Medfly eradication in California:

The impact of malathion-bait sprays (directed against medfly, Ceratitis capitata [Wiedemann]) on an endemic gall midge (Rhopalomyia californica Felt) and its parasitoids was investigated during 1982–83 in the south San Francisco Bay area of northern California. In a heavily sprayed area (Woodside), a population explosion of the midge was detected following 24 applications of malathion bait. The midge population reached levels ca. 90x greater than those observed in an adjacent unsprayed area (Jasper Ridge). In a moderately sprayed area (Portola Valley), the midge population increased as much as 5x that observed in the adjacent unsprayed area (Jasper Ridge), following 12 applications of malathion bait. In laboratory tests, the malathion bait was toxic to both the midge and its parasitoids. The major parasitoids were Torymus koebelei (Huber), Zatropis capitis Burks, Platygaster californica (Ashmead) and Mesopolobus sp. Population increases of the midge following malathion-bait sprays were attributed to destruction of parasitoids and other natural enemies of the midge. If the environmental impact of malathion-bait sprays is related to the number of applications (as suggested in this study), then it would be worthwhile to determine the appropriate bait-spray strategy for a given situation, so as to minimize adverse effects on nontarget species, yet insure suppression or eradication of medfly.

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Résumé L'impact des pièges tratiés au malathion (destinés à Ceratitis capitata Wiedem) sur Rhopalomyia californica Felt et ses parasitoïdes a été examiné en 1982–1983 dans le sud de la zone de la baie de San Francisco en Californie. Dans une zone fortement traitée (Woodside), une explosion de population a été décelée après 24 traitements. La population de R. californica a atteint des niveaux 90 fois supérieurs à ceux observés dans une zone contiguë non traitée (Jasper Ridge). Dans une zone modérément traitée (Portola Valley), avec 12 traitement, la population de R. californica a atteint jusqu'a 5 fois celle de Jasper Ridge. Au laboratoire, le piège à malathion a été toxique tant pour R. californica que pour ses parasitoïdes, dont les principaux étaient: Torymus koebelei (Huber), Zatropis capitis Burks, Platygaster californica(Ashmead) et Mesopolobus sp. L'accroissement de la population de C. capitata après traitement a été attribué à la destruction de parasitoïdes et d'autres ennemis naturels. Si l'effet su l'environnement du traitement est lié au nombre d'interventions (comme le suggère cette étude), alors cela vaudrait la peine de définir une stratégie de traitement appropriée à une situation donnée, de façon à minimiser les effets négatifs sur des espèces non visées, tout en assurant la suppression ou l'éradication de C. capitata.

     

Digitalis-induced cell stimulation : Support for a two-receptor model

Digitalis glycosides are potent polyclonal B cell activators in digitalis-resistant species. The stimulatory capacity is not mediated via their interaction with Na⁺, K⁺ ATPase (EC 3.6.1.3) but is due to binding to a distinct mitogen receptor located in the cell membrane. Potassium was found to influence the dose-response profile of digitalis-induced mitogenesis, thus suggesting a physiological relationship between the stimulating receptor on lymphoid cells and the Na⁺, K⁺ ATPase.     

Genetic control of effector cell characteristics: con A-induced suppressor cells carry H-2 I region encoded determinants.

Activation of splenic lymphocytes with Con A leads to the formation of suppressor cells capable of interfering with the activity of several polyclonal B-cell-activating substances. Thus, these suppressor cells, or their products, most probably act directly on B cells. Suppressor cells could be recovered from the effluent cell population of nylon wool columns, and they were absent from the spleens of athymic nude mice. Furthermore, they were absent from the thymus of normal as well as cortison-treated mice. Cortisone treatment did not abolish the formation of Con A-induced suppressor cells in the spleen. Treatment of activated suppressor cells with antisera specific for distinct products of the H-2 I region revealed that they carried I-J cell surface antigens. We conclude that the suppressor cells in our test system, which unlike other Con A-induced suppressor cell populations have a direct effect on B cells, had antigenic characteristics similar to those previously described for I-J carrying suppressor cells.     

Development of bis-locked nucleic acid (bisLNA) oligonucleotides for efficient invasion of supercoiled duplex DNA

In spite of the many developments in synthetic oligonucleotide (ON) chemistry and design, invasion into double-stranded DNA (DSI) under physiological salt and pH conditions remains a challenge. In this work, we provide a new ON tool based on locked nucleic acids (LNAs), designed for strand invasion into duplex DNA (DSI). We thus report on the development of a clamp type of LNA ON—bisLNA—with capacity to bind and invade into supercoiled double-stranded DNA. The bisLNA links a triplex-forming, Hoogsteen-binding, targeting arm with a strand-invading Watson–Crick binding arm. Optimization was carried out by varying the number and location of LNA nucleotides and the length of the triplex-forming versus strand-invading arms. Single-strand regions in target duplex DNA were mapped using chemical probing. By combining design and increase in LNA content, it was possible to achieve a 100-fold increase in potency with 30% DSI at 450 nM using a bisLNA to plasmid ratio of only 21:1. Although this first conceptual report does not address the utility of bisLNA for the targeting of DNA in a chromosomal context, it shows bisLNA as a promising candidate for interfering also with cellular genes.     

Re-expression of proteins involved in cytokinesis during cardiac hypertrophy

Cardiomyocytes stop dividing after birth and postnatal heart growth is only achieved by increase in cell volume. In some species, cardiomyocytes undergo an additional incomplete mitosis in the first postnatal week, where karyokinesis takes place in the absence of cytokinesis, leading to binucleation. Proteins that regulate the formation of the actomyosin ring are known to be important for cytokinesis. Here we demonstrate for the first time that small GTPases like RhoA along with their downstream effectors like ROCK I, ROCK II and Citron Kinase show a developmental stage specific expression in heart, with high levels being expressed in cardiomyocytes only at stages when cytokinesis still occurs (i.e. embryonic and perinatal). This suggests that downregulation of many regulatory and cytoskeletal components involved in the formation of the actomyosin ring may be responsible for the uncoupling of cytokinesis from karyokinesis in rodent cardiomyocytes after birth. Interestingly, when the myocardium tries to adapt to the increased workload during pathological hypertrophy a re-expression of proteins involved in DNA synthesis and cytokinesis can be detected. Nevertheless, the adult cardiomyocytes do not appear to divide despite this upregulation of the cytokinetic machinery. The inability to undergo complete division could be due to the presence of stable, highly ordered and functional sarcomeres in the adult myocardium or could be because of the inefficiency of degradation pathways, which facilitate the division of differentiated embryonic cardiomyocytes by disintegrating myofibrils.     

Measles virus matrix protein specifies apical virus release and glycoprotein sorting in epithelial cells

In polarized epithelial cells measles virus (MV) is predominantly released at the apical cell surface, irrespective of the sorting of its two envelope glycoproteins F and H. It has been reported previously that the viral matrix (M) protein modulates the fusogenic capacity of the viral envelope glycoproteins. Here, extant MV mutants and chimeras were used to determine the role of M protein in the transport of viral glycoproteins and release of progeny virions in polarized epithelial CaCo2 cells. In the absence of M, envelope glycoproteins are sorted to the basolateral surface, suggesting that they possess intrinsic basolateral sorting signals. However, interactions of M with the glycoprotein cytoplasmic tails allow M-glycoprotein co-segregation to the apical surface, suggesting a vectorial function of M to retarget the glycoproteins for apical virion release. Whereas this may allow virus airway shedding, the intrinsic sorting of the glycoproteins to the basolateral surface may account for systemic host infection by allowing efficient cell-cell fusion.     

Path integration and the neural basis of the 'cognitive map'

The hippocampal formation can encode relative spatial location, without reference to external cues, by the integration of linear and angular self-motion (path integration). Theoretical studies, in conjunction with recent empirical discoveries, suggest that the medial entorhinal cortex (MEC) might perform some of the essential underlying computations by means of a unique, periodic synaptic matrix that could be self-organized in early development through a simple, symmetry-breaking operation. The scale at which space is represented increases systematically along the dorsoventral axis in both the hippocampus and the MEC, apparently because of systematic variation in the gain of a movement-speed signal. Convergence of spatially periodic input at multiple scales, from so-called grid cells in the entorhinal cortex, might result in non-periodic spatial firing patterns (place fields) in the hippocampus.     

Grid cells use HCN1 channels for spatial scaling

Entorhinal grid cells have periodic, hexagonally patterned firing locations that scale up progressively along the dorsal-ventral axis of medial entorhinal cortex. This topographic expansion corresponds with parallel changes in cellular properties dependent on the hyperpolarization-activated cation current (Ih), which is conducted by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. To test the hypothesis that grid scale is determined by Ih, we recorded grid cells in mice with forebrain-specific knockout of HCN1. We find that, although the dorsal-ventral gradient of the grid pattern was preserved in HCN1 knockout mice, the size and spacing of the grid fields, as well as the period of the accompanying theta modulation, was expanded at all dorsal-ventral levels. There was no change in theta modulation of simultaneously recorded entorhinal interneurons. These observations raise the possibility that, during self-motion-based navigation, Ih contributes to the gain of the transformation from movement signals to spatial firing fields.     

First report of molecular diagnosis of Tunisian hemophiliacs A: identification of 8 novel causative mutations

ABSTRACT: INTRODUCTION: Hemophilia A is an X linked recessive hemorrhagic disorder caused by mutations in the F8 gene that lead to qualitative and/or quantitative deficiencies of coagulation factor VIII (FVIII). Molecular diagnosis of hemophilia A is challenging because of the high number of different causative mutations that are distributed throughout the large F8 gene. Molecular studies of these mutations are essential in order to reinforce our understanding of their pathogenic effect responsible for the disorder. Aim In this study we have performed molecular analysis of 28 Tunisian hemophilia A patients and analyzed the F8 mutation spectrum. METHODS: We screened the presence of intron 22 and intron 1 inversion in severe hemophilia A patients by southern blotting and polymerase chain reaction (PCR). Detection of point mutations was performed by dHPLC/sequencing of the coding F8 gene region. We predict the potential functional consequences of novel missense mutations with bioinformatics approaches and mapping of their spatial positions on the available FVIII 3D structure. RESULTS: We identified 23 different mutations in 28 Tunisian hemophilia A patients belonging to 22 unrelated families. The identified mutations included 5 intron 22 inversions, 7 insertions, 4 deletions and 7 substitutions. In total 18 point mutations were identified, of which 9 are located in exon 14, the most mutated exonic sequence in the F8 gene. Among the 23 mutations, 8 are novel and not deposited in the HAMSTeRS database nor described in recently published articles. CONCLUSION: The mutation spectrum of Tunisian hemophilia A patients is heterogeneous with the presence of some characteristic features. Virtual slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1693269827490715.     

Response to Therapeutic Plasma Exchange as a Rescue Treatment in Clinically Isolated Syndromes and Acute Worsening of Multiple Sclerosis: A Retrospective Analysis of 90 Patients

Objectives

Experience with therapeutic plasma exchange (TPE) for acute relapses in clinically isolated syndrome (CIS) or multiple sclerosis (MS) patients has been derived from small and inhomogeneous patient populations so far. In the present study, we retrospectively evaluated features associated with TPE response in a larger cohort of CIS and MS patients with acute worsening of disease.

Participants

Ninety CIS and MS patients with acute relapses or acute worsening of symptoms were firstly treated with TPE. The population consisted of 62 women and 28 men with a median age of 38 years (range 18–69 years).

Outcome Measures

Primary endpoint was the clinical response to TPE, focused on the functional improvement of the target neurologic deficit. Secondary endpoint was an improvement in expanded disability status scale (EDSS) scoring.

Results

A clinical response to TPE was observed in 65 out of 90 patients (72.2%), with marked improvement in 18 (20.0%) and moderate improvement in 47 out of 90 patients (52.2%). The median EDSS was reduced from 3.75 before to 3.0 after TPE (p = 0.001). Response to TPE was significantly more frequent in patients with relapsing courses of disease (CIS, RR-MS, p = 0.001), no disease modifying drugs (p = 0.017), gadolinium-positive (Gd⁺) MRI lesions (p = 0.001) and EDSS ≤ 5.0 before TPE (p = 0.014). In the multiple logistic regression analysis only the detection of Gd⁺ MRI lesions was significantly altered (p = 0.004).

Conclusion

Clinical response to TPE was achieved in the majority of our patients. We identified clinical and diagnostic features in CIS and MS relapses that might be helpful to identify patients responding to TPE. Gd⁺ MRI lesions before treatment were the best predictor of the response to TPE in our cohort.