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PubMed2002

Legal issues in complementary and integrative medicine. A guide for the clinician.

Physicians integrating CAM therapies into clinical practice face many legal challenges, including the fact that legal rules governing CAM providers and practices are new and evolving in many cases. Laws vary by state, and their application depends on the specific clinical scenario in question. As more evidence accumulates regarding safety and efficacy or lack thereof of specific therapies for given conditions, physicians will find clinical knowledge more abundantly mapped and that the parameters of liability are increasingly clear. Meanwhile, good clinical practice and a working knowledge of major legal rules can help provide physicians with a good measure of legal protection in situations involving integration of CAM providers and therapies in conventional medical practice.

Complementary Therapies↗
PubMed2002

Commentary: changes.

It is argued that change perception can provide a powerful way to explore various aspects of vision, such as visual attention and the accumulation of information across saccades. Several studies of change perception are discussed, and their results consolidated with existing knowledge to cast new light on our understanding of the visual system.

Animals↗
PubMed2002

T type 1/type 2 subsets balance in B-cell chronic lymphocytic leukemia--the three-color flow cytometry analysis.

The impairments in immune cell functions as well as changes in cytokine network are the cause of malignant cell accumulation and secondary immune deficiencies in B-cell chronic lymphocytic leukemia (B-CLL). To broaden the knowledge of immune system in B-CLL we tried to evaluate the Th1/Th2 and Tc1/Tc2 balance in B-CLL patients in comparison with healthy individuals and changes of this pattern during disease progression. The three-color flow cytometry technique was used to analyze IL-4 and IFNgamma expression in peripheral blood CD3+CD4+ and CD3+CD8+ cells. The results indicate the dominance of T type 1 cells and T-cell-mediated immunity in B-CLL patients that is however shifted towards T type 2 during disease progression.

Biomarkers↗
PubMed2003

Effusion cytology in ovarian cancer: new molecular methods as aids to diagnosis and prognosis.

Carcinoma of the ovary is the leading cause of death from gynecologic cancer in western countries. Ovarian carcinoma is commonly associated with the accumulation of fluid that contains malignant cells in the peritoneal and pleural cavities. This article details the current knowledge regarding the diagnostic and biologic characteristics of ovarian carcinoma cells in effusions, and the genotypic and phenotypic differences between solid primary tumors and metastatic lesions. Finally, we present a new approach, by which the analysis of fresh frozen viable cells allows us to study in vivo the links between expression and activity of extracellular mediators, membrane receptors, intracellular signaling, and transcription factors, and their potential therapeutic and prognostic significance.

Cell Biology↗
PubMed2002

A type 2 response in lipopolysaccharide (LPS)-stimulated whole blood cell cultures from periodontitis patients.

It is acknowledged that periodontitis results from the interaction of the host immune response with bacteria accumulating on the tooth surfaces. Although bacteria are essential, they are insufficient to cause the disease. Despite this knowledge it remains unclear why certain individuals are more susceptible to periodontitis than others. Therefore the present study investigated whether differences exist in the actual immune response between periodontitis patients and controls after stimulation of peripheral blood cells. Whole blood cell cultures (WBCC) were stimulated with LPS from Escherichia coli during 18 h and the release of prostaglandin E2 (PGE2), IL-1beta, IL-6, IL-8, IL-10, IL-12p40, IL-12p70 and tumour necrosis factor-alpha (TNF-alpha) was measured. The levels of PGE2 were two-fold higher in the WBCC from periodontitis patients than from controls. In contrast, the levels of IL-12p70 in WBCC from patients were two-fold lower. Furthermore, WBCC from patients secreted lower levels of IL-1beta and higher levels of IL-8 when compared with WBCC from controls. No differences were observed with respect to IL-6, IL-10, IL-12p40 and TNF-alpha production. It is known from the literature that LPS-stimulated WBCC reflect specifically the behaviour of the monocytes and that monocytes are peripheral precursors of antigen-presenting cells (APC). Therefore it is concluded that the monocytes in the present WBCC from periodontitis patients are responsible for the higher levels of PGE2 and lower levels of IL-12p70. Since it is has been shown that APC-derived IL-12p70 induces type (Th1) cells that promote cellular immunity, while APC-derived PGE2 induces type 2-helper (Th2) cells that promote humoral immunity, it is postulated that APC from periodontitis patients may have a bias in directing Th2 responses and thereby promoting the humoral immunity in periodontitis.

Adult↗
PubMedDate not supplied

Integrated databases and computer systems for studying eukaryotic gene expression.

MOTIVATION: The goal of the work was to develop a WWW-oriented computer system providing a maximal integration of informational and software resources on the regulation of gene expression and navigation through them. Rapid growth of the variety and volume of information accumulated in the databases on regulation of gene expression necessarily requires the development of computer systems for automated discovery of the knowledge that can be further used for analysis of regulatory genomic sequences. RESULTS: The GeneExpress system developed includes the following major informational and software modules: (1) Transcription Regulation (TRRD) module, which contains the databases on transcription regulatory regions of eukaryotic genes and TRRD Viewer for data visualization; (2) Site Activity Prediction (ACTIVITY), the module for analysis of functional site activity and its prediction; (3) Site Recognition module, which comprises (a) B-DNA-VIDEO system for detecting the conformational and physicochemical properties of DNA sites significant for their recognition, (b) Consensus and Weight Matrices (ConsFrec) and (c) Transcription Factor Binding Sites Recognition (TFBSR) systems for detecting conservative contextual regions of functional sites and their recognition; (4) Gene Networks (GeneNet), which contains an object-oriented database accumulating the data on gene networks and signal transduction pathways, and the Java-based Viewer for exploration and visualization of the GeneNet information; (5) mRNA Translation (Leader mRNA), designed to analyze structural and contextual properties of mRNA 5'-untranslated regions (5'-UTRs) and predict their translation efficiency; (6) other program modules designed to study the structure-function organization of regulatory genomic sequences and regulatory proteins. AVAILABILITY: GeneExpress is available at http://wwwmgs.bionet.nsc. ru/systems/GeneExpress/ and the links to the mirror site(s) can be found at http://wwwmgs.bionet.nsc.ru/mgs/links/mirrors.html+ ++.

Algorithms↗
PubMed2004

Recovery of bacteria by continuous renal replacement therapy in septic shock and by ultrafiltration from an in vitro model of bacteremia.

BACKGROUND: Severe sepsis is frequently associated with inflammation, multiple-organ dysfunction syndrome, and the accumulation of excess fluid that can be removed by continuous renal replacement therapy. Appropriate therapy for sepsis requires knowledge of the antibiotic susceptibility of the causative organism. However, bacterial isolation and identification are often unsuccessful. The objective of this study was to determine whether bacteria could be recovered from continuous renal replacement therapy ultrafiltrates of clinically septic patients who were either blood culture positive or repeatedly culture negative. DESIGN: Clinical study. SETTING: Adult medical intensive care unit. SUBJECTS: Six clinically septic, blood culture-positive or repeatedly culture-negative patients and four clinically nonseptic patients. INTERVENTIONS: We performed continuous renal replacement therapy on patients. In addition, we devised an in vitro system mimicking human bacteremia to determine whether bacteria traverse the hemofilter. In these experiments, a reservoir containing reconstituted blood was inoculated with Enterococcus faecalis and hemofiltered. The ultrafiltrates were centrifuged or secondarily filtered for bacterial recovery. MEASUREMENTS AND MAIN RESULTS: Bacterial pathogens were recovered in culture from ultrafiltrates of all the clinically septic patients. Ultrafiltrates of the nonseptic patients were sterile. E. faecalis, the bacterium inoculated into the reconstituted blood, was the only organism recovered from the in vitro-derived ultrafiltrates. CONCLUSIONS: Pathogenic bacteria were shown to traverse the hemofilter. Culture of ultrafiltrates of clinically septic, blood culture-negative patients may be useful in recovery of the etiological organism and confirmation of the clinical diagnosis and management of sepsis.

Adult↗
PubMed2006

The links between allergy and otitis media with effusion.

PURPOSE OF REVIEW: In this review we will examine evidence indicating that allergic inflammation is present in middle ear effusion. We will also discuss several of the problems relating to the diagnosis of allergy and allergic sensitization, and why anti-allergy treatments have been unsuccessful. This will provide a rationale for future studies in the field linking allergic inflammation with otitis media with effusion. RECENT FINDINGS: Recent findings in atopic children demonstrated higher levels of eosinophils, T lymphocytes, and interleukin-4+ and interleukin-5+ cells compared with nonatopic patients. T-helper 2 cells and cytokines were found not only in middle ear effusions in atopic children but also in specimens from adenoid tissue. This demonstrates a strong correlation between allergic reaction in the middle ear and the upper airway. SUMMARY: In summary, as our knowledge of the allergic and nonallergic influences on inflammation broadens, the paradigms of treatment may be altered. The accumulating experimental and clinical data suggest that it may be wiser to screen every child with otitis media with effusion for allergic rhinitis and ultimately to manage those with allergic inflammation differently to nonatopic individuals with otitis media with effusion.

Humans↗
PubMed2005

Tension pneumocephalus.

Pneumocephalus, air in the cranial cavity, is a common occurrence following cranial surgery. However, tension pneumocephalus, accumulation of air trapped in the cranial cavity causing a mass effect and abnormal neurological signs, is uncommon. Knowledge about conditions that contribute to tension pneumocephalus, a potentially fatal complication, including the related signs and symptoms, is imperative. Immediate collaboration with a physician allows for timely treatment and patient recovery. Treatment measures include preoperative teaching, immediate removal of intracranial air, supine positioning, administration of 100% oxygen, repair of the bony and dural defect, and, if indicated drain placement into the air cavity, temporary tracheotomy, and antibiotics.

Education, Nursing, Continuing↗
PubMed2001

Two hits revisited again.

INTRODUCTION AND METHODS: Since the concept of the "two hit hypothesis" was introduced over 20 years ago, a wealth of genetic data has accumulated on the mutations found at tumour suppressor loci. Perhaps surprisingly, these data conceal large gaps in our knowledge which genetic and functional studies are beginning to uncover. The "two hit hypothesis" must be updated to take account of this new information. RESULTS AND DISCUSSION: Here, we discuss both the results of recent studies and some of the questions that they highlight. In particular, how valid are conclusions from inherited Mendelian syndromes when applied to sporadic cancers? Why is allelic loss so common and how does it occur? Are the "two hits" random or interdependent? Is abolition of protein function always optimal for tumorigenesis? Can "third hits" occur and, if so, why? How can mismatch repair deficiency and the methylator phenotype be incorporated into the "two hit" hypothesis? We suggest that the "two hit hypothesis" is not fixed but is evolving as our knowledge expands.

Humans↗
PubMed1982

True hermaphroditism with hydrocolpos.

A case of true hermaphroditism with hydrocolpos in a 7-month-old infant is presented. This is, to the authors' knowledge reported case of association of both anomalies. Hydrocolpos is a clinical entity characterized by vaginal distension with accumulation of fluid, which can cause respiratory embarrassment and urinary, intestinal and circulatory obstruction. It is a condition of great rarity. It is usually detected in the neonatal period, although it has been reported in older children, and it calls for urgent treatment. True hermaphroditism is a rare form of intersexuality, which can only be considered to exist if both male and female elements can be identified in the gonad.

Disorders of Sex Development↗
PubMed2003

Genetic alterations in pancreatic carcinoma.

Cancer of the exocrine pancreas represents the fifth leading cause of cancer death in the Western population with an average survival after diagnosis of 3 to 6 months and a five-year survival rate under 5%. Our understanding of the molecular carcinogenesis has improved in the last few years due to the development of novel molecular biological techniques. Pancreatic cancer is a multi-stage process resulting from the accumulation of genetic changes in the somatic DNA of normal cells. In this article we describe major genetic alterations of pancreatic cancer, mutations in the proto-oncogene K-RAS and the tumor suppressors INK4A, TP53 and DPC4/SMAD4. The accumulation of these genetic changes leads to a profound disturbance in cell cycle regulation and continuous growth. The knowledge of the underlying molecular mechanisms will offer new therapeutic and diagnostic options and hopefully improve the outcome of this aggressive disease.

Animals↗
PubMed2004

Molecular regulation of pancreatic stellate cell function.

Until now, no specific therapies are available to inhibit pancreatic fibrosis, a constant pathological feature of chronic pancreatitis and pancreatic cancer. One major reason is the incomplete knowledge of the molecular principles underlying fibrogenesis in the pancreas. In the past few years, evidence has been accumulated that activated pancreatic stellate cells (PSCs) are the predominant source of extracellular matrix (ECM) proteins in the diseased organ. PSCs are vitamin A-storing, fibroblast-like cells with close morphological and biochemical similarities to hepatic stellate cells (also known as Ito-cells). In response to profibrogenic mediators such as various cytokines, PSCs undergo an activation process that involves proliferation, exhibition of a myofibroblastic phenotype and enhanced production of ECM proteins. The intracellular mediators of activation signals, and their antagonists, are only partially known so far. Recent data suggest an important role of enzymes of the mitogen-activated protein kinase family in PSC activation. On the other hand, ligands of the nuclear receptor PPARgamma (peroxisome proliferator-activated receptor gamma) stimulate maintenance of a quiescent PSC phenotype. In the future, targeting regulators of the PSC activation process might become a promising approach for the treatment of pancreatic fibrosis.

Animals↗
PubMed1977

Desquamative interstitial pneumonitis. Cellular phase of fibrosing alveolitis.

Since the original description of desquamative interstitial pneumonitis in 1967, several investigators have questioned the specificity of the disease. The concept of desquamative interstitial pneumonitis and usual fibrosing interstitial pneumonitis as two manifestations of a nonspecific disease spectrum has been proposed. Twenty-six patients with desquamative interstitial pneumonitis were evaluated with respect to clinicopathologic correlates. Biopsies were reviewed without knowledge of the patients' clinical course. The absolute histopathologic criteria for the diagnosis were (1) intra-alveolar accumulations of free alveolar cells with PAS-positive diastaseresistant cytoplasmic granules; (2) mononuclear cell interstitial inflammation; and (3) absence of necrosis, hyaline membranes, intra-alveolar fibrosis, asbestos bodies, and birefringent crystalline dust material. Transmission electron microscopic studies revealed the dominant alveolar lining cell to be the granular pneumocyte, with a prominent population of free alveolar macrophages. Patients were segregated into group 1 (cellular phase) and 2 (cicatrized phase). Although favorable short-term responses to corticosteroid therapy were observed in both groups, long-term responses were variable. Apparent complete remissions were noted in both groups.

Adult↗
PubMed2000

Functional genomics.

We are in the midst of a genomics revolution. The first chapter of this revolution will end later this year with the completion of the first draft of the entire human genome; estimates for the exact number of genes in the human genome vary from 50,000 to 140,000. This endeavor has been a major catalyst for the genomics revolution and has moved science into uncharted territories, which has led to the need to establish both new disciplines and a new vocabulary. Thus we now have pharmacogenomics, genotyping, pharmacogenetics, microarrays, biochips, differential display, bioinformatics and cheminformatic. The meeting provided a taste of the wealth of information that is now being accumulated under the name of both genomics and proteomics. The challenge ahead will be turning this information into knowledge and then translating this knowledge into new therapies.

Journal Article↗
PubMed2004

Applicability of the principles of developmental pharmacology to the study of environmental toxicants.

Although nontherapeutic xenobiotics represent the vast majority of environmental exposures during childhood, study of these compounds in children has lagged behind drug studies. Some useful extrapolation can be made from the latter, however. An increased impetus for pediatric pharmacology studies resulted from evidence of shortcomings in algorithmic approaches to dosing and the recognition of differing efficacy and toxicity in children compared with adults. With some drugs, developmental differences resulted in increased toxicity or failed efficacy; however, in others, decreased toxicity has been demonstrated. Thus, pediatric patients may not be classified arbitrarily as a susceptible population but certainly a different one compared with adults. Better designed pediatric pharmacology studies use well-documented, nonlinear changes in body composition across childhood, as well as knowledge about the impact of physical growth, mediated by complex hormonal changes. Developmental differences in all components of drug disposition, including absorption, distribution, metabolism, and excretion, have been characterized. Of these, the ontogeny of metabolism, particularly tissue-specific metabolism, is the most complex. Many knowledge gaps persist within developmental pharmacology; however, recent Food and Drug Administration regulatory action likely will ensure continued accumulation of pediatric therapeutic data. Although these data can provide important a priori information for improved environmental study design, evaluation-specific toxicant disposition by pediatric patients is clearly needed.

Adult↗
PubMed1991

Nuclear location of synthetic oligonucleotides microinjected somatic cells: its implication in an antisense strategy.

Synthetic oligonucleotides are widely used to modulate gene expression. However their development as genetic tools and as molecule of therapeutic interest is restricted by the poor knowledge of their mechanism of action and of their uptake by cells. We recently found that microinjected oligonucleotides accumulates in the nucleus of the cells. These observations are described and their implications are discussed.

Animals↗
PubMed1992

Fludarabine infusion potentiates arabinosylcytosine metabolism in lymphocytes of patients with chronic lymphocytic leukemia.

Our previous work has shown that incubation of K562 cells or lymphocytes from patients with advanced chronic lymphocytic leukemia (CLL) with arabinosyl-2-fluoroadenine (F-ara-A) potentiates the rate of arabinosylcytosine 5'-triphosphate (ara-CTP) synthesis during subsequent treatment with arabinosylcytosine (ara-C). To test the biochemical modulation of ara-CTP in a clinical setting, we designed a protocol to administer fludarabine (Fludara, F-ara-AMP) and ara-C in a pharmacologically directed sequence for patients with CLL refractory to conventional fludarabine therapy. ara-C was infused in seven patients with progressive CLL at a dose rate that maximizes ara-CTP accumulation (0.5 g/m2 during 2 h). Fludarabine (30 mg/m2 during 30 min) was infused 20 h later, followed by a second, identical dose of ara-C at 24 h, when the concentration of F-ara-A 5'-triphosphate (F-ara-ATP) was maximal in CLL cells. Comparison of ara-CTP pharmacokinetics in circulating CLL cells demonstrated that the ara-CTP area under the curve increased by a median of 1.5-fold (range, 1.1- to 1.7-fold) after fludarabine infusion. Plasma pharmacokinetics indicated that neither the median steady-state ara-C concentrations nor the levels of its deamination product arabinosyluracil were significantly affected by fludarabine infusion. The median rate of ara-CTP elimination was slightly faster after fludarabine treatment (t1/2, 6.7 versus 5.8 h), suggesting that catabolism of ara-CTP was not responsible for the increased ara-CTP area under the curve. The rate of ara-CTP accumulation by CLL cells after fludarabine infusion, however, was increased by a median of 1.3-fold in seven of the eight patients (range, 1.2- to 1.8-fold); the peak occurred within 1 h of the end of the infusion. In vitro incubation of leukemic lymphocytes with F-ara-A before ara-C also showed a median 1.3-fold increase in the rate of ara-CTP accumulation. Thus, infusion of fludarabine before ara-C augments ara-CTP metabolism in leukemic lymphocytes. This knowledge should be considered in the design of combination chemotherapy.

Antineoplastic Agents↗