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Evolutionarily different RNA motifs and RNA-protein complexes to achieve selenoprotein synthesis.

A wealth of RNAs or RNA motifs are instrumental in controlling a variety of post-transcriptional or post-translational regulations. In this regard, selenocysteine incorporation in response to a redefined UGA stop codon certainly constitutes an intriguing and fascinating process. Translation elongation factors specialized for selenocysteine are needed to decode UGA selenocysteine codons. Discrimination between UGA selenocysteine and UGA stop codons also necessitates selenoprotein mRNA hairpins, called SECIS, that are internal to the coding frame in eubacteria or contained in the 3' untranslated regions in archaea/eukaryotes. This dichotomy leads to SECIS RNAs with distinct sequences and structures that tether the specialized translation elongation factor in a direct or indirect fashion, depending on the location of the SECIS RNA. The scope of this review is to bring a sharper focus on the SECIS RNA structures and SECIS RNA-protein complexes involved. Obviously, the examples described here highlight once again the versatility in form and function of RNA.

Base Sequence↗

Arthrogryposis multiplex congenita.

The common factor causing congenital arthrogryposis is lack of fetal movements. This can result from a large number of disorders. They may be neuropathic, affecting the brain, the spinal cord, or the peripheral nerves; they may be abnormalities of the muscles, such as myasthenia gravis, congenital muscular dystrophies or mitochondrial cytopathies; they may be diseases of the connective tissues; or they may be conditions which limit the space within the uterus; or they may result from defects of the uterine environment. These are discussed in turn. Typical clinical findings are given and it is emphasised that the arthrogryposis is often a manifestation of certain syndromes, some the result of abnormal chromosomes. Although it is not within the scope of this review article to describe these in detail, examples are given. In particular the subgroup of distal arthrogryposes and amyoplasia are considered. The importance of trying to define a cause is especially the need to give reliable genetic advice to the parents and also to establish a prognosis. The diagnosis will often be made by the associated symptoms and signs, and sometimes by tests such as electromyography and muscle biopsy. Although some of the diseases will be fatal early in life, there are many instances when the child will survive into adult life; if due attention is given to the treatment, particularly orthopedic procedures, and to social and educational management. This can only be done realistically if there is a good idea of the natural history of the condition underlying the arthrogryposis.

Arthrogryposis↗

Botulinum neurotoxins: from paralysis to recovery of functional neuromuscular transmission.

The neuromuscular junction is one of the most accessible mammalian synapses which offers a useful model to study long-term synaptic modifications occurring throughout life. It is also the natural target of botulinum neurotoxins (BoNTs) causing a selective blockade of the regulated exocytosis of acetylcholine thereby triggering a profound albeit transitory muscular paralysis. The scope of this review is to describe the principal steps implicated in botulinum toxin intoxication from the early events leading to a paralysis to the cellular response implementing an impressive synaptic remodelling culminating in the functional recovery of neuromuscular transmission. BoNT/A treatment promotes extensive sprouting emanating from intoxicated motor nerve terminals and the distal portion of motor axons. The current view is that sprouts have the ability to form functional synapses as they display a number of key proteins required for exocytosis: SNAP-25, VAMP/synaptobrevin, syntaxin-I, synaptotagmin-II, synaptophysin, and voltage-activated Na+, Ca2+ and Ca2+-activated K+ channels. Exo-endocytosis was demonstrated (using the styryl dye FM1-43) to occur only in the sprouts in vivo, at the time of functional recovery emphasising the direct role of nerve terminal outgrowth in implementing the restoration of functional neurotransmitter release (at a time when nerve stimulation again elicited muscle contraction). Interestingly, sprouts are only transitory since a second distinct phase of the rehabilitation process occurs with a return of synaptic activity to the original nerve terminals. This is accompanied by the elimination of the dispensable sprouts. The growth or elimination of these nerve processes appears to be strongly correlated with the level of synaptic activity at the parent terminal. The BoNT/A-induced extension and later removal of "functional" sprouts indicate their fundamental importance in the rehabilitation of paralysed endplates, a finding with ramifications for the vital process of nerve regeneration.

Acetylcholine↗

Oligonucleotide-mediated gene therapy for muscular dystrophies.

Several new approaches to gene therapy for the muscular dystrophies involve oligonucleotides as targeting vectors. These oligonucleotides are designed to repair genetic mutations, to modify genomic sequences in order to compensate for gene deletions, or to modify RNA processing in order to ameliorate the effects of the underlying gene mutation. Among the various approaches currently under investigation for dystrophin mutations that cause Duchenne muscular dystrophy is the use of chimeric RNA/DNA oligonucleotides ("chimeraplasts") to repair point mutations. Studies in the mdx mouse and the GRMD dog have demonstrated that point mutations in the dystrophin gene can be corrected by chimeraplasts that have been injected into muscles. The scope of this review includes a summary of the current status of chimeraplast-mediated gene repair for dystrophin mutations, ongoing studies to apply chimeraplast-mediated gene repair to frame-shift deletions of the dystrophin gene, and major hurdles that need to be overcome to translate current experimental successes into a viable therapeutic modality for Duchenne muscular dystrophy.

Animals↗

Functional diversity and regulation of different interleukin-1 receptor-associated kinase (IRAK) family members.

Interleukin-1 receptor-associated kinase (IRAK) was first described as a signal transducer for the proinflammatory cytokine interleukin-1 (IL-1) and was later implicated in signal transduction of other members of the Toll-like receptor (TLR)/IL-1 receptor (IL-1R) family. In the meantime, four different IRAK-like molecules have been identified: two active kinases, IRAK-1 and IRAK-4, and two inactive kinases, IRAK-2 and IRAK-M. All IRAKs mediate activation of nuclear factor-kappaB (NF-kappaB) and mitogen-activated protein kinase (MAPK) pathways. Although earlier observations suggested that IRAKs have redundant functions, this hypothesis is now challenged by knockout studies. Furthermore, recent data imply a role for IRAK-1 in tumor necrosis factor receptor (TNFR) superfamily-induced signaling pathways as well. The scope of this review is to highlight the specific role of different IRAKs and to discuss several mechanisms that contribute to their activation and regulation.

Amino Acid Sequence↗

The Smads: transcriptional regulation and mouse models.

The field of transforming growth factor-beta (TGF-beta) signaling sees periodic discoveries that revolutionize our thinking, redirect our experiments, and peak our excitement. One of the first such discoveries was less than a decade ago: the molecular cloning of the type I and type II TGF-beta receptors. This breakthrough defined a novel family of serine/threonine kinase receptors, which led to the description of an ever-expanding superfamily. The discovery of how these receptors are grouped on the cell surface, bind TGF-beta and are activated by specific phosphorylation events further defined the uniqueness of this system in comparison to other families of growth factor receptors. Now, once again, the TGF-beta field has been revolutionized. This time, the discovery is the Smad family of proteins. Although one can hardly imagine TGF-beta without the Smads, the cloning of the Smads and their implication in TGF-beta signaling was only four years ago. Since that time, great advances have been made in our understanding of the Smads as transcription factors, which are activated by receptor mediated phosphorylation. In addition, animal models for a loss of Smad function have provided insight into the role of specific Smads in a variety of physiologic systems. The Smad field has been growing exponentially. A comprehensive review of all aspects of the Smads, therefore, would be beyond the scope of a single review. Instead, this review highlights some of the general aspects of Smad function, and then focuses on the role of specific Smad family members in transcriptional regulation, animal physiology, and disease processes.

Animals↗

Antigen processing by proteasomes: insights into the molecular basis of crypticity.

Eight to eleven amino acid residues are the sizes of predominant peptides found to be associated with MHC class I molecules. Proteasomes have been implicated in antigen processing and generation of such peptides. Advanced methodologies in peptide elution together with sequence determination have led to the characterisation of MHC class I binding motifs. More recently, screening of random peptide phage display libraries and synthetic combinatorial peptide libraries have also been successfully used. This has led to the development and use of predictive algorithms to screen antigens for potential CTL epitopes. Not all predicted epitopes will be generated in vivo and the emerging picture suggests differential presentation of predicted CTL epitopes ranging from cryptic to immunodominant. The scope of this review is to discuss antigen processing by proteasomes, and to put forward a hypothesis that the molecular basis of immunogenicity can be a function of proteasomal processing. This may explain how pathogens and tumours are able to escape immunosurveillance by altering sequences required by proteasomes for epitope generation.

Antigen Presentation↗

Realism, instrumentalism, and scientific symbiosis: psychological theory as a search for truth and the discovery of solutions.

Scientific realism holds that scientific theories are approximations of universal truths about reality, whereas scientific instrumentalism posits that scientific theories are intellectual structures that provide adequate predictions of what is observed and useful frameworks for answering questions and solving problems in a given domain. These philosophical perspectives have different strengths and weaknesses and have been regarded as incommensurate: Scientific realism fosters theoretical rigor, verifiability, parsimony, and debate, whereas scientific instrumentalism fosters theoretical innovation, synthesis, generativeness, and scope. The authors review the evolution of scientific realism and instrumentalism in psychology and propose that the categorical distinction between the 2 is overstated as a prescription for scientific practice. The authors propose that the iterative deployment of these 2 perspectives, just as the iterative application of inductive and deductive reasoning in science, may promote more rigorous, integrative, cumulative, and useful scientific theories.

Humans↗

Introduction to the special section on developing guidelines for the evidence-based assessment (EBA) of adult disorders.

The goal of this special section is to encourage greater awareness of evidence-based assessment (EBA) in the development of a scientifically supported clinical psychology. In this introductory article, the authors describe the elements that authors in this special section were asked to consider in their focused reviews (including the scope of available psychometric evidence, advancements in psychopathology research, and evidence of attention to factors such as gender, age, and ethnicity in measure validation). The authors then present central issues evident in the articles that deal with anxiety, depression, personality disorders, and couple distress and in the accompanying commentaries. The authors conclude by presenting key themes emerging from the articles in this special section, including gaps in psychometric information, limited information about the utility of assessment, the discrepancy between recommended EBAs and current training and practice, and the need for further data on the process of clinical assessment.

Adult↗

Molecular Markov processes.

Markov processes are encountered in many contexts in physics and chemistry. This review surveys the scope of their application.

Journal Article↗

Current issues in adeno-associated viral vector production.

Adeno-associated virus (AAV) is currently one of the most promising systems for human gene therapy. Numerous preclinical studies have documented the excellent safety profile of these vectors along with their impressive performances in their favored target, consisting of highly differentiated postmitotic tissues such as muscle, central nervous system and liver. Clinical trials have been conducted confirming these data, but also emphasizing the requirement of further high-tech developments of the production and purification procedures that would allow both scaling-up and improvement of vector batch quality, necessary to human application. The scope of this review will be the state of the art in the various production methods of recombinant AAV (rAAV), delimiting their respective perimeter of application and also their main advantages and drawbacks, and thereby shedding light on the main challenges to take in the near future to bring AAV vectors more widely into the clinics.

Animals↗

Learning issues for nurses in renal satellite centres.

The introduction of 'satellite' dialysis centres has increased local access to renal services for patients living in rural and remote areas across Australia and is, therefore, consistent with rural health policies. Rural health strategies also aim to maintain and improve the skills of health professionals through regular review of the scope of their practice and evaluation of the education required. Yet, the results of the present national study of nurses working in satellite dialysis centres indicate that, for many, the context of practice influences their ability to access ongoing professional education to support and extend their nursing practice. The present study showed that there was a range of educational backgrounds among nurses working in rural 'satellite' centres with reportedly limited access to specific dialysis-related professional development. In the present paper we report on factors that influence the ability of nurses working in satellite dialysis centres to access ongoing professional education.

Adolescent↗

Management of peptic ulcer disease not related to Helicobacter.

Most peptic ulcers not due to Helicobacter pylori are caused by non-steroidal anti-inflammatory drugs (NSAID), among which an important subset are due to vascular protective ("low-dose") aspirin therapy. Non-steroidal anti-inflammatory drugs ulcers heal quite quickly when treated with a proton pump inhibitor (PPI), even though the NSAID is continued. If the NSAID can be stopped, the ulcers heal readily with either a PPI or a histamine H2-receptor antagonist (H2-RA). If anti-inflammatory treatment is still needed after ulcers are healed, prophylactic co-therapy with a PPI or misoprostol will reduce the risk of ulcer recurrence by about 60-80%. The alternative of switching to a highly selective cyclooxygenase-2 inhibitor has been shown to reduce the risk of a complicated ulcer by about 50-60%, unless low-dose aspirin treatment needs to be given as well for vascular disease. Idiopathic ulcers are becoming more frequent as H. pylori prevalence falls. Some may be sequelae of previous NSAID ulceration even though the NSAID has been ceased and the original ulcer had healed. These are best treated with an H2-RA or a PPI, followed by long-term maintenance with either of these (often in half the healing dosage) to prevent recurrence. Ulcers due to Zollinger-Ellison syndrome and other hypergastrinemia syndromes are rare, and largely beyond the scope of this review.

Anti-Inflammatory Agents, Non-Steroidal↗

Endothelin-1 and endothelin receptor antagonists in cardiovascular remodeling.

Endothelins build a peptide family composed of three isoforms, each of them containing 21 amino acids. Endothelin-1 is the isoform mainly responsible for any cardiovascular action and therefore the sole scope of this review. Endothelin-1 is the most potent endogenous vasoconstrictor known; in addition it acts as a potent (co)mitogen. There is a substantial body of experimental evidence that endothelin-1 may contribute not only to sustained vasoconstriction, but also to remodeling within the cardiovascular system. Thus, with the help of endothelin receptor antagonists (available for a few years) the involvement of mainly ETA receptors in structural diseases such as heart failure, pulmonary hypertension, atherosclerosis, restenosis, systemic hypertension, and chronic renal failure has been shown. These data make endothelin receptor antagonists, and especially those selective for the ETA receptor, promising agents for the treatment of chronic cardiovascular diseases associated with remodeling. Currently several chemically distinct, orally available members of this novel class of therapeutic agents are under clinical investigation.

Animals↗

Tissue transplant-transmitted infections.

Tissue bankers, as well as those transplanting tissues, have been sensitized to the possibility of transmission of fatal infection via tissue transplants, particularly following recent reports of a few cases of AIDS or HIV infection from bone, semen, and skin grafts. It is beyond the scope of this review to describe the steps taken by tissue banks to enhance the safety of tissue transplants. Of note is the fact that a number of new donor screening tests, such as those for antibody to HIV, HBcAg, hepatitis C virus, and human T cell lymphotropic virus type I, have recently been implemented. In addition, rapid advances in the medical history screening of tissue donors and tissue procurement, processing, and preservation continue. Viral inactivation studies are also being undertaken. All these measures are being introduced to increase the safety of tissue transplants.

Bacterial Infections↗

[Expired diagnosis?--the potential of exhaled breath analysis].

Analysis of breath condensate is an innovative approach to biochemical information from the lung. It provides a new tool to estimate and characterize the burden of oxidative and inflammatory processes in the airways/lung. Clinical applications in asthma, COPD and CF can be envisioned as well as determining organ-specific inflammation in mechanically ventilated patients or monitoring patients with transplanted lungs. However, besides inflammation other important areas have begun to be evaluated, such as the demonstration of p53 mutations in NSCLC patients or an increased ratio of EBC nitrite to tidal volume in mechanically stressed lungs. Of course a careful validation of each and every parameter is paramount to the use in clinical applications. The comparison to BAL is oftentimes called for but at the same time is not the comparison to a gold standard because of the well-known problems of BAL. The scope of this review is a summary of facts and theories concerning exhaled breath condensate generation, collection and analysis but at the same time the representation of the many aspects that remain to be resolved.

Breath Tests↗

Breast imaging.

The majority of information available today indicates that the most efficient and accurate method of screening women to detect early-stage breast cancer is an aggressive program of patient self-examination, physical examination by well-trained, motivated personnel, and high-quality x-ray mammography. There are two important factors in the implementation of mammographic screening. The first is the availability of facilities to perform high-quality, low-dose mammography, which is directly related to the second factor: the expense to society for support of this large-scale effort. Cost-benefit analysis is beyond the scope of this review. In 1979 Moskowitz and Fox attempted to address this issue, using data from the Breast Cancer Detection Demonstration Project in Cincinnati, but additional analysis is required. The cost for each "curable" cancer that is detected must be compared with the psychological, social, and personal losses that accrue, as well as the numerous medical expenses incurred, in a frequently protracted death from breast cancer. All other imaging techniques that have been reviewed should be regarded as adjuncts to rather than replacements for mammographic screening (Table 1). Ultrasound and computerized tomography are helpful when the physical examination and mammogram are equivocal. Other techniques, such as transillumination, thermography, and magnetic-resonance imaging, should be considered experimental. In patients with clinically evident lesions, x-ray mammography is helpful to evaluate the suspicious area, as well as to "screen" the remaining tissue in both breasts and to search for multicentric or bilateral lesions. Mammography is the only imaging technique that has been proved effective for screening. The low doses required by present-day mammographic technology pose a possible risk that is so small it is not measurable. The image quality has improved considerably over the past decade, and data supporting the benefits of mammography are increasing. As a result, the American Cancer Society has recently modified its recommendations to include mammographic screening of asymptomatic women beginning at the age of 40 years (Table 2). Before any new system can be considered a replacement for mammographic screening, carefully executed trials are necessary to prove efficacy beyond anecdotal claims.

Adult↗

Cortico-amygdala circuits: role in the conditioned stress response.

The amygdala plays a crucial role in the orchestration and modulation of the organism response to aversive, stressful events. This response could be conceived as the result of two interdependent components. The first is represented by sets of visceral and motor responses aimed at helping the organism to cope with the present event. The second is the acquisition and modulation of memories relative to the stressful stimulus and its context. This latter component contributes to the instatement of conditioned stress responses that are essential to the capability of the organism to predict future exposures to similar stimuli in order to avoid them or counteract them effectively. In the amygdala, these two components become fully integrated. Massive networks link the amygdala to the hypothalamus, midbrain and brainstem. These networks convey visceral, humoral and nociceptive information to the amygdala and mediate its effects on the hypothalamic-pituitary-adrenal axis as well on autonomic and motor centers. On the other hand, interactions between the amygdala and interconnected cortical networks play a crucial role in acquisition, consolidation and extinction of learning relative to the stressful stimulus. Within the scope of this review, current evidence relative to the interaction between the amygdala and cortical networks will be considered in relationship to the integration of the conditioned response to stress.

Amygdala↗