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PubMed2002

SecB, one small chaperone in the complex milieu of the cell.

SecB is only one of a plethora of cytosolic chaperones in E. coli whose common property is that they bind nonnative proteins. It plays a crucial role during protein export via the general secretory pathway by modulating the partitioning of precursors between folding or aggregation and delivery to the membrane-bound translocation apparatus. In this latter role SecB demonstrates specific binding to a unique partner, SecA. SecB has the potential to participate in functions outside of export acting as a general nonspecific chaperone to provide buffering capacity of the nonnative state of proteins in the cytosolic pool. We discuss the interactions of SecB with its many binding partners in light of its recently determined structure, emphasizing both kinetic and thermodynamic parameters.

Adenosine Triphosphatases↗

PubMed2005

Actin polymerization machinery: the finish line of signaling networks, the starting point of cellular movement.

Dynamic assembly of actin filaments generates the forces supporting cell motility. Several recent biochemical and genetic studies have revealed a plethora of different actin binding proteins whose coordinated activity regulates the turnover of actin filaments, thus controlling a variety of actin-based processes, including cell migration. Additionally, emerging evidence is highlighting a scenario whereby the same basic set of actin regulatory proteins is also the convergent node of different signaling pathways emanating from extracellular stimuli, like those from receptor tyrosine kinases. Here, we will focus on the molecular mechanisms of how the machinery of actin polymerization functions and is regulated, in a signaling-dependent mode, to generate site-directed actin assembly leading to cell motility.

Actin Cytoskeleton↗

PubMed2005

Differential signaling in presynaptic neurotransmitter release.

Neuronal communication is tightly regulated by presynaptic signaling, thereby temporarily and locally secreting one or more transmitters in order to exert propagation or modulation of network activity. In the last 2 decades our insight into the molecular regulation of presynaptic transmitter vesicle traffic and fusion has exponentionally grown due to the identification of specific functional interactions between presynaptic proteins involved in these processes. In addition, a plethora of extracellular and intracellular messengers regulate neurotransmitter release, occasionally leading to short- or long-term adaptations of the synapse to altered environmental signals. Important in this respect is the ability of various nerve terminals to diverge their output by differentiation in secretion of co-localized transmitters. This divergence in presynaptic signaling may converge in the postsynaptic target neuron or spread to neighbouring cells. In this review differential presynaptic signaling mechanisms will be related to their potential divergent roles in transmitter release.

Animals↗

PubMed2005

The HERC proteins: functional and evolutionary insights.

HERC proteins are defined as containing both HECT and RCC1-like domains in their amino acid sequences. Six HERC genes have turned up in the human genome which encode two different sorts of polypeptides: while the small HERC proteins possess little more than the two aforementioned domains, the large ones are giant proteins with a plethora of potentially important regions. It is now almost 10 years since the discovery of the first family member and information is starting to accumulate pointing to a general role for these proteins as ubiquitin ligases involved in membrane-trafficking events. In this review, the available data on these six members are discussed, together with an account of their evolution.

Evolution, Molecular↗

PubMed2005

Lactoferrin: a modulator of immune and inflammatory responses.

Lactoferrin is an iron-binding glycoprotein of the transferrin family. Abundant expression and secretion of lactoferrin, in particular in milk and fluids of the digestive tract, are related to its implication in the first line of host defense. Lactoferrin is also a prominent component of the secondary granules of neutrophils (PMNs) and is released in infected tissues and blood during the inflammatory process. In addition to its direct antimicrobial properties, the abilities of lactoferrin to regulate the immune response and to protect against infection and septic shock have been described in numerous in vitro and in vivo studies. Although the cellular and molecular mechanisms that account for the modulation of the inflammatory and immune responses by lactoferrin are not yet totally elucidated, many are now established. At the cellular level, lactoferrin modulates the migration, maturation and function of immune cells. At the molecular level and in addition to iron binding, interactions of lactoferrin with a plethora of compounds, either soluble or membrane molecules, account for its modulatory properties. This paper reviews our current understanding of the cellular and molecular mechanisms that explain the regulatory properties of lactoferrin in host defence.

Animals↗

PubMed1999

Physiological significance of STAT proteins: investigations through gene disruption in vivo.

Signal transducers and activators of transcription (STATs) were discovered as mediators of type I interferon-induced gene expression. This family of transcription factors has been found in widespread signaling pathways, especially those involving cytokines regulating the immune response. Because a plethora and often confusing set of activators for STAT proteins was observed in cell culture models, it became important to define the physiologically relevant actions of these molecules. One approach to this question has been through the targeted disruption of STAT genes in transgenic mice. Now that all seven STAT genes have been disrupted, both the high degree of STAT selectivity as well as many surprising and unexpected complexities are beginning to be characterized.

Animals↗

PubMed2004

[Alpha-melanocyte-stimulating hormone. Its current significance for dermatology].

Alpha-melanocyte-stimulating hormone (alpha-MSH) is a tridecapeptide that was originally characterized as a neuropeptide derived from the pituitary gland. alpha-MSH is synthesized from pro-opiomelanocortin (POMC) by the action of specific prohormone convertases which cleave POMC into alpha-MSH, adrenocorticotropin and beta-endorphin. The various effects of alpha-MSH are mediated via melanocortin receptors. The skin as well as the majority of cutaneous cell types express POMC. Proinflammatory stimuli such as ultraviolet (UV) light induce POMC expression and alpha-MSH secretion. Receptors for alpha-MSH are not only expressed by melanocytes, where they mediate melanogenesis and proliferation, but also by virtually every cutaneous cell type. Accordingly, alpha-MSH elicits a plethora of biological actions in these cell types including immunomodulation, protection from oxidative stress and UV-induced apoptosis, modulation of secretory epithelial function and regulation of extracellular matrix composition. These actions may be exploited in future by using super potent and truncated MSH peptides for the treatment of various skin disorders including inflammatory dermatoses.

Adjuvants, Immunologic↗

PubMed1998

[Aphthae and aphthous lesions of the mouth mucosa].

Recurrent aphthae (or aphthoses) are the most frequent inflammatory lesions of the oral mucosa. Aphthae can clearly be defined, but may also be barely discernible from aphthoid erosions and ulcers of heterogeneous origin. Although a subject of molecular research, the etiopathogenesis of oral aphthoses is still unknown. However, the clinical differentiation of a "benign" type of aphthosis from a "pernicious" one, such as Behçet's disease (BD), is a diagnostic matter of great significance. BD has been found clinically in increasing numbers in central Europe and represents an (auto-)hyperimmune multisystem life-threatening vasculitis. In this disorder possible damage can occur to many visceral organs and/or the cerebrospinal system. The prognosis of BD may depend on the changing involvement of very different organs, as well as the early recognition of the disease per se. The most prominent feature is a multilesional aphthous stomatitis that is almost never absent during acute episodes of BD. Hence, the occurrence of this peculiar type of aphthosis strongly indicates an active BD. The plethora of other aphthoid lesions can be challenging to the diagnostic competence of all physicians and may confuse the correct recognition of the severity of the disease present. This review particularly details the wide range of diagnostic, therapeutic and prognostic aspects of the various oral aphthoses.

Behcet Syndrome↗

PubMed2003

[Therapy and secondary prevention of venous thromboembolism with vitamin K antagonists].

Oral anticoagulation with vitamin-K-antagonists is very effective in secondary prevention of venous thromboembolism. In Germany, most commonly Phenprocoumon is used, while most of the evidence-based data are available for Warfarin. The initial treatment of acute venous thromboembolism requires immediate anticoagulation with heparin and a subsequent overlapping treatment with oral anticoagulants. During this phase, anticoagulation may be unstable with increased risk for bleeding. An INR target range between 2 and 3 provides effective protection with minimal risk for major bleeding. The individual risk for bleeding may be estimated by a clinical score. Six months of oral anticoagulation is the standard duration for a first episode of venous thromboembolism, while recurrencies are treated for at least one to two years. The duration may be tailored to the individual patient according to underlying risk factors for recurrencies and for bleeding. Because of a plethora of practical problems and the narrow therapeutic window, there is a need for new antithrombotic agents. These may allow a longer duration of secondary prevention with improved protection against recurrencies without sacrificing safety.

Administration, Oral↗

PubMed2002

Studying genotype-phenotype relationships: cardiovascular disease as an example.

Cardiovascular disease is a multifactorial disorder resulting from the complex interaction of a plethora of both environmental and genetic factors. The "candidate gene" approach aims at identifying the genes contributing to cardiovascular disease assessing their entire polymorphic spectrum and the consequences of their combination in appropriate large association studies. In view of the sequence data available for the entire human genome, candidate sequences will more easily be traced and located in their chromosomal context. More powerful sequencing devices are available and will hopefully give reliable and reproducible data not only on the nucleotide sequence diversity in different populations throughout candidate regions of the human genome. The choice and the assessment of disease-related or intermediate phenotypes, especially in clinical settings, will be again more crucial in the future when the knowledge of gene sequence variation significantly increases. Identification of relevant genes and genetic variants involved in the different pathophysiological steps leading to cardiovascular disease may considerably improve our understanding of the mechanisms of the disease course. This may help to identify high-risk individuals and groups or subgroups in whom specific therapeutic interventions are indicated or necessary, leading to an individually adapted clinical management.

Cardiovascular Diseases↗

PubMed2004

Role of endogenous antisense RNA in cardiac gene regulation.

Endogenous antisense RNA has been detected for a range of eukaryotic genes and now appears to be a common phenomenon in mammalian cells. Its abundance compared to levels of its complementary sense mRNA indicates that antisense RNA may be involved in posttrancriptional regulation of a gene. In general a downregulating effect on gene expression has been demonstrated or suggested. Due to the heterogeneity in origin and character of different antisense transcripts alternative functions such as stabilizing the corresponding sense transcript and being part of gene recombination must be considered. Regulation by endogenous antisense RNA has been shown for a plethora of genes, including cardiac genes, such as myosin heavy chainMHC, atrial light chain, and troponin I. There is now growing evidence that antisense transcription is involved in human disease, and it is reasonable to consider antisense as a target for intervention procedures. Here we review the progress in our understanding of as well as the controversies arising from investigating the regulatory mechanisms of antisense RNA, with special focus on cardiac genes. Finally, links between antisense transcription and heart disease and the possible use of antisense as a target of cardiac intervention procedures are discussed.

Animals↗

PubMed2004

Regulation of bone morphogenetic proteins in early embryonic development.

Bone morphogenetic proteins (BMPs), a large subgroup of the TGF-beta family of secreted growth factors, control fundamental events in early embryonic development, organogenesis and adult tissue homeostasis. The plethora of dose-dependent cellular processes regulated by BMP signalling demand a tight regulation of BMP activity. Over the last decade, a number of proteins have been identified that bind BMPs in the extracellular space and regulate the interaction of BMPs with their cognate receptors, including the secreted BMP antagonist Chordin. In the early vertebrate embryo, the localized secretion of BMP antagonists from the dorsal blastopore lip establishes a functional BMP signalling gradient that is required for the determination of the dorsoventral - or back to belly - body axis. In particular, inhibition of BMP activity is essential for the formation of neural tissue in the development of vertebrate and invertebrate embryos. Here we review recent studies that have provided new insight into the regulation of BMP signalling in the extracellular space. In particular, we discuss the recently identified Twisted gastrulation protein that modulates, in concert with metalloproteinases of the Tolloid family, the interaction of Chordin with BMP and a family of proteins that share structural similarities with Chordin in the respective BMP binding domains. In addition, genetic and functional studies in zebrafish and frog provide compelling evidence that the secreted protein Sizzled functionally interacts with the Chd-BMP pathway, despite being expressed ventrally in the early gastrula-stage embryo. These intriguing discoveries may have important implications, not only for our current concept of early embryonic patterning, but also for the regulation of BMP activity at later developmental stages and tissue homeostasis in the adult.

Animals↗

PubMed2004

A systematic review of home treatment services--classification and sustainability.

BACKGROUND: In view of the plethora of different community-based mental health services, there is a clear need for a classification based on service components rather than labels. Moreover, the sustainability of experimental services beyond their research studies is rarely reported. METHODS: As part of a systematic review of home treatment for mental health problems, authors of all included studies were followed up for data on service components and sustainability. Associations between components were explored. RESULTS: There was evidence of a core group of components co-occurring in home treatment services: regularly visiting at home, taking responsibility for health and social care, having smaller caseloads, multidisciplinary teams, integrated psychiatrists and a high proportion of contacts at home. Fifty-four per cent of services no longer existed, of which almost half had ended by the study's publication date. There was a significant association between sustainability and the study's hospitalisation outcome. CONCLUSIONS: Some of the related service components presented here were associated with reducing hospitalisation. This group cannot, however, be used to provide a new taxonomy of services. It is imperative that future studies prospectively record and report service components to enable better classification. It is of concern that policy is currently predicated on research findings regardless of whether or not the experimental service was sustainable.

Community Mental Health Services↗

PubMed1999

The prevalence of psychiatric disorders and use of care by homeless people in Paris.

BACKGROUND: Homelessness is a growing problem in the cities of the western world, and homeless people have a plethora of mental health and social difficulties. These are, nevertheless, difficult to evaluate epidemiologically. METHOD: In this paper we present a population survey using the Composite International Diagnostic Interview (CIDI) conducted in the city of Paris in winter 1996 on a representative sample of 838 homeless people. Night shelters as well as food kitchens were randomly sampled, and the mean response rate was around 65%. RESULTS: The sample was relatively young and predominantly male (85%). Forty percent were born outside France, 96% had worked at some time, and one-third reported no resources at all. The lifetime prevalence of psychiatric disorders was 57.9%, while the 1-year prevalence was 29.1%. For definite psychotic disorders, prevalence was 16% (lifetime) and 6% (1 year). Generally, this Parisian homeless population had some access to care: in the preceding 6 months 57.7% of them had been medically attended and 14.2% of these had been hospitalised. The survey was cross-sectional, and did not evaluate regular access to care or the quality of care. CONCLUSIONS: The implications for health and social systems are discussed in the light of comparisons with European and North American data.

Adult↗

PubMed2003

A readers' guide to the interpretation of diagnostic test properties: clinical example of sepsis.

BACKGROUND: One of the most challenging practical and daily problems in intensive care medicine is the interpretation of the results from diagnostic tests. In neonatology and pediatric intensive care the early diagnosis of potentially life-threatening infections is a particularly important issue. FOCUS: A plethora of tests have been suggested to improve diagnostic decision making in the clinical setting of infection which is a clinical example used in this article. Several criteria that are critical to evidence-based appraisal of published data are often not adhered to during the study or in reporting. To enhance the critical appraisal on articles on diagnostic tests we discuss various measures of test accuracy: sensitivity, specificity, receiver operating characteristic curves, positive and negative predictive values, likelihood ratios, pretest probability, posttest probability, and diagnostic odds ratio. CONCLUSIONS: We suggest the following minimal requirements for reporting on the diagnostic accuracy of tests: a plot of the raw data, multilevel likelihood ratios, the area under the receiver operating characteristic curve, and the cutoff yielding the highest discriminative ability. For critical appraisal it is mandatory to report confidence intervals for each of these measures. Moreover, to allow comparison to the readers' patient population authors should provide data on study population characteristics, in particular on the spectrum of diseases and illness severity.

Bayes Theorem↗

PubMed2006

Investigating the heterogeneity of cell growth in microbial colonies by FTIR microspectroscopy.

Microorganisms rarely occur as individual cells in nature and are, instead, organized in complex multicellular communities such as colonies, fruiting bodies, or biofilms. Interest in the natural microbial life-style has increased during the last decade and a whole plethora of techniques has been used to gain insight into the development, structure and composition of diverse microbial communities. We have developed a technique for investigating the spatial heterogeneity of microbial growth in macro-colonies which essentially entails excision of the colonies with the underlying agar, freezing and subsequent cryotoming of the colonies, then FTIR microspectroscopic mapping of the cryosections. Colonies from Legionella, Bacillus, and Candida strains were chosen as model systems of multi-cellular communities to evaluate the technique. The results obtained indicate pronounced cell population heterogeneity even in relatively young colonies cultivated under laboratory conditions. Spectral data obtained from different positions within, e.g., a colony of Legionella bozemanii 120 h old indicated that levels of the storage material poly-beta-hydroxybutyric acid were significantly higher in cells at the surface of the colonies than in those growing at the bottom next to the agar surface. Similarly, in a 24-h-old macro-colony of Bacillus megaterium significantly more of the capsular compound polyglutamic acid was detected in upper layers than in deeper layers of the colony. Results demonstrate that FTIR microspectroscopy can be an useful tool for investigation of the spatial heterogeneity of cell growth within microbial macro-colonies. It is suggested that the method also can be adapted to the analysis of more complex multicellular communities, for example fruiting bodies, biofilms, or colonies growing under natural conditions.

Bacterial Physiological Phenomena↗

PubMed2004

Study of usage pattern of nonsteroidal anti-inflammatory drugs (NSAIDs) among different practice categories in Indian clinical setting.

OBJECTIVE: The aim of the study was to evaluate the usage pattern of nonsteroidal anti-inflammatory drugs (NSAIDs) in diverse clinical practice settings in India. METHODS: The study was conducted in Mumbai city and its suburbs, involving 1,916 doctors from among general practice to specialist practice. The data were collected with the help of a semi-structured questionnaire and were analysed statistically to bring out differences in NSAID usage among different groups of prescribers. RESULTS: All the 1,916 doctors prescribed NSAIDs frequently with prescriptions ranging from 1 to 15 daily; they short-listed and prescribed only two to five NSAIDs from among a plethora of drugs available including fixed-dose combinations (FDCs). It is significant that FDCs were prescribed by more than 39% of doctors in all the categories, the highest prescribers being orthopaedic surgeons (76%) and lowest general practitioners (GPs; 39%). Apart from recommended usage, NSAIDs such as ibuprofen, diclofenac and aspirin were used for pelvic inflammatory disease, and indomethacin for pre-term labour and patent ductus arteriosus. Dosage variation, both in terms of dose and frequency of administration, has been observed for several NSAIDs in the GPs category as well as in the specialist categories-except that of paediatricians. In patients suffering from bronchial asthma, there has been significant use of aspirin and ibuprofen by GPs despite contra-indication for their use in such patients. Most prescribers perceived that NSAIDs are associated with mild gastrointestinal (GI) adverse events. Ibuprofen, a drug with reportedly better gastric tolerance, was perceived to cause GI adverse events, though to a lesser extent than aspirin; fewer prescribers perceived that diclofenac and piroxicam cause GI adverse events when compared with aspirin and ibuprofen. There were significant differences among the five practice categories with regard to preferences for NSAIDs. The first choice NSAIDs were ibuprofen, aspirin, diclofenac, paracetamol, piroxicam and ibuprofen+paracetamol FDC. CONCLUSIONS: This study has shown that there exist significant differences in the usage pattern and preferences of NSAIDs among different practice categories in India. The data have also revealed that there is a need for awareness programmes on rational prescribing of NSAIDs towards optimal therapeutics and improved patient care in India.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed1998

A new structural model for P-glycoprotein.

Multidrug resistance to anti-cancer drugs is a major medical problem. Resistance is manifested largely by the product of the human MDR1 gene, P-glycoprotein, an ABC transporter that is an integral membrane protein of 1280 amino acids arranged into two homologous halves, each comprising 6 putative transmembrane alpha-helices and an ATP binding domain. Despite the plethora of data from site-directed, scanning and domain replacement mutagenesis, epitope mapping and photoaffinity labeling, a clear structural model for P-glycoprotein remains largely elusive. In this report, we propose a new model for P-glycoprotein that is supported by the vast body of previous data. The model comprises 2 membrane-embedded 16-strand beta-barrels, attached by short loops to two 6-helix bundles beneath each barrel. Each ATP binding domain contributes 2 beta-strands and 1 alpha-helix to the structure. This model, together with an analysis of the amino acid sequence alignment of P-glycoprotein isoforms, is used to delineate drug binding and translocation sites. We show that the locations of these sites are consistent with mutational, kinetic and labeling data.

ATP Binding Cassette Transporter, Subfamily B, Mem↗