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PubMed1997

Factors that may influence future approaches to the eating disorders.

The past thirty years have seen dramatic changes in our approach to the eating disorders. These include marked improvements in the recognition and understanding of the disorders, and the reduction of the morbidity and mortality of anorexia and bulimia nervosa. Bulimia nervosa itself, now the focus of so much attention, was described less than twenty years ago. While these gains, including those in the level of knowledge and appreciation by the public, have been transmitted to the benefit of patients, there remain significant difficulties in treating people with eating disorders. Critical research may address gaps in knowledge and lead to more efficacious treatments. At the same time, however, changes in the health care system are occurring rapidly and these will have an effect on both research and treatment. The purpose of the present article is to highlight scientific and systemic factors that the authors feel will play an important role in how people with eating disorders are responded to in the coming years. In addressing the eating disorders we are confining our remarks to anorexia and bulimia nervosa, and not to obesity; the latter would require consideration of many other issues, beyond the scope of this review.

Adolescent↗

PubMed2005

Ejaculatory disorders: epidemiology and current approaches to definition, classification and subtyping.

Ejaculatory disorders (disorders of emission, ejaculation and orgasm) are the most frequent sexual complaint. Conventional algorithms on ejaculatory disorders are based on an organic or psychogenic dichotomy, with the latter being traditionally considered the main etiological cause. The scope of this review is to propose a new classification of ejaculatory disorders, with special emphasis on epidemiology and subtyping of the most frequent: premature ejaculation (PE). There is growing agreement on definition, diagnosis, and treatment options. In many cases, ejaculatory disorders can be classified by psycho-neuro-uro-endocrine symptoms. Epidemiological data, new classifications and subtyping, together with new diagnostic procedures and the availability of pharmacological aids, place this topic in the mainframe of sexual medicine. This will soon demolish the barriers to seeking help perceived by patients suffering ejaculatory disorders.

Ejaculation↗

PubMed2006

Renal transplantation in HUS patients with disorders of complement regulation.

Haemolytic uraemic syndrome (HUS) is the primary diagnosis of 4.5% of children on chronic renal replacement therapy. Approximately 5% of all HUS cases have an "atypical" or recurrent course. Atypical HUS is an inadequate term that applies to a heterogeneous group of conditions. We describe this group as non-diarrhoeal (D-) ), non-EHEC (EHEC - ) HUS. Patients in the non-diarrhoeal, non-EHEC, relapsing group are much more likely to exhibit severe hypertension, histological findings of arterial as well as arteriolar disease, chronic and end-stage renal failure. In general, these patients have an alarmingly high risk of graft loss from disease recurrence or thrombosis ranging from 60-100%. Family history is crucial, and where family members have relapsing disease, transplantation is a very high risk procedure (recurrence 100%). Patients with (D-)HUS need very careful consideration before transplantation, including molecular investigation of complement regulators (and von Willebrandt protease (ADAMTS13) activity, although this goes beyond the scope of this review). Guidelines are accessible under http://www.espn.ucwm.ac.uk . On no account should live related donation take place unless the risks of graft loss are understood. International collaboration to identify safer ways of transplanting these challenging patients is urgently needed.

ADAM Proteins↗

PubMed2003

Pharmacotherapy of painful diabetic neuropathy.

The scope of this review is to describe the epidemiology, physiology, symptomatology, and treatment of diabetic painful neuropathy, which is a common complication of diabetes with significant morbidity. This article focuses on treatment options. Various clinical trials of several classes of medications (eg, antidepressants, anticonvulsants, and topical medications) and alternative treatments (eg, acupuncture, electrostimulation, magnets) are reviewed. Physicians have a large panel of medications that can be used effectively solely or in combination at their disposal. However, a number of these treatments have significant side effects, which are noted, that limit their use. As the understanding of the pathophysiologic mechanisms of diabetic neuropathy improves, new medications are under investigation, which are reviewed in this article. There is great hope that the future may hold treatments that would prevent nerve damage.

Diabetic Neuropathies↗

PubMed1996

Separation of negatively charged carbohydrates by capillary electrophoresis.

Capillary electrophoresis (CE) has recently emerged as a highly promising technique consuming an extremely small amount of sample and capable of the rapid, high-resolution separation, characterization, and quantitation of analytes. CE has been used for the separation of biopolymers, including acidic carbohydrates. Since CE is basically an analytical method for ions, acidic carbohydrates that give anions in weakly acid, neutral, or alkaline media are often the direct objects of this method. The scope of this review is limited to the use of CE for the analysis of carbohydrates containing carboxylate, sulfate, and phosphate groups as well as neutral carbohydrates that have been derivatized to incorporate strongly acidic functionality, such as sulfonate groups.

Carbohydrate Sequence↗

PubMedDate not supplied

Mechanical loads and the isovolumic and filling indices of left ventricular relaxation.

In this report we have emphasized the significant influence of loading conditions on LV relaxation. Changes in inotropic state, ischemia, hypertrophy, and a host of other factors were not discussed herein. Ventricular asynchrony is likewise beyond the scope of this review, but it should be recognized that complex loading interactions among fibers within the LV wall influence relaxation and filling in ventricles that contract and relax nonsynchronously. Intact heart and isolated muscle experiments indicate that changes in preload do not influence relaxation rates when systolic pressure or total load remains constant. It appears, therefore, that the relaxation changes that occur with volume loading are primarily due to changes in systolic pressure or load. Indeed, an increase in systolic pressure may cause a substantial decrease in isovolumic relaxation rate, especially if there is a slow rise and a late peak in LV pressure. By contrast, an abrupt increase in late systolic load augments relaxation rate. Intact heart studies indicate that an abrupt load increment near the end of ejection results in premature and more rapid isovolumic relaxation, while an increase in left atrial pressure increases the filling rate; isolated muscle studies indicate that a load increment at the end of isometric relaxation causes an increase in isotonic relaxation rate. Thus, loading conditions during the periods of ejection, isovolumic relaxation, and filling can influence relaxation parameters and should be considered in clinical and experimental studies of LV relaxation.

Animals↗

PubMed1992

Protein secretion in gram-positive bacteria.

Gram-positive bacteria often secrete large amounts of proteins into the surrounding medium. This feature makes them attractive as hosts for the industrial production of extracellular enzymes. Compared to Escherichia coli, relatively little is known about the mechanism of protein secretion in these organisms. However, the recent identification of Bacillus subtilis genes whose gene products are highly homologous to some of the Sec (secretion) proteins of E. coli strongly suggests that important principles of protein translocation across the plasma membrane might be highly conserved. In contrast, the steps following the actual translocation event might be different in Gram-positive and Gram-negative bacteria. The scope of this review is to outline the recent progress that has been made in the elucidation of the secretion pathway in Gram-positive bacteria and to discuss potential applications in strain improvement for the industrial production of extracellular proteins.

Bacterial Proteins↗

PubMed1995

Eicosanoids, fatty acids and neutrophils: their relevance to the pathophysiology of disease.

PUFA and their eicosanoid metabolites are potent biological modifiers. They have beneficial effects in a number of diseases, which may result in part from their direct actions on neutrophils as well as from their ability to modulate eicosanoid biosynthesis. A consideration of their interactions with other cell types, e.g. lymphocytes and macrophages, is beyond the scope of this review. Small alterations in structure can result in large changes in the neutrophil response. This will have important implications for the further development and use of fatty acids for therapeutic purposes.

Animals↗

PubMed2006

Display technologies: application for the discovery of drug and gene delivery agents.

Recognition of molecular diversity of cell surface proteomes in disease is essential for the development of targeted therapies. Progress in targeted therapeutics requires establishing effective approaches for high-throughput identification of agents specific for clinically relevant cell surface markers. Over the past decade, a number of platform strategies have been developed to screen polypeptide libraries for ligands targeting receptors selectively expressed in the context of various cell surface proteomes. Streamlined procedures for identification of ligand-receptor pairs that could serve as targets in disease diagnosis, profiling, imaging and therapy have relied on the display technologies, in which polypeptides with desired binding profiles can be serially selected, in a process called biopanning, based on their physical linkage with the encoding nucleic acid. These technologies include virus/phage display, cell display, ribosomal display, mRNA display and covalent DNA display (CDT), with phage display being by far the most utilized. The scope of this review is the recent advancements in the display technologies with a particular emphasis on molecular mapping of cell surface proteomes with peptide phage display. Prospective applications of targeted compounds derived from display libraries in the discovery of targeted drugs and gene therapy vectors are discussed.

Animals↗

PubMed2004

Bcl-2 proteins: master switches at the intersection of death signaling and the survival control by Raf kinases.

Bcl-2 family members are central to the control of cell survival. Work of the last years has established that the function of these proteins can be regulated by mitogenic signaling cascades. Within the scope of this review, we will discuss the contribution of Bcl-2-dependent signaling pathways to cell survival by Raf kinases and also address the underlying mechanisms.

Animals↗

PubMed2007

The diagnostic workup of patients with neuropathic pain.

Determining the causes of neuropathic pain is more than an epistemological exercise. At its essence, it is a quest to delineate mechanisms of dysfunction through which treatment strategies can be created that are effective in reducing, ameliorating, or eliminating symptomatology. To date, predictors of which patients will develop neuropathic pain or who will respond to specific therapies are lacking, and present therapies have been developed mainly through trial and error. Our current inability to make therapeutically meaningful decisions based on ancillary test data is illustrated by the following: In a study specifically designed to assess the response of patients with painful distal sensory neuropathies to the 5% lidocaine patch, no relationship between treatment response and distal leg skin biopsy, QST, or sensory nerve conduction study results could be established. From a mechanistic perspective, the hypothesis that the lidocaine patch would be most effective in patients with relatively intact epidermal innervation, whose neuropathic pain is presumed attributable to "irritable nociceptors," and least effective in patients with few surviving epidermal nociceptors, presumably with "deafferentation pain," was unproven. The possible explanations are multiple and outside the scope of this review. However, these findings, coupled with the disparity in C-fiber subtype involvement in diabetic small-fiber neuropathy, and the recently reported inability of enzyme replacement therapy in Fabry disease to influence intraepidermal innervation density, while having mixed effects on cold and warm QST thresholds, and beneficial effects on sudomotor findings, when therapeutic benefit was demonstrated, lead one to conclude that the specificity of ancillary testing in neuropathic pain is inadequate at present, and reinforce the aforementioned caveats about inferential conclusions from indirect data. The diagnosis of neuropathic pain mechanisms is in its nascent stages and ancillary testing remains "subordinate," "subsidiary," and "auxiliary" as defined in Webster's Third New International Dictionary. As a consequence of these difficulties, the recent approach by Bennett and his colleagues may have merit. They have hypothesized (and provide data in support) that chronic pain can be more or less neuropathic on a spectrum between "likely," "possible," and "unlikely," based on patient responses on validated neuropathic pain symptom scales, when compared with specialist pain physician certainty of the presence of neuropathic pain on a 100-mm visual analog scale. The symptoms most associated with neuropathic pain were dysesthesias, evoked pain, paroxysmal pain, thermal pain, autonomic complaints, and descriptions of the pain as being sharp, hot, or cold, with high sensitivity. Higher scores for these symptoms correlated with greater clinician certainty of the presence of neuropathic pain mechanisms. Considering each individual patient's chronic pain as being somewhere on a continuum between "purely nociceptive" and "purely neuropathic" may have diagnostic and therapeutic relevance by enhancing specificity, but this requires clinical confirmation. Thus, symptom assessment remains indispensable in the evaluation of neuropathic pain, ancillary testing notwithstanding

Autonomic Nervous System↗

PubMed2006

Evolution of cancer stem cells.

Cancer as a disease driven by cancer stem cells is a concept that has emerged over the last few years. However, several issues relating to this phenomenon as yet remain unaddressed. A fundamental question is one relating to the identification of events leading to transformation of a normal tissue stem cell to a cancer stem cell. Complete knowledge of this evolutionary process may be crucial for the development of novel effective therapies that influence patient prognosis. The scope of this review is to discuss reports that have begun to elucidate stem cell transformation either as an isolated event or as a progression as an attempt towards understanding some of the critical events involved in the process.

Animals↗

PubMed2006

Sea anemone venom as a source of insecticidal peptides acting on voltage-gated Na+ channels.

Sea anemones produce a myriad of toxic peptides and proteins of which a large group acts on voltage-gated Na+ channels. However, in comparison to other organisms, their venoms and toxins are poorly studied. Most of the known voltage-gated Na+ channel toxins isolated from sea anemone venoms act on neurotoxin receptor site 3 and inhibit the inactivation of these channels. Furthermore, it seems that most of these toxins have a distinct preference for crustaceans. Given the close evolutionary relationship between crustaceans and insects, it is not surprising that sea anemone toxins also profoundly affect insect voltage-gated Na+ channels, which constitutes the scope of this review. For this reason, these peptides can be considered as insecticidal lead compounds in the development of insecticides.

Amino Acid Sequence↗

PubMed1977

Neonatal oncology.

All known tumor types have been reported in the neonate. A numerical listing and discussion are beyond the scope of this review. Wells and Fraumeni give some insight into common congenital malignant neoplasms. Table 2 lists the percentage of neonatal deaths caused by type-specific cancers. Retinoblastoma is probably the most common malignant tumor in the neonate. About seven per cent of these tumors have been apparent at birth. This tumor is not discussed in either article because it is not lethal until muypes in neonatal and pediatric patients. Some congenital malformations in the in the neonate are recognized as being frankly benign (cysts), potentially malignant (teratomas), and frankly malignant (neuroblastoma). A high percentage of teratomas are benign in the newborn period. Leukemia in the newborn appears to be more aggressive yet neuroblastoma has a better prognosis. More studies are needed to help us define why the neonate does better with some tumors and worse with others. Surface cell markers on neonatal leukemia, B and T cell function studies, and other immunologic surveillance studies are needed. Study of neonatal oncology may add to our knowledge of carcinogenesis and oncogenesis in the future.

Child↗

PubMed1997

Modulation of ventilatory control during exercise.

The control of ventilatory responses to mild or moderate dynamic exercise has been the subject of considerable debate for over a century. The prevailing view has been that the ventilatory response to exercise is stereotypical and rather unmalleable. However, paradigms involving novel associations of stimulus inputs have been shown to modulate breathing in short and longer time scales. The scope of this review includes examples of modified ventilatory responses to exercise which have been investigated in terms of neural mechanisms. An attempt to synthesise the available data into a model of neuromodulation is presented.

Animals↗

PubMed1979

Recent advances in human cellular immunobiology.

Several recent advances in human cellular immunology will have increasing impact on surgical science. First, lymphocytes are composed of diverse subpopulations with different biological properties. Second, lymphocytes and phagocytes expressed distinctive cell surface markers that reflect the specialized function of each cell. Third, different subpopulations of lymphocytes probably have one or only a few specific functions rather than being multipotential. Despite the seemingly complex heterogeneity of the immune system, the component parts collaborate in a highly integrated fashion. The recent elucidation of suppressor cells and their interaction with effector cells, for example, is a major conceptual advance. Fourth, the technology of immunologic science has advanced significantly. More discriminating methods for detecting lymphocyte markers and the ability to physically separate and analyze lymphocyte subpopulations will permit increasingly more refined insights into normal and abnormal immune responses. A number of important advances at the molecular level involving the disciplines of immunogenetics and immunochemistry have also been described but are beyond the scope of this review. Much work remains, however, in correlating these in vitro observations in the laboratory with in viro activity in the patient. It is now evident that the outcome of an immune response (or lack of it) represents a net balance of different components in the immunologic network that determine the time course, intensity of response, and the actual mechanisms of antigen elimination. A better understanding of these component parts of a normal immune response, and their deviations in disease states, is essential for designing more sophisticated therapeutic manipulations of the immune system. Attempts at "immune manipulation" aimed at stimulating or depleting the entire system are no more likely to be successful or reproducible than are attempts to "manipulate" the entire endocrine system. More meaningful results will occur when one can deal with individual components of an immune response (such as suppression or killing) and can precisely monitor the consequences of altering them.

Animals↗

PubMed2006

3. Protein-protein interactions of the developing enamel matrix.

Extracellular matrix proteins control the formation of the inorganic component of hard tissues including bone, dentin, and enamel. The structural proteins expressed primarily in the enamel matrix are amelogenin, ameloblastin, enamelin, and amelotin. Other proteins, like biglycan, are also present in the enamel matrix as well as in other mineralizing and nonmineralizing tissues of mammals. In addition, the presence of sulfated enamel proteins, and "tuft" proteins has been examined and discussed in relation to enamel formation. The structural proteins of the enamel matrix must have specific protein-protein interactions to produce a matrix capable of directing the highly ordered structure of the enamel crystallites. Protein-protein interactions are also likely to occur between the secreted enamel proteins and the plasma membrane of the enamel producing cells, the ameloblasts. Such protein-protein interactions are hypothesized to influence the secretion of enamel proteins, establish short-term order of the forming matrix, and to mediate feedback signals to the transcriptional machinery of these cells. Membrane-bound proteins identified in ameloblasts, and which interact with the structural enamel proteins, include Cd63 (cluster of differentiation 63 antigen), annexin A2 (Anxa2), and lysosomal-associated glycoprotein 1 (Lamp1). These and related data help explain the molecular and cellular mechanisms responsible for the removal of the organic enamel matrix during the events of enamel mineralization, and how the enamel matrix influences its own fate through signaling initiated at the cell surface. The knowledge gained from enamel developmental studies may lead to better dental and nondental materials, or materials inspired by Nature. These data will be critical to scientists, engineers, and dentists in their pursuits to regenerate an entire tooth. For tooth regeneration to become a reality, the protein-protein interactions involving the key dental proteins must be identified and understood. The scope of this review is to discuss the current understanding of protein-protein interactions of the developing enamel matrix, and relate this knowledge to enamel biomineralization.

Amelogenin↗

PubMed2003

Manipulation of the mouse genome: a multiple impact resource for drug discovery and development.

Few would deny that the pharmaceutical industry's investment in genomics throughout the 1990s has yet to deliver in terms of drugs on the market. The reasons are complex and beyond the scope of this review. The unique ability to manipulate the mouse genome, however, has already had a positive impact on all stages of the drug discovery process and, increasingly, on the drug development process too. We give an overview of some recent applications of so-called 'transgenic' mouse technology in pharmaceutical research and development. We show how genetic manipulation in the mouse can be employed at multiple points in the drug discovery and development process, providing new solutions to old problems.

Animals↗