Showing papers in "Critical Reviews in Clinical Laboratory Sciences in 2003"

Dipeptidyl-peptidase IV from bench to bedside: an update on structural properties, functions, and clinical aspects of the enzyme DPP IV.

Abstract: Dipeptidyl-peptidase IV/CD26 (DPP IV) is a cell-surface protease belonging to the prolyloligopeptidase family. It selectively removes the N-terminal dipeptide from peptides with proline or alanine in the second position. Apart from its catalytic activity, it interacts with several proteins, for instance, adenosine deaminase, the HIV gp120 protein, fibronectin, collagen, the chemokine receptor CXCR4, and the tyrosine phosphatase CD45. DPP IV is expressed on a specific set of T lymphocytes, where it is up-regulated after activation. It is also expressed in a variety of tissues, primarily on endothelial and epithelial cells. A soluble form is present in plasma and other body fluids. DPP IV has been proposed as a diagnostic or prognostic marker for various tumors, hematological malignancies, immunological, inflammatory, psychoneuroendocrine disorders, and viral infections. DPP IV truncates many bioactive peptides of medical importance. It plays a role in glucose homeostasis through proteolytic inactivation of...

Platelet-Activating Factor, a Pleiotrophic Mediator of Physiological and Pathological Processes

Abstract: Platelet-activating factor (PAF) is a potent proinflammatory phospholipid with diverse pathological and physiological effects. This bioactive phospholipid mediates processes as diverse as wound healing, physiological inflammation, apoptosis, angiogenesis, reproduction and long-term potentiation. Recent progress has demonstrated the participation of MAP kinase signaling pathways as modulators of the two critical enzymes, phospholipase A2 and acetyltransferase, involved in the remodeling pathway of PAF biosynthesis. The unregulated production of structural analogs of PAF by non-specific oxidative reactions has expanded this superfamily of signaling molecules to include "PAF-like" lipids whose mode of action is identical to that of authentic PAF. The action of members of this family is mediated by the PAF receptor, a G protein-coupled membrane-spanning molecule that can engage multiple signaling pathways in various cell types. Inappropriate activation of this signaling pathway is associated with many diseases in which inflammation is thought to be one of the underlying features. Inactivation of all members of the PAF superfamily occurs by a unique class of enzymes, the PAF acetylhydrolases, that have been characterized at the molecular level and that terminate signals initiated by both regulated and unregulated PAF production.

Acetaldehyde, Microbes, and Cancer of the Digestive Tract

Abstract: Excessive alcohol consumption and heavy smoking are the main risk factors of upper digestive tract cancer in industrialized countries. The association between heavy drinking and cancer appears to he particularly prominent in Asian individuals who have an inherited deficient ability to detoxify the first metabolite of ethanol oxidation, acetaldehyde. Alcohol itself is not carcinogenic. However, according to cell culture and animal experiments acetaldehyde is highly toxic, mutagenic, and carcinogenic. In addition to somatic cells, microbes representing normal human gut flora are also able to produce acetaldehyde from ethanol. After the ingestion of alcoholic beverages, this results in high local acetaldehyde concentrations in the saliva, gastric juice, and the contents of the large intestine. In addition, microbes may produce acetaldehyde endogenously without alcohol administration. This review summarizes the epidemiological, genetic, and biochemical evidence supporting the role of locally produced acetaldehyde in the pathogenesis of digestive tract cancer. Special emphasis is given to those factors that regulate local acetaldehyde concentration in the contents of the gastrointestinal tract. The new evidence presented in this review may open a microbiological approach to the pathogenesis of digestive tract cancer and may have an influence on future preventive strategies.

Calcium and cardiac arrhythmias: DADs, EADs, and alternans.

Abstract: Rapid progress has been made in understanding the molecular mechanisms by which calcium ions mediate certain cardiac arrhythmias. Principal advances include imaging of cytosolic calcium in isolated cells and in intact tissues, use of fluorescent indicators and monophasic action potentials to record membrane potentials in isolated tissue, and sequencing of the genes that encode critical ion channel proteins. In this review, five types of arrhythmias are discussed where calcium ion currents, or currents controlled by calcium, appear to be responsible for arrythmogenesis. These include: (1) the delayed afterpotential that occurs in conditions of intracellular calcium overload such as digitalis toxicity; (2) the early afterdepolarization that occurs when action potential duration is prolonged; (3) the slowly conducted calcium-dependent action potential (the slow response) in the SA and AV nodes; (4) the phenomenon of calcium transient alternans during ischemia, which is related to action potential duration alternans and t-wave alternans; (5) catecholamine-induced cardiac arrhythmias in families with mutations of the sarcoplasmic reticulum calcium-release channel. For each type of arrhythmia, the clinical implications of emerging knowledge are discussed. An especially important issue is whether ventricular fibrillation during acute coronary artery occlusion is due to calcium transient alternans. Ventricular fibrillation due to acute ischemia is an important subset of the 400,000 sudden cardiac deaths that occur annually in the U.S. Certain drugs, including beta blockers, fish oils, verapamil, and diltiazem, seem to specifically prevent ventricular fibrillation in this setting, and in most cases an effect of the drug on cytosolic calicum appears to be involved.

Basic and clinical aspects of copper.

Abstract: An oxygen-rich atmosphere obligated living organisms to cope with reactive oxygen species (O2-, H2O2, OH*) that were the unavoidable by-products of cellular metabolism. As a redox cofactor Cu was selected as a co-catalyst for numerous biological processes, many involving the utilization of oxygen. Inadequate or excessive intake of Cu can be pathogenic and life-threatening. Mutations to genes that code for Cu-transporting ATPase enzymes are the molecular basis of Wilson and Menkes diseases and more recently Cu has been identified as a preemptory factor in amyloid and prion diseases. This review is dedicated to bringing historical and timely information on Cu transport, metabolism and homeostasis to the attention of those not familiar with this important mineral. Other comprehensive reviews are available to the interested readers.

Lipoprotein(a): an emerging cardiovascular risk factor.

Abstract: Lipoprotein(a) is a cholesterol-enriched lipoprotein, consisting of a covalent linkage joining the unique and highly polymorphic apolipoprotein(a) to apolipoprotein B100, the main protein moiety of low-density lipoproteins. Although the concentration of lipoprotein(a) in humans is mostly genetically determined, acquired disorders might influence synthesis and catabolism of the particle. Raised concentration of lipoprotein(a) has been acknowledged as a leading inherited risk factor for both premature and advanced atherosclerosis at different vascular sites. The strong structural homologies with plasminogen and low-density lipoproteins suggest that lipoprotein(a) might represent the ideal bridge between the fields of atherosclerosis and thrombosis in the pathogenesis of vascular occlusive disorders. Unfortunately, the exact mechanisms by which lipoprotein(a) promotes, accelerates, and complicates atherosclerosis are only partially understood. In some clinical settings, such as in patients at exceptionally low risk for cardiovascular disease, the potential regenerative and antineoplastic properties of lipoprotein(a) might paradoxically counterbalance its athero-thrombogenicity, as attested by the compatibility between raised plasma lipoprotein(a) levels and longevity.

Molecular mechanisms and regulation of iron transport.

Abstract: Iron homeostasis is primarily maintained through regulation of its transport. This review summarizes recent discoveries in the field of iron transport that have shed light on the molecular mechanisms of dietary iron uptake, pathways for iron efflux to and between peripheral tissues, proteins implicated in organellar transport of iron (particularly the mitochondrion), and novel regulators that have been proposed to control iron assimilation. The transport of both transferrin-bound and nontransferrin-bound iron to peripheral tissues is discussed. Finally, the regulation of iron transport is also considered at the molecular level, with posttranscriptional, transcriptional, and posttranslational control mechanisms being reviewed.

Carrier Testing for Autosomal- Recessive Disorders

Abstract: The aim of carrier testing is to identify carrier couples at risk of having offspring with a serious genetic (autosomal recessive) disorder Carrier couples are offered genetic consultation where their reproductive options, including prenatal diagnosis, are explained The Ashkenazi Jewish population is at increased risk for several recessively inherited disorders (Tay-Sachs disease, Cystic fibrosis, Canavan disease, Gaucher disease, Familial Dysautonomia, Niemann-Pick disease, Fanconi anemia, and Bloom syndrome) Unlike Tay-Sachs disease, there is no simple biochemical or enzymatic test to detect carriers for these other disorders However, with the rapid identification of disease-causing genes in recent years, DNA-based assays are increasingly available for carrier detection Approximately 5% of the world's population carries a mutation affecting the globin chains of the hemoglobin molecule Among the most common of these disorders are the thalassemias The global birth rate of affected infants is at least 2 per 1000 (in unscreened populations), with the greatest incidence in Southeast Asian, Indian, Mediterranean, and Middle Eastern ethnic groups Carriers are detected by evaluation of red cell indices and morphology, followed by more sophisticated hematological testing and molecular analyses The following issues need to be considered in the development of a carrier screening program: (1) test selection based on disease severity and test accuracy; (2) funding for testing and genetic counselling; (3) definition of the target population to be screened; (4) development of a public and professional education program; (5) informed consent for screening; and (6) awareness of community needs

The renal kallikrein-kinin system: its role as a safety valve for excess sodium intake, and its attenuation as a possible etiologic factor in salt-sensitive hypertension.

Abstract: The distal tubules of the kidney express the full set of the components of the kallikrein-kinin system, which works independently from the plasma kallikrein-kinin system. Studies on the role of the renal kallikrein-kinin system, using congenitally kininogen-deficient Brown-Norway Katholiek rats and also bradykinin B2 receptor knockout mice, revealed that this system starts to function and to induce natriuresis and diuresis when sodium accumulates in the body as a result of excess sodium intake or aldosterone release, for example, by angiotensin II. Thus, it can be hypothesized that the system works as a safety valve for sodium accumulation. The large numbers of studies on hypertensive animal models and on essential hypertensive patients, particularly those with salt sensitivity, indicate a tendency toward the reduced excretion of urinary kallikrein, although this reduction is modified by potassium intake and impaired renal function. We hypothesize that the reduced excretion of the renal kallikrein may be attributable to a genetic defect of factor(s) in renal kallikrein secretion process and may cause salt-sensitive hypertension after salt intake.

Laboratory Markers and Germ Cell Tumors

Abstract: The International Germ Cell Consensus Classification (IGCCC) of testicular germ cell tumors (TGCT) in 1997 included three serum tumor markers, serum lactate dehydrogenase catalytic concentration (S-LD), serum alpha fetoprotein concentration (S-AFP), and serum human chorionic gonadotropin concentration (S-hCG). The recommendation should be implemented for all patients with TGCT and is also useful for patients with ovarian and extragonadal germ cell tumors. A fourth serum tumor marker for TGCT, S-LD isoenzyme 1 (S-LD-1), is also relevant for TGCT. Patients with seminoma have a raised S-LD-1 more often than a raised S-AFP and S-hCG, whereas patients with nonseminoma have a raised S-AFP more often than a raised S-LD-1 and S-hCG. A new model combining IGCCC and S-LD-1 predicts survival better than previous staging systems. LD-1 is related to a characteristic chromosomal abnormality in all types of TGCT, a high copy number of chromosome 12p. In contrast, AFP and hCG are found mainly in nonseminomatous germ cell tumors and they related to the histologic differentiation of the tumors. The different biologic background for the serum tumor markers may contribute to the difference in their clinical behavior.

Syndromic immunodeficiencies: genetic syndromes associated with immune abnormalities.

Abstract: In syndromic immunodeficiencies, clinical features not directly associated with the immune defect are prominent. Patients may present with either infectious complications or extra-immune medical issues. In addition to the immunologic abnormality, a wide range of organ systems may be affected. Patients may present with disturbances in skeletal, neurologic, dermatologic, or gastrointestinal function or development. These conditions can be caused by developmental abnormalities, chromosomal aberrations, metabolic disorders, or teratogens. For a number of these conditions, recent advances have resulted in an enhanced understanding of their genetic basis. The finding of immune deficits in a number of defined syndromes with congenital anomalies suggests that an underlying genetic syndrome should be considered in those patients in whom a significant non-immune feature is present.

Pseudohyperaldosteronism: pathogenetic mechanisms.

Abstract: Pseudohyperaldosteronism is characterized by a clinical picture of hyperaldosteronism with suppression of plasma renin activity and aldosterone. Pseudohyperaldosteronism can be due to a direct mine...

The usefulness of laboratory tests in the early assessment of severity of acute pancreatitis.

Abstract: Acute pancreatitis is a disorder that affects approximately 200,000 individuals in the U.S. annually. While most cases are mild, up to 30% of patients will have a complicated course with prolonged hospitalization and significant morbidity and mortality. Early institution of several therapeutic interventions, such as enteral nutrition, prophylactic antibiotics, endoscopic retrograde cholangiopancreatography (ERCP) and intensive care monitoring, have been shown to decrease the morbidity associated with severe acute pancreatitis. However, the ability of clinicians to predict, upon presentation, which patient will have mild or severe pancreatitis has remained poor over the years, thus leading to a delay in the institution of such treatments. Researchers have focused on markers that might improve upon clinical prediction alone. While data have shown the predictive value of tools such as Ranson's and Glasgow's criteria, C-reactive protein (CRP) and the APACHE score, their application in clinical practice has be...

Nonepithelial tumors and tumor-like lesions of the prostate gland.

Abstract: Many significant benign and malignant nonepithelial tumors and stromal tumor-like lesions arise in the prostate gland. Although such lesions are rare, their recognition by the pathologist is essential because their treatment and prognosis are quite variable. In this review, lesions of the specialized prostatic stroma, that is, lesions that can be seen in the stroma of the prostate but not in that of other organs, except for the phyllodes type of lesions, are discussed. Benign and malignant lesions of the soft tissues that occur in the stroma of other organs and are seen with some frequency in the prostate are also discussed. Few of the rarer soft tissue lesions are mentioned. Lesions and tumors with melanocytic differentiation, hematopoietic derivation, and germ cell tumors are described. It is hoped that this review will serve as a useful reference when encountering some of these lesions, all of which are referenced to their original and subsequent reports. Some non-English language references are also cited to reflect the international recognition of these lesions or to give credit to the author who first described the entity.

The emerging role of gene therapy in the treatment of cardiovascular diseases.

Abstract: Cardiovascular disease is the number one source of morbidity and mortality in the United States. Therapies directed at a variety of cardiovascular diseases have blossomed over the last several decades. The advent of gene therapy, first as an intriguing tool, and subsequently with the early successes of gene trials involving the treatment of SCID, led to the development of gene therapy as a potentially exciting and viable therapy in cardiovascular diseases. A variety of novel vector technologies and delivery systems have been developed to more efficiently deliver the gene product to the desired organ or tissue bed. Early clinical trials focused on stimulating angiogenesis. Subsequently, a number of other aspects of cardiovascular disease have been identified as potential targets for gene therapy, including the prevention of restenosis, the prevention and treatment of thrombosis, and the prevention of transplant vasculopathy. With over forty clinical human trials either completed or currently enrolling, cardiovascular gene therapy has proven to be safe and initial results suggest its efficacy.