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PubMed2004

Molecular components of physiological stress responses in Escherichia coli.

In order to survive under and adapt to different conditions Escherichia coli has evolved elaborate systems that are able to sense and respond to environmental stimuli. Very often, different stresses act on a bacterium simultaneously and a variety of stresses have similar effects on cellular molecules and processes. Therefore, the various stress response systems have to interact (cross talk) with each other. A complex network of global regulatory systems with a multitude of molecular components ensures a coordinated and effective answer. Such regulatory components include DNA, mRNAs, sRNAs, proteins, such as DNA-and RNA binding proteins, alternative sigma factors and two-component systems, as well as small molecular weight molecules, as for example (p)ppGpp. These regulatory systems govern the expression of a plethora of further effectors that aim at maintaining stability of the cellular equilibrium under the various conditions. Using five of the most important stress response systems, we will discuss the roles and mechanisms of such regulatory and effector molecules in more detail. The heat shock response, controlled by the sigma factor sigma32, and the envelope stress response, controlled by the sigma factor sigmaE and the Cpx two-component system, both result in an increased expression of chaperones and proteases in response to misfolded proteins. The cold shock response governs expression of RNA chaperones and ribosomal factors, ensuring accurate translation at low temperatures. The general stress response depends on the sigma factor sigmaS, which controls the expression of more than 50 genes conferring resistance to many different stresses. The (p)ppGpp-dependent stringent response reduces the cellular protein synthesis capacity and controls further global responses upon nutritional downshift. A lot has been learned in recent years about the mechanisms of action of single components. However, the main challenge for the future is to achieve an understanding of the interactions of these components under different physiological conditions.

Adaptation, Physiological↗

PubMed1984

Molecular mechanisms of action of general anesthetics.

While a plethora of information exists describing particular changes caused by anesthetics on the molecular architecture of membranes, it is clear that models for anesthetic action remain unproven by rigid scientific criteria. This article describes historical and contemporary theories of how anesthetics act on a molecular level, and examines the discrepancies between these hypotheses and current data.

Anesthetics↗

PubMed1995

Structure and function of amiloride-sensitive Na+ channels.

A new molecular biological epoch in amiloride-sensitive Na+ channel physiology has begun. With the application of these new techniques, undoubtedly a plethora of new information and new questions will be forthcoming. First and foremost, however, is the question of how many discrete amiloride-sensitive Na+ channels exist. This question is important not only for elucidating structure-function relationships, but also for developing strategies for pharmacological or, ultimately, genetic intervention in such diseases as obstructive nephropathy, Liddle's syndrome, or salt-sensitive hypertension where amiloride-sensitive Na+ channel dysfunction has been implicated [17, 62]. Epithelia Na+ channels purified from kidney are multimeric. However, it is not yet clear which subunits are regulatory and which participate directly as a part of the Na+ conducting core and what is the nature of the gate. The combination of electrophysiologic techniques such as patch clamp and the ability to study reconstituted channels in planar lipid bilayers along with molecular biology techniques to potentially manipulate the individual subunits should provide the answers to questions that have puzzled physiologists for decades. It seems clear that the robust versatility of the channel in responding to a wide range of differing and potentially synergistic regulatory inputs must be a function of its multimeric structure and relation to the cytoskeleton. Multiple mechanisms of regulation imply multiple regulatory sites. This hypothesis has been validated by the demonstration that enzymatic carboxyl methylation and phosphorylation have both individual and synergistic effects on the purified channel in planar lipid bilayers. Of the multiple mechanisms proposed for channel regulation, evidence is now available to support the ideas that channels may be activated (or inactivated) by direct modifications including phosphorylation and carboxyl methylation, by activation or association of regulatory proteins such as G proteins, and by recruitment from subapical membrane domains. The observation that channel gating is achieved primarily through regulation of open probability without alterations in conductance may simplify future understanding of the molecular events involved in gating once the regulatory sites have been identified. As more Na+ channels or Na+ channel subunits are cloned from different epithelia, it will become possible to piece together the puzzle of epithelial Na+ channels. It is interesting to observe that renal Na+ channel proteins contain a subunit which falls into the 70 kD range. This size protein is in the range reported for the aldosterone-induced proteins [12, 46, 153].(ABSTRACT TRUNCATED AT 400 WORDS)

Amiloride↗

PubMed1991

MRI in tuberculous meningoencephalitis: report of four cases and review of the neuroimaging literature.

The contribution of MRI is reported in four adult patients with tuberculous meningoencephalitis (TbM) and with autopsy correlation in one. Contrast-enhanced T1-weighted MRI revealed the characteristic basal meningeal inflammation of TbM and its focal spreading into adjacent brain. Mixed and T2-weighted pulse sequences delineated a plethora of parenchymal abnormalities. Their relation to TbM was established by a close matching of the patient's neurological findings, contrast enhancement or a change in lesion size. The latter accurately reflected the clinical course in all patients. It remained difficult, however, to distinguish between ischaemic and inflammatory changes, which in some locations were intermixed even histologically. From our experience and that of other groups, MRI provides more diagnostic information in TbM than CT. Moreover, MRI promises to be a useful tool for monitoring treatment response.

Adolescent↗

PubMed1988

Immunohistochemical evidence for the presence of peptides derived from proenkephalin, prodynorphin and proopiomelanocortin in the guinea pig pineal gland.

By using a plethora of region-specific antisera, this light microscopic immunohistochemical study revealed that derivatives from the three opioid precursors, i.e. proenkephalin, prodynorphin and proopiomelanocortin are differentially distributed in the pineal gland of guinea pig. Various molecular forms of immunoreactive opioid peptides derived from proenkephalin or prodynorphin were present in a minority of pinealocytes as well as in nerves. In contrast to this dual distribution pattern of opioid-active peptides, the opioid-inactive derivative from proopiomelanocortin, alpha-melanocyte stimulating hormone, was exclusively present in a large proportion of pinealocytes. A multiple and differential origin and function of opioidergic pineal innervation involving sympathetic, parasympathetic and sensory components is suggested. alpha-MSH is proposed as a pineal hormone which may act in concert with melatonin to regulate pineal rhythms or may function like MSH of pituitary origin.

Animals↗

PubMed1995

Transgenic and gene knockout mice in cancer research.

Transgenic animal technology, and the use of germline manipulation for the creation of targeted gene mutations, has resulted in a plethora of murine models for cancer research. Our understanding of some of the important issues regarding the mechanisms controlling cell division, differentiation and death has dramatically advanced in recent years through exploitation of these techniques to generate transgenic mice. In particular, the generation of mice with targeted mutations in genes encoding proteins of oncological interest has proved to be a useful way of elucidating the function of these gene products in vivo. Transgenic mouse models have provided some insight into the complex oncogenic events contributing to cellular dysregulation and the loss of growth control that can lead to tumorigenesis. These animal studies have highlighted the fact that there are many different stages at which the loss of cell cycle control can occur, as a result of mutations affecting proteins anywhere from the cell surface to the nucleus. Although mutations affecting growth factors, growth factor receptors, signal transduction molecules, cytoplasmic proteins or nuclear proteins might appear to be very distinct, the end result of these changes may be accelerated and unchecked cell growth ultimately leading to cancer. It is beyond the scope of this review to mention every animal model that has been developed for cancer research, especially since many of the early studies have been covered extensively in previous reviews. This article will instead focus on a small selection of transgenic and knockout animal models which exemplify how proteins from distinct localisations along multiple pathways can contribute to loss of cell cycle control and the pathogenesis of cancer.

Animals↗

PubMed1989

The Na+ cycle of extreme alkalophiles: a secondary Na+/H+ antiporter and Na+/solute symporters.

Extremely alkalophilic bacteria that grow optimally at pH 10.5 and above are generally aerobic bacilli that grow at mesophilic temperatures and moderate salt levels. The adaptations to alkalophily in these organisms may be distinguished from responses to combined challenges of high pH together with other stresses such as salinity or anaerobiosis. These alkalophiles all possess a simple and physiologically crucial Na+ cycle that accomplishes the key task of pH homeostasis. An electrogenic, secondary Na+/H+ antiporter is energized by the electrochemical proton gradient formed by the proton-pumping respiratory chain. The antiporter facilitates maintenance of a pHin that is two or more pH units lower than pHout at optimal pH values for growth. It also largely converts the initial electrochemical proton gradient formed by respiration into an electrochemical sodium gradient that energizes motility as well as a plethora of Na+ solute symporters. These symporters catalyze solute accumulation and, importantly, reentry of Na+. The extreme nonmarine alkalophiles exhibit no primary sodium pumping dependent upon either respiration or ATP. ATP synthesis is not part of their Na+ cycle. Rather, the specific details of oxidative phosphorylation in these organisms are an interesting analogue of the same process in mitochondria, and may utilize some common features to optimize energy transduction.

Bacteria↗

PubMedDate not supplied

Cardiac efficiency.

Efficiency is defined as the ratio of the energy delivered by a system to the energy supplied to it. Depending on the particular question being addressed, there exist a plethora of definitions of efficiency in medical texts, thus hampering their comparison. If only the ventricular work seen by the arterial system is under investigation, pressure-volume work will serve as a useful numerator. If, on the other hand, external and internal work together, i.e. the total mechanical work, is of interest, the pressure-volume area might be employed. Total myocardial oxygen consumption (MVO2) will be a useful denominator in the case of aerobic energy production. The MVO2 for the unloaded contraction must be assessed if, as in other energy transfer systems, net efficiency is to be addressed. If even smaller steps in the chain of energy transfer are to be investigated MVO2 for the arrested heart must be assessed. With an appropriate therapy, hemodynamic determinants can be varied, to improve cardiac efficiency. Nonetheless, measurement of all variables necessary for the calculation of efficiency remains a challenge, in particular in the clinical setting. Separation of the direct effects of drugs on efficiency is even more difficult, since hemodynamic conditions can hardly be controlled throughout the observation period, and changes in efficiency might be secondary to changes in hemodynamics. Whether the heart by itself employs mechanisms to improve its efficiency is still a matter of discussion: there is evidence that when oxygen supply decreases, the heart can switch from one substrate to a less costly one, or possibly can improve efficiency through better use of oxygen. Moreover, the heart seems to "sense" an even more decreased oxygen supply and reduce function in response. Myocardial stunning could be regarded as a protective mechanism as well, with function remaining depressed and the oxygen supply being normal or close to normal. One may conclude from the decreased efficiency that the excess oxygen consumption is used up for repair processes. The improved efficiency found in hypertrophied hearts represents another adaptive process. The underlying mechanism is unclear: a shift towards isomyosin V3 or some undefined shift in metabolic pathway is discussed. It is also still a moot question towards which objective the efficiency of the heart is adjusted. It has been described that under physiologic conditions, the efficiency of both the left and the right ventricle ought to be maximized.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1978

The paratrigeminal nucleus. I. Neurons and synaptic organization.

The paratrigeminal nucleus, a diffuse collection of neurons on the lateral medullary surface, lies embedded in the fibres of the restiform body, ascending spinocerebellar tract and the spinal tract of the trigeminal nerve. Its rostrocaudal extent is approximately 1500--2000 micrometer in the rat, 2800--3500 micrometer in the rhesus monkey, and 5000--6000 micrometer in the human, where it is a well-defined nucleus. In Golgi preparations the neuronal somata are generally fusiform, ranging from 8--15 micrometer in width and 15--25 micrometer in length. Electron microscope studies show that their polar dendritic processes are thick and long and they intertwine in bundles among islands of cells or myelinated fibres. The perikarya have a high nucleus to cytoplasm ratio and the scanty cytoplasm is conspicuous for its paucity of organelles and its plethora of polysomal arrays. The neuropil is complex and contains a heterogeneous population of axonal varicosities displaying markedly different axoplasmic structures. Many different types of large granular vesicle-containing axons prevail. These axons engage in axo--somatic, axo--dendritic, axo--spinous and axo--axonic synapses with the processes of the cells within the nucleus.

Animals↗

PubMed1990

Development of the ultrastructural features of neuropeptide Y-immunoreactive neurons in the rat visual cortex.

Immunohistochemical studies have localized neuropeptide Y into a small population of non-pyramidal neurons in the mammalian cerebral cortex. In the rat, these cells are distributed in layers II-VI and are characterized at the ultrastructural level by an abundance of cytoplasm containing a plethora or organelles, most conspicuous of which are cisternae of granular endoplasmic reticulum stacked in parallel arrays. In the present study, we used electron microscopic immunocytochemistry to examine the ultrastructural development of neuropeptide Y-labelled neurons in the rat visual cortex from birth, when they first appear in this cortical area, until postnatal day 32. At birth and in the subsequent few days, neuropeptide Y neurons, found exclusively in layers V and VI, often show a deeply infolded nucleus and little cytoplasm containing few organelles. At the end of the first postnatal week, labelled cells are still restricted to layers V and VI and display immature features. However, at this stage, cells often show irregularly enlarged proximal dendrites filled with organelles. During the second postnatal week, neuropeptide Y-immunoreactive cell bodies appear for the first time in layers II and III, and at the end of this week they have a distribution similar to that observed in the adult. Labelled cells are overall more differentiated than at earlier ages showing some of the ultrastructural features which distinguish them in the adult. No differences in maturation are evident between immunoreactive neurons located in the superficial layers and those in the deep layers, suggesting that the neuropeptide Y neurons in the more superficial layers express the peptide after having completed their migration and have acquired their characteristic ultrastructural features. Maturation proceeds during the third postnatal week. At the end of this stage, neuropeptide Y-containing cells acquired their mature nuclear and cytoplasmic features and an adult complement of synapses.

Animals↗

PubMed1992

Adhesion molecules and tumor cell interaction with endothelium and subendothelial matrix.

Cancer metastasis poses the greatest challenge to the eradication of malignancy. The majority of clinical and experimental evidence indicates that metastasis is a non-random, organ-specific process. Tumor cell interaction with endothelium and subendothelial matrix constitutes the most crucial factor in determining the organ preference of metastasis. A plethora of cell surface adhesion molecules, which encompass four major families (i.e., integrins, cadherins, immunoglobulins and selectins) and many other unclassified molecules, mediate tumor-host interactions. Adhesion molecules and adhesion processes are involved in most, if not all, of the intermediate steps of the metastatic cascade. Decreased E-cadherin expression and increased CD44 expression are clearly correlated with the acquisition of the invasive capacity of primary tumor cells. Similarly, altered expression pattern of many other adhesion molecules such as upregulated expression of the laminin receptors and depressed expression of fibronectin receptors (alpha 5 beta 1) appears to be involved in tumor cell invasion into the subendothelial matrix. Tumor cell-endothelium interactions involve several well-defined sequential steps that can be analyzed by the 'Docking and Locking' hypothesis at the molecular level. Tumor cell-matrix interactions are determined by the repertoire of adhesion receptors of tumor cells and the unique composition of organ-specific matrices. Our experimental data, together with others', suggest that the integrin alpha IIb beta 3 is one of the major players in these tumor-host interactions. Tumor-host interaction is a dynamic process which is constantly modulated by a host of factors including various cytokines, growth factors and arachidonate metabolites such as 12(S)-HETE. Delineation of the molecular mechanisms of tumor-host interactions may provide additional means to intervene in the metastatic process.

Animals↗

PubMed1992

Automated St-segment trending: what does it mean?

This article is the first segment of what we hope will become a regular feature in the Journal of Clinical Monitoring. The Monitoring Dilemmas series is designed for clinicians who are struggling with the information presented by new monitoring. The past decade has seen an explosion in the number and type of clinical monitors in daily use. Health-care providers are increasingly faced with a plethora of monitoring data, often without guidance on how to interpret it. Each Monitoring Dilemma consists of a case report that describes a clinical dilemma brought on by information from a monitor--a dilemma that would not even have been considered had the monitor not been in place or existence. The case reports are sent to experts in the particular fields concerned. To prevent "Monday morning quarterbacking," each reviewer is sent several envelopes, each containing information that progressively reveals more and more about the case. The case is presented as it actually evolved, and the experts comment as the case unfolds. Thus, the reader can share the dilemma with the reviewers, as well as with the original clinicians. We welcome your comments on this new section. We also welcome your own Monitoring Dilemmas. Please contact the Section Editor, Dr Partridge, for more details.

Aged↗

PubMed1991

Reactive oxygen species, antiproteases, and cytokines in sepsis.

Although the shock syndrome is recognized as a form of "mediator poisoning", a plethora of details is hardly converging into a coherent concept of chronological and molecular order. As a model for organ failure in septic shock, three alternative experimental approaches with a common pathology are presented: When galactosamine-sensitized mice receive either lipopolysaccharide or leukotriene D4 or tumor necrosis factor alpha they develop fulminant hepatitis within few hours with a lethal outcome within one day. Detailed pharmacological intervention studies allow to conclude that endotoxin-induced leukotriene D4 release induces a transient ischemia by the known vasoconstrictive action of this eicosanoid. A following reperfusion/reoxygenation phase gives rise to superoxide formation which inactivates alpha 1 proteinase inhibitor. Thus a serine protease becomes active which is responsible for the processing of a monocytic tumor necrosis factor alpha precursor to be released into the circulation after proteolytic cleavage. By this sequence the final central mediator of shock and sepsis becomes systematically abundant. The concept arising from these studies reconciles previously known findings and provides a link between the role of reactive oxygen species in inflammation, the balance of proteases and antiproteases in the extracellular space and the release of the cytokine tumor necrosis factor in sepsis and shock.

Animals↗

PubMed1991

Could treatment with scavengers of oxygen free radicals minimize complications in cardiac surgery?

Cardiac surgical complications may be caused by a plethora of events. Oxygen free radicals may participate in the pathophysiology of cardiopulmonary bypass and myocardial ischaemia-reperfusion injury. The evidence of free radical production during bypass is limited, and studies of the effect of free radical scavengers even more limited. Experimental work points towards a role of oxygen free radicals in reperfusion damage of the ischaemic myocardium, but clinical data are lacking. Hitherto the clinical availability of free radical scavengers/antioxidants has been scarse. At present more such drugs are becoming clinically applicable, and trials on their effect are highly warranted, in particular as an adjuvant in myocardial protection.

Animals↗

PubMed1987

Development of the ultrastructural features of somatostatin-immunoreactive neurons in the rat visual cortex.

The peroxidase-antiperoxidase immunocytochemical technique has been used to examine the development of the ultrastructural features of somatostatin (SRIF)-immunoreactive neurons in the visual cortex of the rat between embryonic day 17 and postnatal day 32. In the adult, stained neurons are distributed in layers II through VI and characterized by an abundance of cytoplasm containing a plethora of organelles, most conspicuous of which are cisternae of granular endoplasmic reticulum organized in parallel arrays. In embryonic tissue, SRIF-positive cells are present in the subplate and in the border between the cortical plate and marginal zone. These cells possess scanty cytoplasm containing a few organelles; synapses onto immunoreactive perikarya and dendrites are evident at this stage. At birth and in early postnatal life, labelled cells are confined to the subplate region. Already at this age a number of cells display signs of ultrastructural features which characterize them in adult life. At the end of the first postnatal week, SRIF-immunoreactive neurons span a considerable spectrum of maturity. At one extreme are a few cells with little cytoplasm surrounding a large nucleus and at the other are the majority of labelled neurons showing abundant cytoplasm including prominent arrays of granular endoplasmic reticulum. Labelled cells first appear in the more superficial layers at the beginning of the second postnatal week and attain a distribution similar to that observed in adult animals at the end of this week. At this time their ultrastructural features closely resemble those of their adult counterparts, and differences in cytoplasmic maturity between superficial and deep labelled cells are not evident. This suggests that the SRIF-producing neurons in the superficial layers begin to express this peptide after they complete their migration and have acquired their morphological features. Maturation proceeds during the third postnatal week; at this stage most cells acquire their mature nuclear and cytoplasmic features and an adult complement of synapses. However, a number of SRIF-immunoreactive cells contain a particularly prominent accumulation of cytoplasmic organelles and appear hypertrophic.

Animals↗

PubMed1994

Report of the American-European consensus conference on ARDS: definitions, mechanisms, relevant outcomes and clinical trial coordination. The Consensus Committee.

The acute respiratory distress syndrome (ARDS), a process of non-hydrostatic pulmonary edema and hypoxemia associated with a variety of etiologies carries a high morbidity, mortality (10-90%) and financial cost. The reported annual incidence in the United States is 150,000 cases, but this figure has been challenged and may be different in Europe. Part of the reason for these uncertainties is the heterogeneity of diseases underlying ARDS and the lack of uniform definitions for ARDS. Thus, those whose wish to know the true incidence and outcome on this clinical syndrome are stymied. The European American Consensus Committee on ARDS was formed to focus on these issues and on the pathophysiologic mechanisms of the process. It was felt that international coordination between North America and Europe in clinical studies of ARDS was becoming increasingly important in order to address the recent plethora of potential therapeutic agents for the prevention and treatment of ARDS.

Clinical Protocols↗

PubMed1990

Management of multiple myeloma.

There has been little progress in the treatment of patients with multiple myeloma, and the average survival time is still only about 3 years. Although there have been significant therapeutic advances in recent years, clinical trials have only just begun. The major concern is, of course, the achievement of major disease control (which can be equated with a cure). The data available to date indicate that this is possible only with the use of allogeneic bone marrow transplantation, with which a survival plateau of around 30% can be attained. The trials should perhaps include the sequential use of all regimens with established efficacy in refractory myeloma. Immunoconjugate therapy with either radioisotopes or cytotoxic agents could also be envisioned, and expansion with suitable biological agents such as interleukin-2 could be considered. There is a plethora of promising treatment possibilities and novel concepts that may improve the dismal outlook for patients with multiple myeloma.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1992

Chemical markers of prebiotic chemistry in hydrothermal systems.

The goal of this chapter is to suggest some organic compounds which may be indicative of prebiotic processes in hydrothermal systems or laboratory simulations of them. While the exact processes which led to the origins of life are not known, studies of life's origins of the past forty years have uncovered a plethora of potential precursor molecules. Some of these same molecules were probably present in hydrothermal systems if chemical processes there had a role in the origins of life. The types of molecules formed in primitive Earth simulation experiments and observed in the interstellar medium, on comets and meteorites will be reviewed in Section 2 of this chapter. Some reactions involving these molecules which may have been important in prebiotic syntheses will be outlined. Since near- to supercritical water is found in hydrothermal systems, its properties and aspects of organic chemistry in supercritical water at high temperature and pressure will be discussed in Section 3. Fischer-Tropsch type (FTT) reactions, which are a potential source of the building blocks of biological molecules in hydrothermal systems, are discussed in Section 4. In the concluding section, Section 5, the possible formation in hydrothermal systems of organic molecules that are believed to have been important for the origins of life is discussed.

Chemistry, Organic↗