The GABA-benzodiazepine interaction fifteen years later

The main steps are presented that led to our current understanding of the interaction between benzodiazepine receptor ligands and the GABA_A receptor. The benzodiazepine receptor is a modulatory site located on the GABA_A receptor-chloride channel complex that has the unique property of being able to mediate positive as well as negative modulation of the chloride channel gating by the GABA_A receptor. Some critical issues concerning the structure of the receptor-channel complex remain to be clarified. Research on the benzodiazepine-GABA interaction has led to novel concepts of drug action and receptor function and provides the basis for a whole spectrum of potential drugs with therapeutic utility.Special issue dedicated to Dr. Erminio Costa     

Mitochondrial ATP synthase: fifteen years later

Mitochondrial Fo.F1-H+-ATP synthase is the main enzyme responsible for the formation of ATP in aerobic cells. An alternating binding change mechanism is now generally accepted for the operation of the enzyme. This mechanism apparently leaves no room for the participation of nucleotides and Pi other than sequential binding to (release from) the catalytic sites. However, the kinetics of ATP hydrolysis by mitochondrial ATPase is very complex, and it is difficult to explain it in terms of the alternating binding change mechanism only. Fo.F1 catalyzes both delta muH+-dependent ATP synthesis and ATP-dependent delta muH+ generation. It is generally believed that this enzyme operates as the smallest molecular electromechanochemical reversible machine. This essay summarizes data which contradict this simple reversible mechanism and discusses a hypothesis in which different pathways are followed for ATP hydrolysis and ATP synthesis. A model for a reversible switch mechanism between ATP hydrolase and ATP synthase states of Fo. F1 is proposed.     

MEK5/ERK5 pathway: The first fifteen years

While conventional MAP kinase pathways are one of the most highly studied signal transduction molecules, less is known about the MEK5 signaling pathway. This pathway has been shown to play a role in normal cell growth cycles, survival and differentiation. The MEK5 pathway is also believed to mediate the effects of a number of oncogenes. MEK5 is the upstream activator of ERK5 in many epithelial cells. Activation of the MEK-MAPK pathway is a frequent event in malignant tumor formation and contributes to chemoresistance and anti-apoptotic signaling. This pathway may be involved in a number of more aggressive, metastatic varieties of cancer due to its role in cell survival, proliferation and EMT transitioning. Further study of this pathway may lead to new prognostic factors and new drug targets to combat more aggressive forms of cancer.     

The last and the next hundred years of malariology

The founding fathers of malariology combined scientific originality, perseverance in research, strong characters, breadth of interest and social concern. A hundred years later research and understanding has made immense progress but the world still bears a huge burden of malaria. For the next century research requires both more specialism and a holistic range if it is to be used in control, requiring multidisciplinary team work. Environmental changes and interventions produce a dynamic and changing pattern of malaria, not the static one of the past. From the original parasite life cycle, research has analysed a series of other cycles at electron microscope, biochemical and genome levels on decreasing size scales and quantitative epidemiological cycles for control. Recent additions to these concepts have been stage-specific antigens, cycles of disease rather than parasites alone, considering populations of parasites rather than just cases, and also genetic variation in each component of the parasite-human host-vector triad. In this volume there emerges for the first time a coherent overall picture of the biomedical aspects of basic malariology as the interacting population genetics of malaria parasites, anophelines and people. This provides a coherent model for the new century dealing with the great biological malaria problems of drug resistance, vaccine development, insecticidal and net control and can feed, with socio-economic work, into the gathering renewal of control efforts. New work on large-scale changes of malaria in space and time enables us to be precise about effects of local and global environmental changes to predict epidemics. Future research will be as much about linking these different scales of understanding as control will be about linking different levels of the health system. The grim situation in poor holoendemic countries also requires practical support of the type that the founders of malariology were involved in. A coherent understanding needs to feed into the new control efforts, from Roll Back Malaria onwards, for the next century.     

Low transmission areas of schistosomiasis in Venezuela: consequences on the diagnosis, treatment, and control

Schistosomiasis low transmission areas as Venezuela, can be defined as those where the vector exists, the prevalence of active cases is under 25%, individuals with mild intensity of infection predominate and are mostly asymptomatic. These areas are the consequence of effective control programs, however, "silent" epidemiological places are difficult to trace, avoiding the opportune diagnosis and treatment of infected persons. Clinic and abdominal ultrasound have not shown to discriminate infected from uninfected persons in areas where besides Schistosoma mansoni, intestinal parasites are the rule. Under these conditions, serology remains as a very valuable diagnostic tool, since it gives a closer approximation to the true prevalence. In this sense, circumoval precipitin test, ELISA-SEA with sodium metaperiodate, and alkaline phosphatase immunoassay joined to coprology allow the identification of the "schistosomiasis cases". In relation to public health, schistosomiasis has been underestimated by the sanitary authorities and the investment on its control is being transferred to other diseases of major social and political relevance neglecting sanitary efforts and allowing growth of snail population. Some strategies of diagnosis and control should be done before schistosomiasis reemergence occurs in low transmission areas.     

Teratogenic Agent Information Centre: fifteen years of counseling and pregnancy follow-up.

The Teratogenic Agent Information Centre was set up 15 years ago in response to a growing demand from a medical profession struggling to cope with the problem of teratogenic risk. Our goal was to provide information on the real nature of the risk and to monitor all at-risk pregnancies so as to obtain data in a field where there are still, unfortunately, many gaps in our knowledge. The results of these 15 years have been most encouraging, in that physicians have been provided with specialized information and the follow-up of gestations had provided considerable clinical data, which has contributed to advancing our understanding in this domain.     

The red algal-higher fungi phylogenetic link: the last ten years

The review of the red algal theory for ancestry of Ascomycetes and Basidiomycetes published 10 years ago by the author is updated. Criticisms are answered and new data are discussed. The production of choline sulfate, lenthionine and lanosol are added to the biochemical similarities between red algae and higher fungi. Distribution of polyols is shown to be in favour of the origin of higher fungi from parasitic red algae. As predicted, NADP-linked glutamate dehydrogenase has been found in red algae, and additional reports of chitin in various algae have been published. New supporting data come from the ultrastructure of red algae: mitosis outside the Ceramiales and ultrastructure of vegetative cells and tetrasporocysts of Corallinaceae. On the other hand, the discovery of proplastids in Holmsella makes it less fungus-like. However, no decisive argument has yet been produced for or against the theory. Further light should be expected from protein and nucleic acid sequences. Promising partial sequences of cytochrome c have indeed been published for red algae but the published 5 S ribosomal RNA sequences have not proven relevant to the problem. Sequences of the slower-evolving large rRNA and cytochrome c of red algae could provide convincing evidence and are urgently needed.     

Malaria and social movements in Mexico: the last 60 years

The Mexican Ministry of Health's anti-malaria campaigns of the last sixty years have overlapped and interacted with both the World Health Organization's Global Eradication Program and a series of major political, social, and demographic movements in Mexico, including economic transformation, migration, urbanization, tourism, rural development, and the building of social and sanitary services. The authors argue that three decades of successful environmentally-oriented malaria work that integrated social and economic development was followed by the Global Campaign's insecticide-based approach that failed in both its economic and public health objectives, ultimately serving to block development efforts, particularly in poorer and southern states.     

Statistical methods for short-term tests in genetic toxicology: the first fifteen years.

Short-term tests (STTs) for detecting and assessing genotoxic or mutagenic effects have catalyzed the development of biostatistical methods for more than one decade. Most notably, the Ames Salmonella/microsome assay created statistical methodology with a range of applications going beyond genotoxicity. Early approaches with parametric statistical methods appeared to be insufficient and have been replaced by non-parametric ones requiring less restrictive distributional assumptions. There have also been successful attempts to use biomathematical models for establishing dose-response relationships. Overdispersion has been recognized as a major problem for the evaluation of mutagenic count data and methods to cope with it have became available. A theory of generalized linear modelling is emerging to combine dose-response modeling with much less restrictive distributional assumptions, while allowing the inclusion of concomitant factors arising from the experimental conditions. The methodological survey below reviews the present state of this development and is intended to promote further research into biostatistical issues and methods of analysis. Appropriate methods for the design and analysis of STTs are discussed. The progress for the Ames assay was only partially transmitted to the analysis of the large number of other short-term assays. Several such assays are reviewed with respect to their present state of statistical evaluation.     

The morphology of the cerebellum the last 25 years.

Advances in our knowledge of the subdivision and the development of the cerebellum during the last 25 years are reviewed. It is concluded that the longitudinal subdivision of the cerebellum has become firmly established in studies of the morphogenesis, the connections and the chemoarchitecture of the cerebellum. A complicated relationship exists between the transverse, lobular subdivision of the cerebellum and the distribution of different mossy fiber systems.     

Paleoprimatological research over the last 50 years: Foci and trends

Since 1930 the approach to fossil primates has undergone a twofold revolution, in more advanced taxonomic thinking, and in the growth of studies relating living primates to the interpretation of past forms. Great strides have also been made in discovering primate fossils–in 1930 there were some 58 genera of extinct primates known, and since then more than 65 new genera have been named. A major aspect of paleoprimatological research today is multidisciplinary field projects, which have accounted for a fuller understanding of dating and context. The application of functional morphology to aspects of primate evolution has allowed better understanding of primate locomotion, diet, and behavior.     

中国腹茧症15年流行病学特征

目的:探讨中国近15年腹茧症的流行病学特征和诊疗经验.方法:总结中国1994年1月-2009年1月问的腹茧症文献资料.结果:中国近15年共报道903例腹茧症,男女比例为1:1.35,平均年龄33.14岁,51.7%分布在华东地区,90.5%以不同表现形式的肠梗阻为主要表现,70.5%属于弥漫型腹茧症,40.2%患者无大网膜,手术以包膜切除为主.结论:腹茧症主要分布在华东地区,术前诊断困难,切除包膜和松解粘连是治疗本病的有效方法.