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PubMed2002

Chronic obstructive lung diseases and occupational exposure.

The scope of this review is to highlight important and interesting articles in the field of the epidemiology of chronic obstructive pulmonary disease and occupational exposure. Relevant information from the literature published within the past year, either on general population samples or on workplaces, indicates that a substantial proportion of asthma and chronic obstructive pulmonary diseases are work related. Methods of investigation include self-reported or interview-obtained questionnaires, job title and job exposure matrix, as well as voluntary or mandatory notifications. Furthermore, data on lung function and immunological tests are available. Specific settings and agents are quoted that have been indicated or confirmed as being linked to chronic obstructive pulmonary disease. In conclusion, occupational exposure to dusts, chemicals and gases will be considered an established, or supported by good evidence, risk factor for chronic obstructive pulmonary disease. The implications of this substantial occupational contribution to asthma and chronic obstructive pulmonary disease must be considered in research planning, in public policy decision-making, and in clinical practice.

Asthma↗

PubMed2001

Allergen-specific immunotherapy in allergic rhinitis.

The scope of this review is to highlight important and interesting articles in the field of allergen-specific immunotherapy in allergic rhinitis published within the past year. The review is not intended to give a full overview of published literature but rather to focus on some subjects that I find significant in relation to the understanding of the specific treatment of allergies and to the selection of different treatment modalities. The most important aspects are how to define the most suitable candidates for the specific treatment, the mechanisms of action of immunotherapy and how to optimize treatment, and finally I include some reflections on the optimal presentation of the allergen to the immune system.

Allergens↗

PubMed2002

How can we learn to live with rivers? The findings of the Institution of Civil Engineers Presidential Commission on flood-risk management.

In the wake of the floods of 1998 and 2000 the Government invited the Institution of Civil Engineers (ICE) to carry out a technical review of flood-risk management in England and Wales and to consider the most appropriate approaches to flood-risk management for the 21st century. The findings of this Commission are published in the ICE report Learning to live with rivers. Further information on the Commission and its work is available at www.icenet.org.uk/presidential.htm. This paper provides an introduction to the need for such a review and the scope of the Commission's work. A summary of the findings of the Commission are presented along with key recommendations for improved flood-risk management in the future.

Advisory Committees↗

PubMed2005

Liver cancer: the role of stem cells.

Studies of aggregation chimaeras and X-linked polymorphisms strongly suggest that liver tumours are derived from single cells (monoclonal), but the important question is, which cell? Stem cell biology and cancer are inextricably linked. In continually renewing tissues such as the gut mucosa and epidermis, where a steady flux of cells occurs from the stem cell zone to the terminally differentiated cells that are imminently to be lost, it is widely accepted that cancer is a disease of stem cells, since these are the only cells that persist in the tissue for a sufficient length of time to acquire the requisite number of genetic changes for neoplastic development. In the liver the identity of the founder cells for the two major primary tumours, hepatocellular carcinoma and cholangiocarcinoma, is more problematic. The reason for this is that no such obvious unidirectional flux occurs in the liver, although it is held that the centrilobular hepatocytes may be more differentiated (polyploid) and closer to cell senescence than those cells closest to the portal areas. Moreover, the existence of bipotential hepatic progenitor cells, along with hepatocytes endowed with longevity and long-term repopulating potential suggests there may be more than one type of carcinogen target cell. Cell proliferation at the time of carcinogen exposure is pivotal for 'fixing' any genotoxic injury into a heritable form, thus any proliferative cell in the liver can be susceptible to neoplastic transformation. Hepatocytes are implicated in many instances of hepatocellular carcinoma, direct injury to the biliary epithelium implicates cholangiocytes in some cases of cholangiocarcinoma, while hepatic progenitor cell/oval cell activation accompanies many instances of liver damage irrespective of aetiology, making such cells very likely carcinogen targets. Of course, we must qualify this assertion by stating that many carcinogens are both cytotoxic and cytostatic, and that hepatic progenitor cell proliferation may be merely a bystander effect of this toxicity. An in-depth discussion of causes of cancer in the liver is beyond the scope of this review, but infectious agents (e.g. hepatitis B and C viruses) play a major role, not just in transactivating or otherwise disrupting cellular proto-oncogenes (hepatitis B virus), but also in causing chronic inflammation (hepatitis C and B viruses). Sustained epithelial proliferation in a milieu rich in inflammatory cells, growth factors and DNA-damaging agents (reactive oxygen and nitrogen species--produced to fight infection), will lead to permanent genetic changes in proliferating cells. Up-regulation of the transcription factor NF-kappaB in transformed hepatocytes, through the paracrine action of TNF-alpha from neighbouring endothelia and inflammatory cells, may be critical for tumour progression given the mitogenic and antiapoptotic properties of proteins encoded by many of NF-kappaB's target genes.

Animals↗

PubMedDate not supplied

Tissue engineering of bone: the reconstructive surgeon's point of view.

Bone defects represent a medical and socioeconomic challenge. Different types of biomaterials are applied for reconstructive indications and receive rising interest. However, autologous bone grafts are still considered as the gold standard for reconstruction of extended bone defects. The generation of bioartificial bone tissues may help to overcome the problems related to donor site morbidity and size limitations. Tissue engineering is, according to its historic definition, an "interdisciplinary field that applies the principles of engineering and the life sciences toward the development of biological substitutes that restore, maintain, or improve tissue function". It is based on the understanding of tissue formation and regeneration and aims to rather grow new functional tissues than to build new spare parts. While reconstruction of small to moderate sized bone defects using engineered bone tissues is technically feasible, and some of the currently developed concepts may represent alternatives to autologous bone grafts for certain clinical conditions, the reconstruction of large-volume defects remains challenging. Therefore vascularization concepts gain on interest and the combination of tissue engineering approaches with flap prefabrication techniques may eventually allow application of bone-tissue substitutes grown in vivo with the advantage of minimal donor site morbidity as compared to conventional vascularized bone grafts. The scope of this review is the introduction of basic principles and different components of engineered bioartificial bone tissues with a strong focus on clinical applications in reconstructive surgery. Concepts for the induction of axial vascularization in engineered bone tissues as well as potential clinical applications are discussed in detail.

Bioartificial Organs↗

PubMedDate not supplied

In search of a stem cell hierarchy in the human breast and its relevance to breast cancer evolution.

By deliberate analogy with the well-established concept of hematopoiesis, the term "mammopoiesis" is occasionally used to describe the development of the different cellular lineages and functional units in the mammary gland. The use of this term signifies a strong bias towards the idea that tissue homeostasis during mammary development, pregnancy, lactation and involution is brought about by the action of somatic stem cells characterized by longevity and multipotency. The progenies hereof eventually differentiate into structurally and functionally well-defined ductal-lobular units. During the past two decades evidence of such a notion in the mouse has developed from being largely circumstantial based on non-clonal in vivo experiments to a quite elaborate characterization of individual candidate stem cells by a number of different properties. Within tumor biology this has led to a renaissance of the concept of tumors as caricatures of tissue renewal. Thus, recent molecular classification of breast cancer based on genome wide expression analysis operates with different subtypes with specific reference to the normal luminal epithelial and myoepithelial/basal lineages in the breast. Apparently some tumors are lineage restricted and others differentiate more broadly as if they have preserved some stem-like properties. This holds promise for the existence of a stem cell hierarchy, the understanding of which may prove to be instrumental in further dissecting the histogenesis of breast cancer evolution. Most attention has been devoted to the question of different cellular origins of cancer subtypes and different susceptibilities of possible stem cells to gain or loss of oncogenes and tumor suppressor genes, respectively. Invaluable progress has been made over the past two decades in culture technology not only in terms of population doubling and clonal growth, but also the availability of lineage specific markers, cell sorting, and three-dimensional functional assays for tissue specific morphogenesis. Transcriptional profiling of stem cell zones has unraveled a hitherto unknown preservation of signaling pathways for maintenance of stem cell properties across tissue boundaries and species. Somatic stem cells have therefore been narrowed down to specific anatomic locations not only in rapidly renewing tissues such as skin and skin derivatives, but also in tissues with slower turnover times, such as lung, kidney and prostate. It is therefore now possible to integrate this information in a search for similar cells within the breast. Even if cell turnover after birth is provided exclusively by dividing lineage-restricted cells, more information about the robustness of breast differentiation programs during tumor progression is still very much required. Complete knowledge of the primary cell of origin of breast cancer and the mechanisms that influence differentiation programs during tumor initiation, promotion and progression may be crucial for the development of novel non-toxic therapies that influence tumor cell behaviour. The scope of this review is to discuss reports that have begun to elucidate the topographic location, key cellular type and lineage fidelity in culture and xenograft models of candidate human breast stem cells and their differentiated progenies with particular emphasis on comparison with the differentiation programs of tumor subtypes.

Animals↗

PubMed1995

Perforin and lymphocyte-mediated cytolysis.

We have discussed in the previous sections the recent progress made toward elucidating the regulatory mechanism of perforin gene transcription and the domain structure of the perforin molecule. It appears that the expression of perforin is, at least partially, controlled at the transcription level through the interaction between killer cell-specific cis- and trans- acting factors. One of such cognate pairs, NF-P motif (an EBS-homologous motif) and NF-P2 (a killer cell-specific DNA-binding protein), has been described. The regulatory mechanism of gene transcription, however, is likely to involve multiple factors which act in a coordinated fashion to bring about the most efficient expression of perforin limited strictly to activated killer lymphocytes. Through studies using synthetic peptides and recombinant perforins, it has been suggested that the N-terminal region of the perforin molecule is an important, though not the only, domain responsible for the lytic activity. Further studies are warranted to elucidate the role(s) of other potential amphiphilic structures located in the central portion of the perforin molecule in the overall pore-forming activity. The molecular basis underlying the resistance of killer lymphocytes to perforin-mediated lysis still remains an open question. Preliminary results, however, suggest that the surface protein(s) restricted to killer cells may account for their self-protection against perforin. Based on recent studies using perforin-deficient mice, the involvement of perforin in lymphocyte-mediated cytolysis both in vivo and in vitro has been confirmed. Two functional roles, a direct (lytic) and an indirect (endocytosis enhancer; conduit), both of which may contribute critically to the cell-killing event can be attributed to perforin. The fact that lymphocytes may also employ perforin-independent killing mechanism(s), e.g. Fas-dependent pathway, is beyond the scope of this review. There is, nevertheless, no doubt that these alternative cytolytic mechanisms may also play important roles in immune effector and/or regulatory responses associated with killer lymphocytes. Obviously, we are still a long way from concluding on the functional relevance of each individual cytolytic mechanism seen in different physiopathological situations. Suffice it to say, however, that a wealth of information on lymphocyte-mediated killing has already emerged through the multidisciplinary efforts conducted in our and other laboratories that promise to further dissect this complicated event in the years to come.

Amino Acid Sequence↗

PubMed1993

The ubiquitin-mediated proteolytic pathway.

Ubiquitin modification of a variety of protein targets within the cell plays important roles in many cellular processes. Among these are regulation of gene expression, regulation of cell cycle and division, involvement in the cellular stress response, modification of cell surface receptors, DNA repair, and biogenesis of mitochondria and ribosomes. The best studied modification occurs in the ubiquitin-dependent proteolytic pathway. Degradation of a protein by the ubiquitin system involves two discrete steps. Initially, multiple ubiquitin molecules are covalently linked in an ATP-dependent mode to the protein substrate. The protein moiety of the conjugate is then degraded by a specific protease into free amino acids with the release of free and reutilizable ubiquitin. This process also requires energy. In addition, stable mono-ubiquitin adducts are also found intracellularly, for example, those involving nucleosomal histones. Despite the considerable progress that has been made in elucidating the mode of action and roles of the ubiquitin system, many problems remain unsolved. For example, very little is known about the cellular substrates of the system and the signals that target them for conjugation and degradation. The scope of this review is to summarize briefly what is currently known on the role of the ubiquitin system in protein turnover, and to discuss in detail the mechanisms involved in selection of substrates for conjugation and in degradation of ubiquitin-conjugated proteins.

Animals↗

PubMedDate not supplied

A practical approach to the molecular biology of kidney diseases: from basic science to bed side.

Nowadays, the term "Molecular Biology" (MB) is generally a pplied to the biochemical processes that involve genes and the expression of proteins for which specific genes code. In recent years, astonishing advances have occurred in this field. Currently, there are many important powerful techniques allowing scientists to study the molecular mechanisms involved in many human genetic diseases. Furthermore, it is important to underline that the possibilities are not limited to the diagnosis and study of these genetic diseases. Indeed, by studying gene expression, MB also allows the molecular study of many acquired diseases such as viral hepatitis and cancer.Therefore, these major advances in the knowledge of gene biology are facilitating the arrival of a new era of gene therapy. This article will describe the most important techniques currently used in MB. Firstly, techniques involved in recombinant DNA technology will be discussed and these will include the study of DNA and the possibility of identifying the expression of abnormal genes, e.g. to identify individuals for paternity. Secondly, a description of techniques designed to study the expression of genes and their regulation will follow and they involve the study of RNA. Thirdly, the impact of genetic molecular studies as tools for medical diagnosis will be discussed and analysed. Finally, a discussion concerning the rational basis for gene therapy and its future perspectives is included. In this article, we have focused on technical or diagnostic aspects ofMolecular Biology. Although Ethics are also an interesting issue to deal with, theseissues are far beyond the scope of this review.

DNA Fingerprinting↗

PubMed2005

Anaesthesia in austere environments.

The scope of this review is by necessity somewhat limited and, as said in the introduction, methods used will depend on the skills and experience of the practitioner involved. The triservice apparatus remains the system of choice for delivering volatile anaesthetic agents to patients in areas without the infrastructure to supply an endless quantity of medical gases, the planned isolated or battle conditions of Boultons scenarios. The TSA's portability, robust design and versatility have stood the test of time. By reviewing intravenous agents the author has attempted to find an evidence base for the most appropriate agent for a non anaesthetic trained doctor finding his or herself called on to provide emergency anaesthesia in the field. The most useful drug is ketamine which has the advantage of cardiovascular stability, preservation of airway reflexes, ease of administration via different routes and versatility for providing analgesia, sedation or general anaesthesia.

Anesthesia↗

PubMed1996

Altered peptide ligand-induced partial T cell activation: molecular mechanisms and role in T cell biology.

The elucidation of the phenomena of T cell antagonism and partial activation by altered peptide ligands has necessitated a revision in the traditional concepts of TCR recognition of antigen and subsequent signal transduction. Whereas previous models supported a single ligand specificity for any particular T cell, many studies using analogs of immunogenic peptides have now demonstrated a flexibility in this recognition. Moreover, interaction with such altered peptide ligands can result in dramatically different phenotypes of the T cells, ranging from inducing selective stimulatory functions to completely turning off their functional capacity. Investigations of the biochemical basis leading to these phenotypes have shown that altered peptide ligands can induce a qualitatively different pattern of signal transduction events than does any concentration of the native ligand. Such observations imply that several signaling modules are directly linked to the TCR/CD3 complex and that they can be dissociated from each other as a direct result of the nature of the ligand bound. Interestingly, many in vivo models of T cell activation are compatible with a selective signaling model, and several studies have shown that peptide analogs can play a role in various T cell biologic phenomena. These data strongly suggest that naturally occurring altered peptide ligands for any TCR exist in the repertoire of self-peptides or, in nature, derived from pathogens, and recent reports provide compelling evidence that this is indeed the case. The concept of altered peptide ligands, their effects on T cell signaling, the hypothesized mechanisms by which they exert their effects, and their possible roles in shaping the T cell immune response are the scope of this review.

Animals↗

PubMed1988

A radiologist looks at AIDS: imaging evaluation based on symptom complexes.

Many other symptom complexes could be discussed that affect virtually every organ system of patients with AIDS or ARC. While important and interesting, these are less likely to come to the attention of the radiologist for assistance in diagnosis and management. The scope of this review has also precluded discussion of infection control, although an effective plan for handling AIDS patients in a radiology department is absolutely vital. My hope is that this review will serve as a reasonable introduction or summary of the current role of the radiologist in dealing with AIDS. Obviously, new developments are coming at an extraordinary pace, and all radiologists must avail themselves of the most current sources of information.

Acquired Immunodeficiency Syndrome↗

PubMed1987

Angiotensin receptor subtypes of the kidney cortex.

Angiotensin II (ANG II) binds with high affinity to specific renal receptors and exerts major influences on hemodynamics and tubular transport. Glomerular and tubular epithelial receptors are well characterized in contrast to pre- and postglomerular and medullary vasculature. Therefore, the scope of this review is limited to an indepth comparison of ANG II receptor kinetics, analogue specificity, and mechanisms of receptor regulation and signal transduction in glomeruli and epithelial cells. Despite the fact that these receptors are in close proximity anatomically, there is evidence from a number of laboratories that permits classification into two distinct receptor subtypes. The receptor of the glomerular mesangium, classified herein as "type A," is characterized by high affinity for ANG II and the heptapeptide, des-Asp1-Ang II (ANG III), "downregulation" with high ambient concentrations of ANG II and signal transduction mediated by phospholipase C-induced Ca2+ transients. The tubular epithelial ANG II receptor, "type B," is of lower affinity for ANG II and ANG III, "upregulated" by high levels of ANG II and mediates inhibition of adenylate cyclase following coupling to an inhibitory GTP binding protein. Both receptors possess secondary mechanisms of signal transduction that may also participate in regulation of cellular function(s). These findings support the hypothesis that at least two distinct classes of ANG II receptors are present in the kidney cortex.

Angiotensin II↗

PubMedDate not supplied

Nuclear hormone and orphan receptors: their role in neuronal differentiation and cytoprotection and in the pathogenesis of Parkinson's disease.

Human nuclear hormone receptors (NHR) and orphan receptors (NOR) act as transcription factors in response to a wide range of circulating hormones and unknown ligands. A role for NHR and NOR in disorders of the subcortical dopaminergic pathways such as Parkinson's disease (PD) is suggested by a wealth of recent data including experimental observations. Both classes of receptors promote the formation of specific neuronal identities, tissue patterning during embryonic development and the maturation of vulnerable monoaminergic and cholinergic neurons. NHR and NOR are also known to exert a neuroprotective function on adult neurons. The scope of this review is to revisit the functional profile of these receptors with particular reference to their activity in the development of selected neuronal populations relevant to the pathophysiology of PD and to discuss how they may relate to the neuropathological and clinical expression of the disease.

Animals↗

PubMed2006

An overview of autonomic regulation of parotid gland activity: influence of orchiectomy.

The parotid gland participates in the digestive process by providing fluid, electrolytes and enzymes that facilitate the onset of digestion. Neurotransmitters, hormones and biologically active peptides regulate its activity. The autonomic system is the main regulatory mechanism of the gland. Sympathetic stimulation induces amylase release through beta(1)-receptor activation and few fluid secretion by alpha(1)-receptor activation. The parasympathetic system controls basal activity of the gland acting on M(1) and M(3) muscarinic acetylcholine receptors and induces the secretion of fluid saliva rich in electrolytes through the modulation of ion channels and the Na(+)-K(+)-ATPase activity. In addition, its activation induces amylase release. The mechanisms involved in amylase secretion by isoproterenol and carbachol, as well as the mechanism of the cholinergic regulation of Na(+)-K(+)-ATPase activity and the changes observed after orchiectomy, are the scope of this review.

Amylases↗

PubMed2006

Changes in white matter late after severe traumatic brain injury in childhood.

Severe traumatic brain injury in childhood, particularly that complicated by raised intracranial pressure, has significant long-term effects on the brain. Since magnetic resonance imaging provides a means of visualizing neuroanatomic structure in exquisite detail, the scope of this review is to revisit the pathology of traumatic brain injury described in recent clinical imaging studies. Acute imaging provides insight into the acute mechanism of focal and diffuse injury. There is some reduction in threshold for white matter pathology in the hemisphere ipsilateral to injury. After injury, there may be long-term effects on white matter architecture and the potential for brain growth. In this context, the pattern of hippocampal rather than parahippocampal gyrus tissue loss provides insight into the likely cause of white matter injury being cerebral hypoperfusion.

Atrophy↗

PubMed1977

The use of luteinizing hormone-releasing hormone in pediatric patients.

Luteinizing hormone-releasing hormone (LH-RH), first synthetized in 1971; became soon available for clinical purposes and was immediately used as a diagnostic tool in children and adolescents as well as in adults. The first results of the LH-RH test in pediatrics were reported in 1972 and soon after discussed in meetings allowing comparison of the data from different groups. From this time, a great number of publications has been devoted to the diagnostic usefulness of LH-RH in the study of pubertal development and of pituitary-gonadal disorders in children and adolescents. Until recently, the theraeputic use of LH-RH has been restricted by the lack of availability of sufficient amounts, so that only few preliminary data have been reported in this field. Thus the scope of this review is mainly to present a critical survey of the data concerning LH-RH test in pediatric patients.

Adolescent↗

PubMed1992

Contested boundaries of bipolar disorder and the limits of categorical diagnosis in psychiatry.

The authors' primary objective is to outline the phenomenology, importance, and available data on issues concerning the boundaries between bipolar disorder and diagnoses such as schizophrenia, unipolar depression, and personality disorders. In addition, by illuminating the many difficulties with the boundaries of one of psychiatry's more robust diagnoses, they hope to awaken in the reader a healthy skepticism about current psychiatric nosology. For a topic of this scope, a literature review must be selective. For each boundary area, a mixture of classic and recent papers covering a range of validating criteria is included whenever possible. Good summary data are cited when available, as are a selection of relevant theoretical papers. The review indicates that current diagnostic criteria for bipolar disorder are generally reasonable, but there are many problem areas, most of which cannot be solved by changes in criteria. Notable among these are 1) the possibility of future manic episodes in unipolar disorder, 2) schizoaffective disorder, bipolar type, and 3) borderline personality disorder with prominent mood swings. The disputes concerning the boundaries of bipolar disorder illustrate the limitations of categorical diagnosis which result from the implementation of diagnostic criteria, the criteria themselves, the fundamental nosologic process, and the phenomena themselves. If these limitations are to be extended, it may be necessary to explore alternative ways of defining psychiatric diagnoses for different settings in research and clinical practice.

Bipolar Disorder↗