A single VH family and long CDR3s are the targets for hypermutation in bovine immunoglobulin heavy chains

Summary: Bovine immunoglobulins are made from genes belonging to a small family of closely related Vh, genes. In this respect cattle resemble all species of domesticated mammals, which also use one VH family The family, named BoVH1, is homologous to the mouse Q52 family, and there are no more than 20 genes of this family in the bovine genome. Another feature of bovine heavy chains is the use of long CDR3s, which have an average of 21 codons. It seems that there are several families of long, closely related D genes rich in glycine and tyrosine responsible for this length. Sequences described as targets for mutations in other species can be found in CDR1, CDR2, and the putative D genes. The mutation mechanism starts at some point between late fetal stage and birth and seems to be antigen Independent. Diversity seems to be generated by hypermutation, although other mechanistns cannot be discomited at this time. Contrary to humans and mice, which have several Vh gene families comprising more than 100 genes, cattle use only a few genes and long CDR3s followed by somatic mutation to generate the necessary diversity to recognize the universe of antigens they will encounter during their life.     

Needs assessment for persons with severe mental illness: What services are needed for successful community living?

The development and implementation of effective community support systems are goals of many public mental health authorities who are attempting to shift the focus and dollars for mental health services from inpatient to community care. This article presents the results of a survey which asked 90 community mental health agency case managers to assess the community support and residential needs of over 1400 of their clients. Medication monitoring and therapy were rated high priority needs. Psychosocial treatment, day and vocational activities also ranked high. Survey responses regarding residential services indicated a need for more supported and supervised options.The study reported was a collaborative effort by county and agency staff.     

Inhibition of 2-nitropropane-induced rat liver DNA and RNA damage by benzyl selenocyanate

We observed that pretreatment of male F344 rats with benzyl selenocyanate, a versatile organoselenium chemopreventive agent in several animal model systems, decreases the levels of DNA and RNA modifications produced in the liver by the hepatocarcinogen 2- nitropropane. To clarify the mechanisms involved, we pretreated male F344 rats with either benzyl selenocyanate, its sulfur analog benzyl thiocyanate, phenobarbital or cobalt protoporphyrin IX; the latter is a depletor of P450. We then determined (1) the ability of liver microsomes to denitrify 2-nitropropane, (2) effects on 2-nitropropane- induced liver DNA and RNA modifications and (3) amount of nitrate excreted in rat urine following administration of the carcinogen. Pretreatment with benzyl selenocyanate or phenobarbital increased the denitrification activity of liver microsomes by 217 and 765%, respectively, increased liver P4502B1 by 31- and 435-fold, respectively, decreased the levels of 2-nitropropane-induced modifications in liver DNA (29-70% and 17-30%, respectively) and RNA (67-85% and 30-50%, respectively), and increased the 24-h urinary excretion of nitrate by 157 and 209%, respectively. Pretreatment with benzyl thiocyanate had no significant effect on any of these parameters. Pretreatment with cobalt protoporphyrin IX decreased liver P4502B 1 by 87%, decreased the denitrification activity of liver microsomes by 76%, decreased the 24 h urinary excretion of nitrate by 88.5%, but increased the extent of 2-nitropropane-induced liver nucleic acid modifications by 17-67%. These results indicate that the metabolic sequence from 2-nitropropane to the reactive species causing DNA and RNA modifications does not involve the removal of the nitro group. Moreover, they suggest that benzyl selenocyanate inhibits 2-NP-induced liver nucleic acid modifications in part by increasing its detoxication through induction of denitrification, although it is evident that other mechanisms must also be involved.      

Comparative study of brain morphology in ants

Brain morphology, with special attention to the three dimensional form of the corpora pedunculata, was studied in thirteen species of ants, representing four subfamilies of Formicidae. The results can be summarized as follows. (1) The neural systems processing optic and olfactory information differ in the evolutionary history among the studied taxa. A positive correlation can be demonstrated in the phylogenetic history of the corpora pedunculata, central body, cerebral bridge and olfactory lobe, but not the optic lobe. Ant species with very large eyes and thus, probably, highly developed vision, show gigantic optic lobes, with no exaggeration of any other brain structure. (2) More social species have more complex chemical communication systems and better developed corpora pedunculata (more surface in foldings of the calyces) and olfactory lobes; however, this tendency seems to reverse in highly social species with a sophisticated polymorphic caste system: individuals of these species are generally less developed neurally. (3) There are differences between the form of the internal and external calyces of the corpora pedunculata, and these differences are proportionately more pronounced in species with complex social organization. (4) Individuals from different worker castes of the same species differ in their brain morphology, but each species shows a different pattern of variation among their castes. (5) Brain structure shows characteristic marks due to the different phylogenetic developments in the taxa studied. For example the trends in brain volume-body size ratio are different for the various subfamilies, suggesting a divergent phylogenetic history.     

Centrally active modulators of glutamate receptors facilitate the induction of long-term potentiation in vivo.

An experimental drug, 1-(1,3-benzodioxol-5-ylcarbonyl)piperidine, that facilitates glutamatergic transmission in brain after systemic administration was tested for its effects on the induction of long-term potentiation in the hippocampus of rats. Intraperitoneal injections of the drug markedly increased the degree and duration of long-term potentiation; similar results were obtained with an analogue of 1-(1,3-benzodioxol-5-ylcarbonyl)piperidine that was also found to improve retention of memory in a radial maze task and in an odor-matching problem. These results define tools for enhancing long-term potentiation in vivo and confirm an important prediction from the hypothesis that long-term potentiation is a substrate of memory.     

Pregnancy outcome associated with natural family planning (NFP): scientific basis and experimental design for an international cohort study

Although natural family planning (NFP) is a form of contraception without ostensible maternal risks (other than pregnancy), potential fetal risks could exist if aging gametes are involved in inadvertent fertilization. In the following report, we first review animal studies firmly establishing that aging sperm and aging oocytes (delayed fertilization) cause chromosomal abnormalities in mammals and other species. We next review human studies associating decreased coital frequency with trisomy and studies of NFP populations that generally show no increased frequency of anomalous offspring or spontaneous abortions. Our rationale for initiating an international cohort study is presented, along with the experimental design selected. Preliminary findings indicate that the experimental design chosen will indeed provide information allowing NFP safety to be assessed definitively.

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Resumen Aunque la planificación familiar natural (PFN) es una forma de anticoncepción sin riesgos maternos ostensibles, (fuera del embarzo) podrían existir posibles riesgos fetales di gametos que están envejeciendo son inadvertidamente fertilizados. La primera revisión de estudios en animales establece firmemente que espermatozoides y oocytos en envejecimiento (fertilización tardía), causan anormalidades cromosómicas en mamíferos y otras especies. A continuación revisamos estudios en humanos que asocian la disminución de la frecuencia coital con trisomía, y estudios de poblaciones practicando PFN que generalmente no muestran aumento en la frecuencia de descendientes anormales o de abortos espontáneos. Presentamos nuestras razones para iniciar el estudio de una cohorte internactional ademas del diseño experimental elegido proveerá información alegando que la inocuidad de la PFN sea definitivamente valorada.

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Resumé Bien que le planning familial naturel (PFN-NFP) soit une forme de contraception ne présentant pas de risques manifestes pour la mère (autres qu'une grossesse), il pourrait y avoir des risques potentiels pour le foetus si des gamètes âgés sont par inadvertance fécondés. Nous passons en revue tout d'abord des études effectuées sur des animaux, établissant fermement que le sperme veillissant et les oocytes vieillissants (fécondation retardée) provoquent des anomalies chromosomales chez les mammifères et d'autres espèces. Nous examinons ensuite des études sur des humains, qui associent diminution coitale et trisomie, et des études de populations pratiquant le PFN, qui ne révèlent généralement pas de fréquence accrue d'enfants anormaux ou d'avortements spontanés. Cette communication expose la raison pour laquelle nous avons entrepris une étude sur une cohorte internationale, ainsi que le concept d'expérimentation que nous avons choisi. Les constatations préliminaires indiquent que ce concept fournira véritablement des informations qui permettront d'évaluer de façon définitive la sécurité du PFN.

     

An optimal regulator for linear systems with multiple state and input delays

This paper presents an optimal regulator for a linear system with multiple state and input delays and a quadratic criterion. The optimal regulator equations are obtained reducing the original problem to the linear‐quadratic regulator design for a system without delays. Performance of the obtained optimal regulator is verified in the illustrative example against the best linear regulators available for the linear system without delays and for two rational approximations of the original time‐delay system. Simulation graphs demonstrating better performance of the obtained optimal regulator with respect to the criterion value are included. Copyright © 2006 John Wiley & Sons, Ltd.     

Positive and negative symptoms covary during clozapine treatment in schizophrenia

Although negative symptoms were traditionally considered to be unresponsive to neuroleptic medication, recent studies have demonstrated that negative symptoms do improve during neuroleptic treatment and that such improvement tends to occur concurrently with improvement in positive symptoms. Clozapine is an atypical neuroleptic that is effective in a significant proportion of otherwise neuroleptic-nonresponsive schizophrenic patients; in contrast to conventional neuroleptics, clozapine is also purported to possess unique efficacy in the amelioration of negative symptoms. How clozapine-associated reduction in negative symptoms relates to change in positive symptoms is not clear. To study the relationship between change in positive and negative symptoms during clozapine treatment, we monitored symptomatology in 40 DSM-III-R schizophrenic patients before and about 8 weeks after a trial of clozapine. Both positive and negative symptoms improved significantly. There was a significant correlation (r = .63,p <.01) between change in positive symptoms and change in negative symptoms; as with conventional neuroleptics, negative symptoms improved concomitantly with positive symptoms during clozapine treatment. Clozapine's apparent greater efficacy on negative symptoms may be related to its greater efficacy on positive symptoms in otherwise neuroleptic-refractory patients and its lesser propensity to cause extrapyramidal side-effects.     

Studies on the effects of the antiandrogen cyproterone acetate on social encounters between pairs of male mice

An attempt was made in two experiments to reinvestigate the effects of the antiandrogen cyproterone acetate (CA) on mouse social behavior in a variety of ethologically-assessed paired encounters. The data confirm that CA reduces offense (threat and attack) in animals when both subjects receive the material but that CA has no such action in other pairings. This suggests that CA's major suppressive effect on "hostility" is expressed in mice via a reduction in "attack-promoting" pheromone production. Indeed, there was evidence in the more chronic study that CA, could augment (via a central mechanism?) offense in subjects paired with docile anosmic opponents. Changes in defense were largely responses to variations in the degree of attack to which animals were subjected. The antihormone also had actions on other aspects of behavior including sexual activity, social investigation and immobility in such tests. CA had a potent suppressive action on the weights of sex accessory glands. The data do not suggest that CA can be used as a specific antihostility agent.     

Quality assurance problems in clinical hyperthermia and their impact on therapeutic outcome: a Report by the Radiation Therapy Oncology Group

Since February 1981, 300 patients with superficial measurable tumors were randomized on an RTOG protocol (81-04) involving fractionated radiation therapy (4.00 Gy twice weekly for a total of 32.00 Gy), either alone or followed immediately by hyperthermia (42.5 degrees C, 60 min). This is a report of 218 eligible patients with single lesions: 107 treated with radiotherapy alone (RT), 111 with radiotherapy plus hyperthermia (RT + HT). Only 56% of the 24 tumors less than 3 cm and 36% of the 53 lesions larger than 3 cm received what was felt to be "adequate" therapy (greater than or equal to 29 Gy and 8 heating sessions). Overall complete response (CR) was observed in 28% of the patients treated with RT, and 32% of the patients receiving RT and heat. Response has been found in previous analyses of this and other RTOG studies to be significantly related to both maximum tumor diameter (less than 3 or greater than or equal to 3 cm) and site/histology (breast/adenocarcinoma, head and neck/squamous, or other site/histologies). In the head and neck tumors less than 3 cm in diameter there was no difference in CR with irradiation alone or combined with hyperthermia (46% vs 43%). However, in the breast, and trunk and extremities a better CR rate was noted with irradiation and heat (55% and 67%) than with irradiation alone (33% and 0). In lesions less than 3 cm treated with irradiation and heat the probability of remaining in response was 80% compared with 15% with irradiation alone. In lesions larger than 3 cm no difference in CR was observed in either treatment group. It has been hypothesized that the response rate is higher in patients with smaller lesions (less than 3 cm) and in breast/chest wall, trunk/extremity lesions because these tumors and anatomical sites are easier to heat adequately. Problems encountered in correlating tumor response with quality of heating include less than optimal heating in larger lesions and the limited ability of current thermometry to accurately represent the temperature distribution in a tumor. Furthermore, differences in equipment and treatment practices among institutions add to the variability in heat administration data collected. In addition, tumor response may be difficult to judge because of short survival of some patients and occasionally rapid tumor regression that may cause necrosis which may be misinterpreted as persistent tumor.(ABSTRACT TRUNCATED AT 400 WORDS)