the hemolymph of ticks

Summary Merozoites of Babesia ovis in the hemolymph of Rhipicephalus bursa and of Babesia bigemina in the hemolymph of Boophilus microplus and Boophilus decoloratus were tested cytochemically for DNA, RNA, lipids and polysaccharides. The nucleus of the merozoites is Feulgen positive. In incompletely developed merozoites the nucleus is uniformly packed with DNA. In fully developed merozoites the DNA-material is concentrated in the peripheral zone of the nucleus. No Feulgen positive material was detected in the cytoplasm of the merozoites. Abundant amounts of RNA occur in all of the cytoplasm of incompletely developed merozoites. In fully developed merozoites, most of the RNA-material is concentrated in the vicinity of the nucleus, where intensely stained pyroninophilic areas were observed, especially in merozoites of B. ovis. No nucleolar RNA was detected. Some merozoites contain small amounts of lipids. PAS positive material is obviously absent in the merozoites tested in this study.

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Mit Unterstützung der Deutschen Forschungsgemeinschaft.     

Visuomotor control within a distributed parieto-frontal network

The aim of this functional magnetic resonance imaging study was to investigate differences in visuomotor control with increasing task complexity. Twelve right-handed volunteers were asked to perform their signature under different degrees of visual control: internally generated movement with closed eyes, signing with open eyes, tracking the line of the projected signature forwards, and tracking the line of the projected signature backwards. There was a gradual onset and disappearance of activation within a distributed network. Parietal, lateral and medial frontal brain areas were activated during all conditions, confirming the involvement of a parieto-frontal system. The weight of activation shifted with increasing task complexity. Internally generated movements activated predominantly the inferior parietal lobule and the ventral premotor cortex, as well as the rostral cingulate area, pre-supplementary motor area (pre-SMA) and SMA proper. Opening the eyes reduced SMA and cingulate activation and activated increasingly the occipito-parietal areas with higher task complexity. Visually guided movements produced an activation predominantly in the superior parietal lobule and dorsal premotor cortex. This study bridges human activation studies with the results of neurophysiological studies with monkeys. It confirms a gradual transition of visuomotor control with increasing task complexity within a distributed parieto-frontal network.     

Immunohistochemical localization of neurofilaments and neuron-specific enolase in 29 cases of neuroblastoma.

Twenty-nine neuroblastomas have been examined with the use of rabbit antibodies specific for each of the three neurofilament polypeptides, with a monoclonal antibody specific for the NF-L polypeptide, and with a rabbit antibody specific for neuron-specific enolase. When frozen material was used, all neuroblastomas were positive with the neurofilaments antibodies. When alcohol-fixed paraffin-embedded material was used, neurofilament staining was weaker and the fixation procedure appeared to destroy the epitopes recognized by the NF-L antibodies preferentially. Although all neuroblastomas were positive for neurone-specific enolase, so were two rhabdomyosarcomas, suggesting that NSE is not an appropriate marker to distinguish the different small blue cell tumors of children.