Receptor mechanism of the neuroprotective effect of GABAergic agents

Molecular genetic investigation of a female infant with Beckwith-Wiedemann syndrome (BWS) showed loss of IGF2 imprinting but no evidence of uniparental disomy. In addition, a deletion of chromosome 18q22.1 was identified in this infant without clinical features of 18q-syndrome (microcephaly, short stature, hypotonia). The association of a chromosome 18 deletion and BWS may be coincidental or may indicate the location of a trans activating regulator element for maintenance of IGF2 imprinting.     

Micronutrients as chemopreventive agents

The concept of chemoprevention of cancer by micronutrients is based upon evidence from human epidemiology and from studies of animal carcinogenesis models for cancer-inhibiting potential of certain minerals and vitamins. These micronutrients are diverse with respect to chemical structures and physiological effects, and include calcium, selenium, carotenoids, and vitamins A, C, D and E. The dietary intake of various micronutrients has been observed to alter significantly the incidence and mortality of a variety of human cancers including those of the oesophagus, stomach, colon, breast and cervix. Studies of laboratory animal models have also provided relevant mechanistic and efficacy data on the role of specific micronutrients as well as minor non-nutrients of dietary origin in the carcinogenic process. Micronutrients and such minor non-nutrients have been found to modulate the formation and bioactivation of carcinogens, modify the promotion and progression of carcinogenesis, alter cellular and host defences, and affect cellular differentiation-ultimately leading to variations in tumour incidences. Our understanding of biochemical and biological mechanisms of carcinogenesis and of inhibition of initiation, promotion and progression by particular micronutrients-both naturally occurring forms and their synthetic analogues-has made it possible to develop strategies for clinical intervention by these agents. It is possible that intervention with individual micronutrients and minor non-nutrients, and/or with a combination of such compounds with different modes of action, will prevent, delay or reverse the process of carcinogenesis and thus reduce the incidence of and mortality due to human cancers. A number of Phase II clinical trials have been initiated with the objective of identifying and evaluating intermediate biomarkers that will be used as surrogate end points for cancer. Several surrogate end points have been standardized and validated for their specificity. The results are very encouraging.     

Faculty as change agents

Although the technical world in which medicine exists is rapidly and constantly changing, the educational world in which the institution exists is extremely resistant to change. Professional organizations are themselves resistant to change. The author explores these reasons and offers suggestions for the implementation of positive change.     

Protease inhibitors as antiviral agents

Currently, there are a number of approved antiviral agents for use in the treatment of viral infections. However, many instances exist in which the use of a second antiviral agent would be beneficial because it would allow the option of either an alternative or a combination therapeutic approach. Accordingly, virus-encoded proteases have emerged as new targets for antiviral intervention. Molecular studies have indicated that viral proteases play a critical role in the life cycle of many viruses by effecting the cleavage of high-molecular-weight viral polyprotein precursors to yield functional products or by catalyzing the processing of the structural proteins necessary for assembly and morphogenesis of virus particles. This review summarizes some of the important general features of virus-encoded proteases and highlights new advances and/or specific challenges that are associated with the research and development of viral protease inhibitors. Specifically, the viral proteases encoded by the herpesvirus, retrovirus, hepatitis C virus, and human rhinovirus families are discussed.     

1,3-Dimethylpyrimidoheterocycles as antibacterial agents

1,3-Dimethylbarbituric acid was used as a versatile precursor for the preparation of annelated pyranopyrimidines 2 and 3a-c besides pyrrolopyrimidine 12. The isolated pyrazolopyrimidines 8a-c and 10 and fused pyrazolopyrimidines 14a-d were also synthesized. In addition the new obtained pyrimidoheterocycles were subjected to bacterial testings.     

Thienocycloheptapyridazines as new muscarinic agents

A series of thienocycloheptapyridazines (3aa-dd), structurally related to Minaprine, was synthesized and compounds tested for their affinity towards muscarinic receptors. All of them showed Ki values in the micromolar range towards both the antagonist 3H-QNB and the agonist 3H-OXO-M, thus indicating that they act as antagonists at the muscarinic receptors. Moreover a theoretical study was performed on their interaction behaviour with a three dimensional (3-D) model of the human m1 muscarinic receptor.     

Mothers as family change agents.

Studied the impact of a counseling program for mothers on the perceptions and behavior of family members. The mother, father, and 1 8-12 yr old problem child of 13 experimental and 11 control families were evaluated before and after 7 weekly counseling sessions. Pre- and postexperimental measures included the Family Concept Q Sort, a family decision-making task, and a behavioral data chart maintained by the mother. The experimental spouses experienced a significant increase in perceived family integration. The experimental families reflected a significant increase in the number of positive responses and a significant decrease in the number of negative responses used by the 3 family members. The undesirable behaviors of problem children within the experimental families decreased significantly. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Dicationic diarylfurans as anti-Pneumocystis carinii agents

Seven dicationic 2,5-diarylfurans have been synthesized, and their interactions with poly(dA-dT) and the duplex oligomer d(CGCCAATTCGCG)2 were evaluated by Tm measurements. The inhibition of topoisomerase II isolated from Giardia lamblia, the inhibition of growth of G. lamblia in cell culture by these furans, and the effectiveness of these compounds against Pneumocystis carinii in the immunosuppressed rat model have been assessed. Strong binding affinities to poly(dA-dT) and to the oligomer were observed for the dicationic furans, and the interaction strength is directly correlated to the biological activity of the compounds. An X-ray structure for the complex of the dicationic amidine derivative, 2,5-bis(4-guanylphenyl)furan (1), with the oligomer demonstrates the snug fit of these compounds with the AATT minor-groove binding site and hydrogen bonds to AT base pairs at the floor of the minor groove. The stronger DNA binding molecules are the most effective inhibitors of topoisomerase II and G. lamblia in cell culture, and there is a correlation for both DNA interaction and topoisomerase II inhibition with the biological activity of these compounds against G. lamblia. Compound 1 is the most effective against P. carinii, it is more active and less toxic than pentamidine on intravenous administration and it is also effective by oral dosage. The results presented here suggest a model for the biological action of these compounds in which the dication first binds in the minor groove of DNA and forms a complex that results in the inhibition of the microbial topoisomerase II enzyme.     

Ischemia-modulating and neuroprotective drugs

A case of cytomegalovirus pneumonia occurring in a patient affected with AIDS is reported. The treatment of this disease is still difficult and remission of CHV-pneumonia after therapy with foscarnet is emphasized.     

Parents as agents of career development.

This study tested the effectiveness of a program for parents to help their adolescent children in career planning. In a pretest–posttest control group design involving 20 families in the experimental group and 20 families as a wait-listed control group, a multivariate analysis of variance (MANOVA) was used to test improvement on five variables concerned with parent–child relations and career development. The MANOVA yielded a significant effect for groups over time. Using an analysis of variance (ANOVA) with repeated measures, four of five univariate tests were also significant. In addition, all parents and six adolescents were interviewed after the program to gain a qualitative assessment of program effectiveness. Interview data tended to support the varied degrees of improvement that the adolescents showed on the quantitative measures. It was concluded that parents can function effectively in fostering the career development of their children, when provided with a structured program that they can follow. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Modulation of rat striatal glutamatergic response in search for new neuroprotective agents: evaluation of melatonin and some kynurenine derivatives

A national study of health and management of cattle in feedlots was conducted. Within this study, the prevalence of Salmonella spp. in fecal samples was determined. Fifty fecal samples were collected from each of 100 feedlots. Within each feedlot, 25 fresh fecal samples were collected from the floor of the pens of cattle which had been on feed the shortest and 25 from those on feed the longest periods of time. The total number of samples collected was 4,977; 2,484 and 2,495 from pens of cattle on feed the shortest and longest times, respectively. Salmonella spp. were recovered from 38% (38 of 100) of the feedlots. Salmonella spp. were recovered from 5.5% (273 of 4,977) of all samples and from 3.5% (88 of 2,484) and 7.4% (185 of 2,495) of samples from pens of cattle shortest and longest on feed, respectively. The most common serotype recovered was S. anatum (27.9%), followed by S. montevideo (12.9%), S. muenster (11.8%), S. kentucky (8.2%), and S. newington (4.3%). The most common serogroups identified were E1 (39.6%), C1 (20.7%), and B (10.4%). Shedding of the serotypes most commonly associated with human illness occurred infrequently (13 of 273: 4.8%). This study provides information on the status of Salmonella spp. from cattle in feedlots and may serve as baseline information for future studies.     

Hydroxyphthalocyanines as potential photodynamic agents for cancer therapy

A series of benzyl-substituted phthalonitriles, substituted at the 3-, 4-, and 4,5-positions, underwent varied condensations with phthalonitrile to give a series of protected (monohydroxy- and polyhydroxyphthalocyaninato)zinc(II) derivatives which were readily cleaved to give several hydroxyphthalocyanines (ZnPc) (phthalocyanine phenol analogues). Their efficacy as sensitizers for the photodynamic therapy (PDT) of cancer was evaluated on the EMT-6 mammary tumor cell line. In vitro, the 2-hydroxy ZnPc (32) was the most active, followed by the 2,3- and 2,9-dihydroxy ZnPc (39 and 45), with the 2,9,16-trihydroxy ZnPc (33) exhibiting the least activity. In vivo, the monohydroxy derivative 32 and the 2,3-dihydroxy derivative 39 were both efficient in inducing tumor necrosis at 1 micromol kg-1, but complete tumor regression was poor, even at 2 micromol/kg. In contrast, the 2,9-dihydroxy isomer 45, at 2 micromol kg-1, induced tumor necrosis in all animals treated, with 75% complete regression. These results underline the importance of the position of the substituents on the Pc macrocycle to optimize tumor response and confirm the PDT potential of the unsymmetrical Pcs bearing functional groups on adjacent benzene rings.     

Alpha-glucosidase inhibitors as potential broad based anti-viral agents

Fusion proteins were constructed between the porcine alpha2A-adrenoceptor and either wild-type (Cys351) or a pertussis toxin-resistant (Gly351) form of the G protein Gi1alpha. Addition of adrenaline to membranes expressing the fusion proteins resulted in concentration-dependent stimulation of their high affinity GTPase activity. The alpha2A-adrenoceptor-wild type Gi1alpha fusion protein produced substantially higher maximal stimulation of GTPase activity in response to adrenaline than that containing Gly351 Gi1alpha. Treatment of the fusion proteins as agonist-regulated enzymes allowed measurement of Vmax and turnover number for adrenaline-stimulation of the GTPase activity of each fusion construct. The turnover number of the alpha2A-adrenoceptor-Cys351 Gly Gi1alpha fusion protein was only 44'S, of that for the alpha2A-adrenoceptor-wild type Gi1alpha fusion protein. These data provide the first direct quantitative evaluation of the effects of a mutation of a G protein on the capacity of an agonist-occupied receptor to activate the mutant.