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PubMed1996

Polycythemia.

Plethora ('a morbid condition due to excess of red corpuscles') has been recognized since antiquity as a manifestation of disease. The use of leeches and blood letting, which was for centuries the mainstay of therapy in many clinical situations, reflected the importance then attached to having too much blood. Greater knowledge has achieved greater precision, so that measurement of packed cell volume (PCV) or hematocrit now defines polycythemia (> 0.51 in men and > 0.48 in women, when blood is sampled without venous occlusion). Clinical and laboratory investigations, mainly in the last 30 years, have enabled the subdivision of polycythemia into different subtypes of radically different etiology which will be described in this Chapter. The last decade, however, has seen the advancing edge of research in this field passing from clinical and routine laboratory testing to studies of cellular proliferation at the molecular level. Detailed understanding is, however, as always elusive, with each new finding revealing deeper layers which in turn need elucidation. The field of polycythemia is nevertheless moving slowly into the molecular era.

Bone Marrow↗

PubMed1984

Management of conversion reaction in five adolescent girls.

Hysteria is a topic which has produced a plethora of articles on adults but, in comparison, there is a scarcity when it involves children and young adolescents. There is considerable confusion in definition, classification, incidence and management. More agreement seems to be found when conversion reactions are specifically considered. This article attempts to present the dilemma that confronts the clinician when faced with an individual patient with a conversion reaction. This may especially apply to the present day practitioner who is likely not to have had much personal experience in managing this condition. Some of the relevant literature is summarized and the five patients are presented in tabular form and individually, together with their outcome at follow-up. The findings are discussed and some conclusions are drawn.

Adolescent↗

PubMed1992

Sex education: more is not enough.

Increasing demands for sex education have been associated with a plethora of recommendations, regulations and resources with resulting variability of content, strategy, quality and outcome. While numerous studies confirm that the health behaviour of teenagers is not altered by the teaching of facts alone, other data suggest that appreciation of personal risk and learned assertiveness skills are associated with changes in population behaviours. Peer led teaching is a powerful and probably essential component of school health and sex education. Evaluated interventions with agreed purpose and acceptable methodologies are essential if there is to be any real expectation of health benefit from sex education.

Adolescent↗

PubMed1995

Do nitric oxide and cGMP play a role in calcium cycling?

The biological molecule NO and its cyclic nucleotide effector molecule cGMP, are involved in a variety of biological systems. This article reviews evidence supporting a role for these molecules in signal transduction. Over the last 10 years, it has become evident that these molecules are important in Ca2+ regulation, particularly in excitable cells. In these cells, cGMP-dependent mechanisms appear to both directly and indirectly regulate Ca2+ transport. Until recently, reports of the actions of cGMP in non-excitable cells have been contradictory, presenting a confusing plethora of effects. In these cells, the cGMP-Ca2+ regulation pathway appears to be concentration-dependent, possibly representing a negative feedback mechanism. Ca2+ entry appears to be activated when low concentrations of cGMP are present, and inhibited at higher concentrations. The role of cGMP in Ca2+ regulation in non-excitable cells has been largely overlooked and further investigation of this issue may provide clues as to the nature of various unknown components that induce Ca2+ entry into these cells.

Animals↗

PubMed1984

Demand-control of proliferative activity in the hemopoietic system of lethally irradiated mice during transfusion-induced regeneration.

The extent of cell proliferation in the hemopoietic system after bone marrow transfusion of fatally irradiated mice depends on the regeneration of proliferative capacity. This may be modified by the demand for differentiated cells in the peripheral blood. This demand was suppressed by induction of transfusion plethora prior to 800 rad whole body irradiation and bone marrow transfusion. Controls were non-plethoric recipients. For 6 days the following parameters were measured: hemopoietic proliferation by the 125-iodo-deoxyuridine (125-IUdR) incorporation technique, CFU-S content and spleen colony histology. There are three general observations from spleen and marrow with respect to 125-IUdR uptake in plethoric mice: (1) initial higher 125-IUdR uptake, (2) reduced rate of increase of 125-IUdR incorporation, (3) this rate of increasing 125-IUdR uptake in spleen was more depressed than in marrow. On day 6 cellularity and CFU-S in spleen was below, and in marrow above that of the control. These data suggest that initially after fatal irradiation of control mice differentiation of transfused CFU-S predominates over proliferation. Later as the mice become anemic and erythropoietin is produced the stimulation to proliferate is greater in the control than in the plethoric mice in which erythrocytic proliferation is suppressed. These data suggest that there are multiple feedback loops that regulate regeneration in the spleen and the bone marrow. These differences may be connected with the microenvironment that preferentially initiates erythropoiesis in the spleen before the marrow and granulopoiesis in the marrow before the spleen.

Animals↗

PubMed1996

Epidermal cytokine and neuronal peptide modulation of contact hypersensitivity reactions.

Cellular and molecular mechanisms underlying contact hypersensitivity reactions have been, and still are, fields under intense investigation, not only for the importance of these reactions in clinical medicine, but also because they are considered prototypic of a vast group of T cell-mediated immune diseases of the skin. Interestingly, potent contributions by non-bone marrow-derived cells have been shown clearly, demonstrating that epidermal cells are far more than mere spectators of these reactions, and undergo a functional activation after contact with the hapten causing the hypersensitivity reaction. In particular, keratinocyte contribution to the onset as well as modulation of contact hypersensitivity reactions through the release of a plethora of cytokines, has been widely documented. Moreover, an important control over these reactions is exerted by local release of neuropeptides by nerve endings. This review paper focuses on epidermal cytokine and neuronal peptide modulation of contact hypersensitivity reactions, trying to document the complexity of the regulatory systems, active during these immune processes of the skin.

Animals↗

PubMed1990

The behavioral medicine service. An administrative model for biopsychosocial medical care, teaching, and research.

The biopsychosocial model has been promoted for its advantages in many important health problems. However, the lack of administrative practice models specifically designed to develop and promote the model hinder the development of systematic clinical applications. This article describes a successful clinical teaching and research practice, The Behavioral Medicine Service, that was conceptualized and developed based on the biopsychosocial model. Systematic planning enabled the service to take advantage of clinical, research, and teaching opportunities and to reduce the constraints imposed on development from within psychiatry and the institution. Advantages of the organizational model include multidisciplinary treatment teams, a systematic method of biopsychosocial assessment and management planning, and continuity of care between several settings: the medical-surgical wards of a general hospital; a behavioral medicine inpatient unit; and outpatient subspecialty clinics for chronic pain, chronic medical illness, anxiety and stress-related disorders, and drug and alcohol abuse. The Human Behavioral Pharmacology Laboratory forms the research arm of the service. Referrals of a diversity of medical and psychiatric problems create a unique learning opportunity for residents. Billing for multimodal team treatment, training residents, establishing clinical research, and managing a plethora of referrals were developmental challenges addressed by the service.

Behavioral Medicine↗

PubMed1994

A review of delirium assessment instruments.

This paper reviews various types of assessment instruments for delirium, including nursing screening scales, symptom checklists, an analog scale, an interview schedule, and symptom rating scales. Their structures and applicability to the clinical and research assessment of delirium are described. Despite the seeming plethora of assessment methods, only a few are suitable for use by researchers.

Delirium↗

PubMedDate not supplied

Genetic toxicology of lysergic acid diethylamide (LSD-25).

The acute and the chronic psychotomimetic potentials of the hallucinogen lysergic acid diethylamide (LSD-25) have been recognized for almost 40 years. That additional types of the biological effects should have come under scrutiny was directly attributable to widespread use and abuse of this drug on a world-wide basis. Although "genetic toxicology" encompasses a broad spectrum of disciplines, including many areas of highly specialized research, perhaps the most germane, and those on which this review has concentrated, are Clastogenicity, Mutagenicity, Teratogenicity and Oncogenicity. Based on our current understanding and interpretation of the available data, the genetic toxicology of LSD provides an excellent example of Newton's "third law of motion", e.g., to every force there is an equal and opposite reaction force. From the published material it is impossible to draw clear cut conclusions regarding any of the above "problem areas" in spite of the considerable scientific effort invested. Most of the in vitro studies performed on the clastogenicity of LSD indicate either suppression of mitosis or enhanced chromosome damage. However, extrapolation of such results to the in vivo situation is very difficult. With regard to in vivo human use of the drug, no concensus is attainable as to chromosome breakage and the inconsistencies within and between studies remain inexplicable. However, several of the "controlled" investigations assessing the in vivo effect of chemically pure LSD suggest a transient increase in lymphocyte chromosome breakage. On the other hand, the results of cytogenetic studies on experimental animals are contradictory. Although human studies are nonexistent, in those experimental organisms tested, using accepted techniques, LSD proved to be, at best, a weak mutagen, if mutagenic at all. Teratogenicity studies in animals are confusing due to the multitude of organisms and plethora of discriminant parameters studied. However, with regard to man there has been ample opportunity and one can conclude that LSD is not teratogenic. As to the drug's oncogenic potential, the 3 reported cases of leukemia in LSD users are most likely the result of coincidence.

Animals↗

PubMed1992

Use of in vivo apparent pA2 analysis in assessment of opioid abuse liability.

Abuse liability testing of opioid drugs was originally motivated by attempts to separate the analgesic effects of opioids from their likelihood for abuse. It has become apparent that the human population group likely to abuse opioids has little overlap with the population group requiring opioids to treat pain, therefore there is no longer a need to separate these two properties of opioids. This is fortunate, since, as reviewed here by Jim Woods and colleagues, the results of the plethora of studies that have attempted to distinguish these two properties in known opioids strongly indicate that they are inseparable. Evaluation of the abuse potential of novel opioids remains, however, critically important in deciding on governmental restrictions on their accessibility. In addition, opioid abuse liability testing contributes enormously to our understanding of the behavioral mechanism of action of these drugs, and in surprising and helpful ways has increased our appreciation of the various test systems used to garner information about them.

Animals↗

PubMed1994

Processing of information from different sources: spatial synaptic integration in the dendrites of vertebrate CNS neurons.

Most synapses on a neuron are distributed along the dendrites. Inputs from different types of presynaptic neurons often distribute to different dendritic compartments. This provides an anatomical framework for spatial synaptic integration. At the same time, a plethora of time- and voltage-dependent responses are present, usually with a distinct distribution over the somato-dendritic membrane. These intrinsic conductances shape the local dendritic response to ligand-gated conductances, and provide the dendrites with a dynamic way of regulating the interaction between synapses. Recent results from neurons in the vertebrate CNS exemplify these mechanisms of dendritic integration.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMed1990

Lymphokine gene therapy for cancer.

The plethora of recombinant lymphokines that have recently become available has led to renewed hope for an immunotherapeutic solution to cancer. Many lymphokines, either singly or in combination, have already shown promise in animal trials and in preliminary human trials. Systemic lymphokine toxicity has been the major constraint on this type of therapy, often precluding the use of doses sufficient to induce tumour regression. To realize the therapeutic potential of recombinant lymphokines against cancer, alternative modes of delivery are needed which maximally stimulate local anti-tumour responses whilst causing minimal systemic toxicity. In this article, Stephen Russell proposes that tumour cell targeted lymphokine gene therapy would optimize lymphokine delivery. Some of the practical difficulties likely to be encountered with such an approach are also discussed.

Animals↗

PubMed1990

Soluble receptors for IL-1 and IL-4: biological activity and therapeutic potential.

Cytokine research has yielded a range of products which have now reached the stage of clinical trials and a plethora of novel therapeutics may be expected. Recently, cytokine receptors have also become an area of intensive research. Preliminary results indicate that recombinant soluble receptors can interfere with the biological functions of cytokines and thus may be appropriate for the treatment of certain pathological conditions where cytokine activity needs to be modulated.

Animals↗

PubMed1996

Manipulating systemic and mucosal immune responses with skin-deliverable adjuvants.

Most medically important bacterial and viral pathogens gain entry into the body either via the skin or a mucosal surface. Vaccination provides a viable and cost-effective strategy for the prevention of such diseases and it has always been a principal aim with vaccinologists, to be able to promote simultaneously, protective immune responses both systemically and at mucosal surfaces. The paradigm that mucosal immunity is best stimulated by exposure to antigen via a mucosal route simply because inductive sites such as Peyer's patches and bronchial associated lymphoid tissues are located in the mucosal epithelium, has promoted a plethora of immunizing strategies aimed at delivering both antigen and adjuvant to mucosal surfaces. We have developed a novel adjuvant system capable of intradermal delivery of antigens complexed in an ISCOSOME delivery vehicle. This adjuvant, referred to as a skin and mucosal adjuvant or SAMA4, was efficacious in eliciting both systemic and mucosal IgG and IgA antibodies in sheep, pigs and mice. SAMA4 does not induce granulomatous lesions at the site of vaccine delivery and can be used to deliver adjuvanted antigens by other routes including intranasal, oral and intravaginal. Using ovalbumin as a test antigen, intradermally delivered ovalbumin-SAMA4 complexes was found to be very effective in promoting a cytotoxic T cell response. Attempts to dissect the mode of action of SAMA4 by flow cytometric analysis of lymphocyte populations from the spleen, lung, liver and thymus revealed an effect of route of vaccine delivery upon the composition of specific lymphocyte subsets in these various organ compartments. From this, it can be inferred that SAMA4 induced a route-dependent re-mobilization and alteration in lymphocyte trafficking patterns. Other mucosal adjuvants such as cholera toxin B and microspheres, when injected intradermally, tended to promote primarily, an IgG and not an IgA response against hte carrier antigen.

Animals↗

PubMed1996

Tick salivary prostaglandins: Presence, origin and significance.

Prostaglandins (PGs) are oxygenated metabolites of polyunsaturated fatty acids, most notably arachidonic acid, that act as 'local hormones', regulating a plethora of physiological processes in mammals and other vertebrates. For a long time, PGs were reported only in higher vertebrates, but more recently they have been reported in lower organisms such as bacteria, yeasts and protozoa, and much information is now available on PGs in insects. Prostaglandins are increasingly reported to exist at the host-parasite interface and are thought to aid the parasite by modulating the inflammatory and immune response. Ticks secrete saliva containing extremely high concentrations of PGs into the host, and in this article Alan Bowman, Jack Dillwith and John Sauer provide a synopsis of the information, to date, on the presence, synthesis and proposed roles for these tick salivary PGs.

Journal Article↗

PubMed1995

The clinical spectrum of actinic elastosis.

A plethora of literature promoting our understanding of the differences between intrinsic (chronologic) aging versus extrinsic aging of the skin has been published during the last two decades. The predominant extrinsic factor is UV radiation; the functional, histologic, and clinical consequences are referred to as photoaging, or dermatoheliosis. Actinic elastosis refers specifically to the degenerative histologic alterations seen by light microscopy in sun-damaged skin. Multiple factors, including anatomic site, extent of sun exposure, and other physical or environmental factors affect the clinical appearance of these changes. We review the clinical spectrum of the actinic elastotic variants.

Humans↗

PubMed1989

Varied acceptance of clinical trial results.

The subject of varied acceptance of clinical trial results is discussed in the context of review of trials with which I have been involved and my subjective evaluation of their impact on the practice of clinical medicine. My experience goes back to 1949 and a World Health Organization trial of hyperimmune gamma globulin against rabies. This was followed by a large trial of secondary prevention of poliomyelitis. I participated in the planning and initiation of the first chronic disease trial, the University Group Diabetes Program (UGDP). The latter lasted for 15 years and its ramifications continue to this day. My next trial was the Coronary Drug Project (CDP), a complex trial with more than 8,000 patients. The trials of aspirin and aspirin combined with persantine (the CDPA, AMIS, PARIS I, and PARIS II) followed. My last three trials were a trial of photocoagulation in diabetic retinopathy (DRS), a six-country trial of the antiarrhythmic drug mexiletine (IMPACT), and a study involving two diagnostic procedures for pulmonary embolism (PIOPED). When one considers, in retrospect, the plethora of trials one is struck by the uniform absence of a priori considerations of the impact on medical practice, or likely lack thereof, of possible outcomes.

Anecdotes as Topic↗

PubMedDate not supplied

Networking with proline-directed protein kinases implicated in tau phosphorylation.

Proline-directed kinases such as the mitogen-activated protein (MAP) kinases, cyclin-dependent protein kinase 5 (CDK5) and glycogen synthase 3 (GSK3) have been implicated in the hyperphosphorylation of the tau protein associated with Alzheimer's disease. Such aberrant phosphorylation of tau appears to compromise on its ability to bind to and stabilize microtubules, and this may contribute to Alzheimer's disease pathology. In this review, the architecture of the intracellular signal transduction pathways that regulate proline-directed kinases is described. The MAP kinases serve as major intersection points in the flow of information from a plethora of extracellular stimuli and affect diverse cellular processes that are often important for cell proliferation. Although brain contains terminally differentiated neurons, many of the known components of MAP kinase-dependent lines of communication are highly expressed in the nervous system. Similar signalling pathways may also regulate CDK5 and GSK3. In mitotic cells, abnormal activation of the protein kinase network at multiple points can contribute to oncogenic transformation. It is proposed that Alzheimer's disease may also result from accumulated defects in the kinase network that governs the proline-directed kinases such that their inappropriate activation is sustained in the affected neurons. A detailed understanding of proline-directed kinase-dependent pathways may permit the identification of rational targets for the therapeutic intervention of Alzheimer's disease and other neurological disorders.

Amino Acid Sequence↗