Methods of Therapy in Alcoholism

Although the philosophy of the community mental health center has been applied to alcoholism since the early part of this decade, it has been pursued much more intensively in recent years, and there has been a decentralization in the management of alcoholics in a series of stages from the jail or work-house to the state hospital and to the clinic and the community. The medical practitioner now has opportunity to treat the alcoholic in private practice.Advances have been made in two directions. Advances in medical management have included reinforcement of the importance of hydration and electrolyte balance, particularly magnesium. Psychopharmacology has contributed three drugs particularly important in the management of acute alcoholism and its complications. These drugs are chlordiazepoxide, chlorpromazine, and thioridazine. Another drug, Antabuse, when properly used, has proven extremely valuable as a deterrent.Equally important have been administrative advances. The importance of the environment and its manipulation has been recognized, and a series of institutional and non-institutional resources, such as clinics, half-way houses, foster homes, and Alcoholics Anonymous has made it less likely that a patient will be turned away without help.     

Reinforcement of reproductive isolation between adjacent populations in the Park Grass Experiment

It has been debated, ever since Charles Darwin and Alfred Russell Wallace disagreed about the matter, whether natural selection plays a role in reinforcing reproductive isolation during the earliest stages of speciation. Recent theory suggests that it can do so, but until now the empirical evidence has conspicuously lacked a case in which reinforcement has actually been observed to split a population. We show that this has occurred at least once in populations of the grass Anthoxanthum odoratum growing in the Park Grass Experiment where flowering time has shifted at the boundaries between plots. As a consequence, gene flow via pollen has been severely limited and adjacent populations that had a common origin at the start of the experiment in 1856 have now diverged at neutral marker loci.     

Protein phosphorylation in pancreatic islets: evidence for separate Ca2+ and cAMP-enhanced phosphorylation of two 57,000 Mr proteins

There is a phosphopeptide that has an Mr of 53,000 to 60,000 in insulin-secreting tissues and there is general agreement that this peptide can be phosphorylated in a calcium-dependent manner. The present report shows that there are at least two phosphoproteins with Mr's near 57,000 in rat pancreatic islet cytosol. One peptide has an Mr of 57,000, a pl of 7.5 - 8 and is phosphorylated in a Ca2+-enhanced manner, and the other has an Mr of 54,000, a pl of 5 - 5.5 and is phosphorylated in a cAMP-enhanced manner, as judged by two-dimensional polyacrylamide gel electrophoresis. Sepharose 4B chromatography indicated that the former polypeptide resides in a native protein complex that has an Mr of about 500,000 and the latter in a complex that has an Mr of about 180,000. Tritiated azido cyclic AMP binds to an islet polypeptide that has an Mr of 54,000. The results suggest that Ca2+ and cAMP could regulate stimulus-secretion coupling in pancreatic islets via protein phosphorylation.     

Methicillin-resistant Staphylococcus aureus: a pervasive pathogen highlights the need for new antimicrobial development

Staphylococcus aureus (S. aureus) has entered the spotlight as a globally pervasive drug-resistant pathogen. While historically associated exclusively with hospital-acquired infections in immunocompromised hosts, the methicillin-resistant form of S. aureus has been spreading throughout communities since the 1990s. Indeed, it has now become a common household term: MRSA. S. aureus has developed numerous mechanisms of virulence and strategies to evade the human immune system, including a host of surface proteins, secreted enzymes, and toxins. In hospital intensive care units, the proportion of MRSA-related S. aureus infections has increased strikingly from just 2 percent in 1974 to 64 percent in 2004. Its presence in the community has been rising similarly, posing a significant public health burden. The growing incidence of MRSA unfortunately has been met with dwindling efforts to develop new, more effective antibiotics. The continued emergence of resistant strains of bacteria such as MRSA demands an urgent revival of the search for new antibiotics.     

Inventing a new diagnostic test for vaginal infection.

Bacterial vaginosis, which is underdiagnosed in clinical practice, has a characteristic fishy smell because of production of diamines. This smell is the basis of a visual rapid diagnostic test that is technically simple to perform. The test has been patented in Europe and America, and a licence agreement has been negotiated. This paper describes the process from idea to invention to patenting and licensing. The combined costs of research and patenting were met by a multinational company in return for rights to exploit the patent invention. The process has taken nine years and has needed clinical, scientific, legal, and commercial input to get the test to the marketplace.     

The Na,K-ATPase of nervous tissue

The Na,K-ATPase has been only partially purified from nervous tissue, yet it is clear that two forms (and +) of the catalytic subunit are present. is a component subunit of the glial Na,K-ATPase, which has a relatively low affinity for binding cardiac glycosides and + has been identified as a subunit of the Na,K-ATPase which has relatively high affinity for cardiac glycosides. The + form may also be sensitive to indirect modulation by neurotransmitters or hormones. The ratio of + / changes in the nervous system during development, and + appears to be the predominant species in adult neurones. Changes in Na,K-ATPase activity have been associated with several abnormalities in the nervous system, including epilepsy and altered nerve conduction velocity, but a causal relationship has not been definitively established. Although the Na,K-ATPase has a pivotal role in Na⁺ and K⁺ transport in the nervous system, a special role for the glial Na,K-ATPase in clearing extracellular K⁺ remains controversial.     

雌激素及应激与人类认知功能的关系

以当前生理学、医学等相关学科研究的最新成果为例介绍了雌激素、应激和人类认知功能三者之间的关系。说明雌激素与应激均可影响人类情绪、中枢学习和记忆功能,不利应激降低雌激素水平,而雌激素又可减少不利应激带来的损害,最后指出雌激素替代治疗的广阔临床应用前景。     

Gene expression signatures in primary immunodeficiencies: the experience from human disease and mouse models

Extensive research on molecular genetics in recent decades has provided a wealth of information regarding the underlying mechanisms of primary immunodeficiency diseases. The microarray technology has made its entry into the molecular biology research area and hereby enabled signature expression profiling of whole species genomes. Perhaps no other methodological approach has transformed molecular biology more in recent years than the use of microarrays. Microarray technology has led the way from studies of the individual biological functions of a few related genes, proteins or, at best, pathways towards more global investigations of cellular activity. The development of this technology immediately yielded new and interesting information, and has produced more data than can be currently dealt with. It has also helped to realize that even a 'horizontally exhaustive' molecular analysis is insufficient. Applications of this tool in primary immunodeficiency studies have generated new information, which has led to a better understanding of the underlying basic biology of the diseases. Also, the technology has been used as an exploratory tool to disease genes in immunodeficiency diseases of unknown cause as in the case of the CD3Delta-chain and the MAPBPIP deficiency. For X-linked agammaglobulinemia, the technique has provided better understanding of the genes influenced by Btk. There is considerable hope that the microarray technology will lead to a better understanding of disease processes and the molecular phenotypes obtained from microarray experiments may represent a new tool for diagnosis of the disease.     

Identification of a novel cytosolic tocopherol-binding protein: structure, specificity, and tissue distribution

Alpha-tocopherol plays an important role as a lipid-soluble antioxidant. It is present in all major mammalian cell types and shows tissue-specific distribution. This suggests the presence of specific proteins involved in intracellular distribution or metabolism of alpha-tocopherol. A diminution of tocopherol plasma concentrations contributes to the development of diseases such as vitamin E deficiency (AVED), atherosclerosis, and prostate cancer. Further evidence has been obtained for the existence of sites in cellular metabolism and signal transduction where alpha-tocopherol potentially plays a regulatory role. A signal transduction modulation specific for alpha-tocopherol has been described in several model systems. Using radioactively labeled alpha-tocopherol as tracer, we have isolated a new alpha-tocopherol-associated protein (TAP) from bovine liver. This protein has a molecular mass of 46 kDa and an isoelectric point of 8.1. From its partial amino acid sequence, a human gene has been identified with high homology to the newly described protein. Sequence analysis has established that the new TAP has structural motifs suggesting its belonging to a family of hydrophobic ligand-binding proteins (RALBP, CRALBP, alpha-TTP, SEC 14, PTN 9, RSEC 45). Human TAP has been cloned into Escherichia coli, and its tissue-specific expression has been assessed by Northern blot analysis.     

Multipurpose Intensive Care Unit in a District General Hospital

The advantages of a four-bedded purpose-built general intensive care unit in a district general hospital are described. In addition to 1,447 inpatients treated between January 1968 and December 1971 the unit was used to conduct outpatient investigations. This has filled an important gap in conventional arrangements, and is practical and economical. The unit has proved to have advantages, not only for seriously ill patients but also has benefited the hospital in other ways. It has been of material assistance in recruiting and training nursing and medical staff and has been welcomed and supported by patients and their relatives. It has also attracted practical support from voluntary organizations whose generosity has enabled much additional equipment to be purchased.     

Long-term changes in zooplankton abundance and water transparency in Lake Geneva

The water quality of Lake Geneva has declined steadily since the 1960s, due to a continuous increase of external phosphorus loading. Average P level in the lake increased steadily to a peak in 1979, and even 1981 in the case of P content in the trophogenic layer. Since then, reduced external inputs related to the delayed effects of phosphorus removal from waste waters initiated many years previously has led to a decrease in P level, and resulted in present stabilization and even improvement in water quality. Long-term changes in zooplankton abundance correspond quite closely to eutrophication level changes. After increasing since the 1960s, maximum zooplankton biomass was recorded for the first time in 1971; a second main peak appeared in 1981 together with the highest eutrophication level. Over the last seven years, zooplankton abundance has decreased continuously, while water transparency has decreased and phytoplankton production has remained at a high level.     

Ivermectin 20 years on: maturation of a wonder drug

Ivermectin has been on the veterinary market for almost a quarter of a century and has been approved for human use for 18 years. Its use has revolutionized the treatment of nematode and arthropod parasites in animals and has provided hope for the control or even eradication of filariases in humans. Although much remains to be learned about how the drug works and how resistance to it will develop, it has earned the title of "wonder drug".     

Purification and characterization of an endogenous inhibitor of the sialyltransferase CMP-N-acetylneuraminate: lactosylceramide alpha 2,6-N-acetylneuraminyltransferase (EC 2.4.99.-).

The presence in the 100,000 g supernatant of rat brain homogenate of an inhibitor of the sialyltransferase has been confirmed. It is also present in chicken and bovine brain and in other rat and bovine organs. The inhibitor has been purified, a preparation with a specific activity 130-fold higher than that of the original 100,000 g supernatant of brain being obtained. It runs as a single peak in polyacrylamide-gel electrophoresis; when run in the presence of SDS, two components appeared. The apparent Mr of the components were 14,800 and 22,400. The inhibitor has been characterized as a heat-stable protein of acidic nature. It has effect on the glycolipid and the glycoprotein sialyltransferase activities but has no effect on the galactosaminyltransferase activity.     

Protein A chromatography for antibody purification

Staphylococcal protein A (SPA) is one of the first discovered immunoglobulin binding molecules and has been extensively studied during the past decades. Due to its affinity to immunoglobulins, SPA has found widespread use as a tool in the detection and purification of antibodies and the molecule has been further developed to one of the most employed affinity purification systems. Interestingly, a minimized SPA derivative has been constructed and a domain originating from SPA has been improved to withstand the harsh environment employed in industrial purifications. This review will focus on the development of different affinity molecules and matrices for usage in antibody purification.     

Isolation and characterization of a plasmid from Treponema denticola

Agarose gel electrophoresis of whole genomic DNA of the oral spirochaete Treponema denticola has revealed a plasmid-like fraction. Purification and restriction enzyme analysis has confirmed the presence of a 2.6-kb circular plasmid, which has been mapped for restriction sites and cloned into the Escherichia coli plasmid pUC18. Southern blot analysis of genomic T. denticola DNA, using the plasmid as a probe, has shown that the plasmid is present only as an extra-chromosomal element. No plasmid-coded recombinant gene product from a PstI insert in pUC18 has been detected in host cells of E. coli by SDS-PAGE or immunoblotting with polyclonal immune rabbit serum to T. denticola. The discovery of this plasmid may provide a useful tool in the application of new molecular approaches in spirochaetal biology.     

Toponomics and neurotoponomics: a new way to medical systems biology

The fluorescence robot imaging technology multi-epitope-ligand-cartography/toponome imaging system has revolutionized the field of proteomics/functional genomics, because it enables the investigator to locate and decipher functional protein networks, the toponome, consisting of hundreds of different proteins in a single cell or tissue section. The technology has been proven to solve key problems in biology and therapy research. It has uncovered a new cellular transdifferentiation mechanism of vascular cells giving rise to myogenic cells in situ and in vivo; a finding that has led to efficient cell therapy models of muscle disorders, and discovered a new target protein in sporadic amyotrophic lateral sclerosis by hierarchical protein network analysis, a finding that has been confirmed by a mouse knockout model. A lead target protein in tumor cells that controls cell polarization as a mechanism that is fundamental for migration and metastasis formation has also been uncovered, and new functional territories in the CNS defined by high-dimensional synaptic protein clusters have been unveiled. The technology can be effectively interlocked with genomics and proteomics to optimize time-to-market and the overall attrition rate of new drugs. This review outlines major proofs of principle with an emphasis on neurotoponomics.