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PubMedDate not supplied

Profiling lymphocyte subpopulations in peripheral blood under efalizumab treatment of psoriasis by multi epitope ligand cartography (MELC) robot microscopy.

CD11a-blocking efalizumab has recently been approved as a systemic treatment of moderate to severe chronic plaque psoriasis. When treating 6 psoriasis patients with efalizumab over 12 weeks in the present study, we observed an overall good tolerability and 5 treatment responders characterized by a decrease of PASI from 21.3 +/- 5.4 to 3.9 +/- 0.6. The accompanying significant increase of peripheral blood lymphocytes from 1.9 +/- 0.7 to 4.3 +/- 1.0 x 10(9)/L (p < 0.05) was analyzed by multi epitope ligand cartography (MELC) robot microscopy. Thereby a high-dimension simultaneous multiplex immunophenotyping was pursued using 39 fluorophore-labeled antibodies including labeled efalizumab and 3 other affinity reagents such as lectins. Due to efalizumab treatment there was a substantial decrease of the cellular expression of CD11a (detected by mab clone 25.3.1) and efalizumab binding sites (EfaBSs). This was paralleled by an increase of the number of EfaBS- and EfaBS+ lymphocytes by a factor of 2.4x and 2.2x, respectively. The latter effect was mainly derived from a subpopulation showing a low degree of EfaBS expression. Efalizumab treatment led furthermore to an increase of the numbers of CD3+, CD4+, CD8+, CD44+, CD45+, CD45R0+, CD45 RA+, CD52+, CD58+, CD247+, HLA-DR+ and Sambucus nigra lectin-reactive lymphocytes (by factors from 2.0 to 3.3x). In terms of a combinatorial molecular phenotype we identified a CD3+/CD4+/CD44+/CD52+ lymphocyte subpopulation which accumulated most predominantly from 0.824 +/- 0.270 x 10(9)/L up to 1.616 +/- 0.152 x 10(9)/L under efalizumab treatment (p < 0.01). Thus, the current study extends the knowledge of efalizumab-dependent perturbations of recirculating blood lymphocyte subpopulations in psoriasis patients.

Adult↗
PubMed1990

New concepts and prospects for unity of anatomy.

Anatomy has accumulated a vast amount of morphological data of the body. In addition, anatomy has long an aggregate of sharply subdivided specialities. Re-organization and systematic integration of the knowledge across these subdivisions with the aim of attaining a more comprehensive approach is not an easy task because of the continued predominance of analytical principles and the deep-rooted academic inclination toward analysis. Despite these difficulties, I have endeavored to formulate a framework for unity of anatomy (Re-arranged comprehensive anatomy). A book of anatomy in a wide sense, in which macroscopic, microscopic, and developmental anatomy of the body are incorporated in one volume, would be of great convenience. Establishment of new concepts of organology as well as profound thinking over the shape and the structure is an urgent task for remodelling of anatomy into a more integrated science.

Anatomy↗
PubMed1987

Lymphatics and blood vessels, lymphangiogenesis and hemangiogenesis: from cell biology to clinical medicine.

The past 15 years have witnessed an explosion of knowledge about blood vascular endothelium due in large part to in vitro growth of endothelial cells from both large blood vessels and capillaries. In contrast, little comparable information has accumulated on endothelium of lymphatics, which lie in intimate contact with parenchymal cells and drain excess fluid, macromolecules, particles, and immunocompetent cells in a continuous recirculation between tissues and bloodstream. While structural and functional differences between the two vascular systems have been described in vivo, in tissue sections, and in isolated preparations, similarities are notable in ultra-structure, biochemistry, physiology, and pharmacologic responsiveness, and these may predominate under pathologic conditions. In 1984, three separate groups described in vitro culture of lymphatic endothelial cells from collecting ducts and cavernous lymphangiomas. Lymphatic, like blood vascular, endothelium grows in confluent monolayers, "sprouts", synthesizes Factor VIII-associated antigen and fibronectin, and ultrastructurally shows Weibel-Palade bodies; overlapping intercellular junctions and anchoring filaments typical of lymphatic endothelium are also found. Genetic, congenital, and acquired disorders such as strangulating fetal nuchal cystic hygromas (Down and Turner syndromes), vascular tumors and dysmorphogenesis (Maffucci and Klippel-Trenaunay syndromes), Kaposi's sarcoma, lymphogenous and hematogenous spread of cancer, and parasitic infestations such as filariasis, share overlapping abnormalities in formation, growth, and/or neoplasia of lymphatics and blood vessels. In these and similar clinical disorders, confusion often exists as to the nature of the cell or tissue of origin, and insight into the role and control of hemangiogenesis and lymphangiogenesis is still in its infancy. Nonetheless, with the ever widening array of investigative techniques, it is not only timely but imperative to explore the endothelial biology underlying these inborn and acquired disorders.

Animals↗
PubMed1989

[The pathochemistry of the diabetic process in the eye based on data on experimental hyperglycemia (alloxan diabetes)].

The paper describes results after a study of pathochemical disturbances of diabetic hyperglycemia on a model of alloxan diabetes. Sugar and amino nitrogen contents in the aqueous humor of the anterior chamber, anterior and posterior segments of the crystalline lens, the iris, ciliary body, choroid and the retina were studied and the data obtained were compared with quantitative contents of sugar and amino nitrogen in the eliminate from the eyes of experimental animals. High amounts of sugar and amino nitrogen, infrequently exceeding 2-3 times in controls, were found to appear in the aqueous humor of the anterior chamber, the crystalline lens, the vitreous body. In all tests the sugar and amino nitrogen contents in the posterior segment of the lens was 10-12% higher than in its anterior segment. The data obtained about accumulation of sugar and amino nitrogen mainly in tissues and media of the eye (the lens, the vitreous) affected by diabetic process already at its early stages widen the knowledge about pathogenesis of the process and peculiarities of its pathochemistry.

Amines↗
PubMed2005

Post-transcriptional gene regulation by gamma herpesviruses.

The Epstein-Barr virus (EBV) SM protein is a member of a highly conserved family of proteins present in most mammalian herpes viruses. There is a significant amount of functional and sequence divergence among the homologs encoded by the human herpes viruses, including differences in mechanism of action and varying effects on splicing and transcription. Nevertheless, in those cases where it has been studied, these proteins are essential for lytic replication of the virus. The mechanism by which SM regulates gene expression operates at the level of mRNA stability, processing, and export. SM enhances expression of EBV lytic genes and has both positive and negative effects on cellular gene expression. In addition to enhancing accumulation of EBV gene mRNAs, SM has important effects on cellular mRNAs, altering the host cell gene expression profile to facilitate viral replication. This article describes the current state of knowledge regarding the role of EBV SM in cellular and viral gene regulation and summarizes some of the similarities and differences with the ORF57 homolog from Kaposi's sarcoma-associated herpes virus (KSHV/HHV8).

Animals↗
PubMedDate not supplied

New concepts in the pulmonary disposition of antibiotics.

Despite interpretive problems associated with studies of antibiotic concentrations in tissues, it is of major interest to correlate the presence of the drug at significant concentrations in lung tissues and fluids at a particular site with its clinical efficacy. All the models described above have their uses as well as their limitations. Measurement of antibiotic concentrations achieved in lung parenchyma, ELF, bronchial mucosa of bronchial secretions has shown variable levels for the same drug. Many respiratory infections are caused by obligate or facultative intracellular pathogens, which may be eradicated as a result of intracellular penetration and accumulation of quinolones, of macrolides, as shown in several models of phagocytic cells, and as a result of intracellular antibacterial activities. For bacterial infections located in extracellular pulmonary sites, a knowledge of achievable concentrations of beta-lactams, of aminoglycosides, of quinolones should be of value, whereas for bacteria multiplying in alveolar macrophages the high concentrations of the new macrolides or new fluoroquinolones that can be achieved in extravascular and intracellular fluids should have clinical relevance. Animal models of severe pneumonia, as well as studies in patients hospitalized in intensive care units, have provided correlation between clinical outcomes and high lung tissue and intramacrophagic concentrations of fluoroquinolones, or of macrolides in legionellosis, or of ceftazidime or imipenem in pseudomonal pneumonia.

Anti-Bacterial Agents↗
PubMed1998

[p16(INK4A)/CDKN2--the "melanoma gene"? Status of research and outlook].

The gene of the cyclin-dependent kinase 4 (CDK4)-inhibitor p16INK4A (CDKN2/MTS1) has been proposed as a candidate for a tumor-suppressor gene located on chromosome 9p21, a frequently deleted region in a series of human cancers including malignant melanoma. An increasing and sometimes conflicting body of data has accumulated regarding the frequency of homozygous deletions and mutations as well as the importance of p16INK4A in malignant melanoma. The purpose of this review is therefore to summarize the current knowledge on p16INK4A and to discuss its biologic significance in the pathogenesis of melanocytic tumors.

Cell Cycle↗
PubMed2005

Clinical implications of aberrant DNA methylation patterns in acute myelogenous leukemia.

Hypermethylation of CpG islands near gene promoter regions is associated with transcriptional inactivation and represents an important mechanism of gene silencing in carcinogenesis. Such epigenetic phenomena can act alongside DNA mutations and deletions to disrupt tumor-suppressor gene function. The methylation status of the promoter-associated CpG islands from 11 well-characterized cancer-related genes was analyzed by methylation-specific polymerase chain reaction in 60 adult patients with acute myelogenous leukemia (AML) at diagnosis. The frequency of aberrant methylation among the patient samples was 45.0% (27/60) for suppressor of cytokine signaling-1, 31.7% (19/60) for p15, 20.0% (12/60) for retinoic acid receptor beta2, 13.3% (8/60) for p73 and E-cadherin, 5.0% (3/60) for O(6)-methylguanine DNA methyltransferase, 3.3% (2/60) for death-associated protein kinase 1 and hMLH1, 1.7% (1/60) for p16, and 0% (0/60) for the tissue inhibitor of matrix metalloproteinases-3 and Ras association domain family 1A. Aberrant DNA methylation was found in AML of all French-American-British subtypes and throughout all cytogenetic risk groups. There appeared to be a trend towards a higher methylation frequency in AML patients with an unfavorable karyotype, but this difference was not statistically significant. Our data indicate that hypermethylation of multiple genes involving fundamental cellular pathways is a common event in AML, which varies greatly in frequency among the genes examined. The accumulation of epigenetic events affecting genes which are involved in regulating cell cycle inhibition, cell adhesion, growth factor signaling, and apoptosis may contribute to the malignant AML phenotype. The growing knowledge of the role of epigenetics in the aberrant silencing of cancer-related genes provides a rationale and molecular basis for targeted therapeutic approaches with demethylating agents in AML.

Adult↗
PubMed1993

HDR versus LDR gynecological brachytherapy revisited.

Despite the obvious breakthrough of high dose-rate (HDR) afterloading systems on the gynecological brachytherapy market, questions still remain regarding the transfer of available expertise gained throughout the last 80 years with low dose-rate (LDR) radium and cesium, especially regarding the conversion of LDR total dose into equivalent HDR dose per fraction and total dose. Calculation of biologically equivalent schedules requires a knowledge of repair capacity and repair kinetics of tumors and normal tissues, both of which influence the biological effect of any radiation dose. The clinical experience with HDR is, however, accumulating and it is acknowledged that the new technique entails an acceptable therapeutic index as compared to the classical LDR. There is thus a state of apparent 'equivalence' between the two treatment modalities. This state is influenced by many factors in which, in contrast to what is frequently claimed, radiobiological factors do not play the most important role. It is probably its high-tech environment which makes HDR an acceptable alternative. Treatment at LDR, indeed, has proven to be quite tolerant to a lack of absolute precision, something that would be disastrous with HDR techniques. Because HDR intracavitary brachytherapy has not been compared in controlled trials with the best existing LDR brachytherapy, but only retrospectively with heterogeneous LDR clinical data, it cannot be claimed to be equivalent, but simply feasible.

Brachytherapy↗
PubMed2004

Mechanisms responsible for parturition; the use of experimental models.

In this review, our knowledge, gleaned from a range of species, of what determines gestation length, how fetal maturation and birth are synchronized and how the uterotonic mechanisms are activated at birth are discussed. Accumulated data indicate that fetal glucocorticoids are involved in, but do not necessarily play a causative role in, the initiation of parturition in eutherian mammals generally. Present observations are consistent with a complex, positive regulatory interaction between estrogens, prostaglandins and oxytocin and are consistent with a role for prostaglandins as the final, common effector in myometrial activation. We are, however, left with the possibility that the initial mechanism for the timing of birth is encoded in the fetal genome and is closely linked to, and activated when, certain prerequisite developmental events have occurred in the fetus. Our understanding of these events in the sheep have led to its extensive use as an experimental model for the study of human clinical correlates of fetal maturation and development and the control of the initiation of parturition.

Animals↗
PubMed2005

The future of 'pure' medical science: the need for a new specialist professional research system.

Over recent decades, medical research has become mostly an 'applied' science which implicitly aims at steady progress by an accumulation of small improvements, each increment having a high probability of validity. Applied medical science is, therefore, a social system of communications for generating pre-publication peer-reviewed knowledge that is ready for implementation. However, the need for predictability makes modern medical science risk-averse and this is leading to a decline in major therapeutic breakthroughs where new treatments for new diseases are required. There is need for the evolution of a specialized professional research system of pure medial science, whose role would be to generate and critically evaluate radically novel and potentially important theories, techniques, therapies and technologies. Pure science ideas typically have a lower probability of being valid, but the possibility of much greater benefit if they turn out to be true. The domination of medical research by applied criteria means that even good ideas from pure medical science are typically ignored or summarily rejected as being too speculative. Of course, radical and potentially important ideas may currently be published, but at present there is no formal mechanism by which pure science publications may be received, critiqued, evaluated and extended to become suitable for 'application'. Pure medical science needs to evolve to constitute a typical specialized scientific system of formal communications among a professional community. The members of this putative profession would interact via close research groupings, journals, meetings, electronic and web communications--like any other science. Pure medical science units might arise as elite grouping linked to existing world-class applied medical research institutions. However, the pure medical science system would have its own separate aims, procedures for scientific evaluation, institutional organization, funding and support arrangements; and a separate higher-professional career path with distinctive selection criteria. For instance, future leaders of pure medical science institutions would need to be selected on the basis of their specialized cognitive aptitudes and their record of having generated science-transforming ideas, as well as their research management skills. Pure medical science would work most effectively and efficiently if practiced in many independent and competing institutions in several different countries. The main 'market' for pure medical science would be the applied medical scientists, who need radical strategies to solve problems which are not yielding to established methods. The stimulus to create such elite pure medical science institutions might come from the leadership of academic 'entrepreneurs' (for instance, imaginative patrons in the major funding foundations), or be triggered by a widespread public recognition of the probable exhaustion of existing applied medical science approaches to solving major therapeutic challenges.

Biomedical Research↗
PubMed1994

In vivo kinetics and spectra of 5-aminolaevulinic acid-induced fluorescence in an amelanotic melanoma of the hamster.

For successful photodynamic diagnosis (PDD) and effective photodynamic therapy (PDT) with the clinically used 'photosensitiser' 5-aminolaevulinic acid (ALA), knowledge of the maximal fluorescence intensity and of the maximal tumour-host tissue fluorescence ratio following systemic or local application is required. Therefore, time course and type of porphyrin accumulation were investigated in neoplastic and surrounding host tissue by measuring the kinetics and spectra of ALA-induced fluorescence in vivo. Experiments were performed in the amelanotic melanoma A-Mel-3 grown in the dorsal skinfold chamber preparation of Syrian golden hamsters. The kinetics of fluorescent porphyrins was quantified up to 24 h after i.v. injection of 100 mg kg-1, 500 mg kg-1 or 1,000 mg kg-1 body weight ALA by intravital fluorescence microscopy and digital image analysis (n = 18). In separate experiments fluorescence spectra were obtained for each dose by a simultaneous optical multichannel analysing device (n = 3). A three-compartment model was developed to simulate fluorescence kinetics in tumours. Maximal fluorescence intensity (per cent of reference standard; mean +/- s.e.) in the tumour arose 150 min post injection (p.i.) (1,000 mg kg-1, 109 +/- 34%; 500 mg kg-1, 148 +/- 36%) and 120 min p.i. (100 mg kg-1, 16 +/- 8%). The fluorescence in the surrounding host tissue was far less and reached its maximum at 240 min (100 mg kg-1, 6 +/- 3%) and 360 min p.i. (500 mg kg-1, 50 +/- 8%) and (1,000 mg kg-1, 6 +/- 19%). Maximal tumour-host tissue ratio (90:1) was encountered at 90 min after injection of 500 mg kg-1. The spectra of tissue fluorescence showed maxima at 637 nm and 704 nm respectively. After 300 min (host tissue) and 360 min (tumour tissue) additional emission bands at 618 nm and 678 nm were detected. These bands indicate the presence of protoporphyrin IX (PPIX) and of another porphyrin species in the tumour not identified yet. Tumour selectivity of ALA-induced PPIX accumulation occurs only during a distinct interval depending on the administered dose. Based on the presented data the optimal time for PDD and PDT in this model following intravenous administration of 500 mg kg-1 ALA would be around 90 min and 150 min respectively. The transient selectivity is probably caused by an earlier and higher uptake of ALA in the neoplastic tissue most likely as a result of increased vascular permeability of tumours as supported by the mathematical model.

Aminolevulinic Acid↗
PubMed1998

Unusual hyperpigmentation developing in congenital reticular ichthyosiform erythroderma (ichthyosis variegata).

We present an unusual new clinical feature which developed in a patient with congenital reticular ichthyosiform erythroderma. This rare ichthyotic disorder is characterized by erythematous ichthyotic skin surrounding slowly enlarging areas of normal skin, and by a pathognomonic ultrastructural pattern, namely perinuclear deposits of a filamentous material in vacuolized keratinocytes. At the age of 18 years, a 23-year-old woman developed several irregular hyperpigmented macules on her limbs, which were almost black in colour. These lesions have not been observed in the other patients affected by the disease nor, to our knowledge, in other ichthyotic disorders. Electron microscopy and immunohistochemistry demonstrated that the lesions were strictly related to the ichthyotic skin and that their dark colour was especially due to melanosome accumulation in activated dendritic melanocytes. An unusual postinflammatory hyperpigmentation, in which the lack of pigment deposition in the keratinocytes is due to a transfer defect in pathological cells, is hypothesized. A characteristic hyperplastic stimulation of the epidermis is also taken into consideration to explain the lack of a similar picture in other erythrodermic ichthyotic disorders with a continuous inflammatory process.

Adult↗
PubMed1999

Chronic lymphocytic leukaemia with symptomatic diffuse central nervous system infiltration responding to therapy with systemic fludarabine.

B-cell chronic lymphocytic leukaemia is an indolent disease characterized by the insidious accumulation of small mature-appearing lymphocytes in the peripheral blood, bone marrow and lymphoid tissues. Direct symptomatic invasion of the central nervous system is exceedingly rare and, to our knowledge, only three cases histologically confirmed as true chronic lymphocytic leukaemia have been reported in the literature. We describe the first case of early Rai stage B-cell chronic lymphocytic leukaemia presenting with symptomatic infiltration of the brain and spinal cord which could be demonstrated radiographically by magnetic resonance imaging. The diagnosis was confirmed by examination of peripheral blood, cerebrospinal fluid, brain and bone marrow biopsies, both morphologically and immunophenotypically by means of flow cytometric analysis. The patient demonstrated a complete response to therapy with standard-dose systemic fludarabine and remains in complete remission 6 months after completion of therapy.

Antineoplastic Agents↗
PubMed2002

Esterification does not impair lutein bioavailability in humans.

Age-related macular degeneration (ARMD) is inversely associated with the accumulation of lutein + zeaxanthin in the macula, but higher lutein intakes are inconsistently related to reduced risk of ARMD in epidemiologic studies. Resolution of efficacy awaits clinical trials designed with knowledge of lutein supplement pharmacokinetics. Lutein bioavailability was determined for lutein diester and unesterified lutein formulations as they might be incorporated into dietary supplements. Healthy subjects (n = 18) consumed a single dose of each formulation (either 0.5 or 0.67 micro mol lutein/kg body, 10 and 8 subjects, respectively) in random order, and the appearance of free lutein + zeaxanthin was measured in serum from 0 to 408 h. Areas under the serum concentration x time curves (AUC), as a measure of bioavailability, were independent of gender, body mass index and lutein dose. The lutein diester formulation was 61.6% more bioavailable than the unesterified lutein formulation with higher mean AUC, maximum serum concentration and ascending slope (P < 0.05). The AUC was greater in 14 of 18 subjects when they consumed the lutein diester formulation. Comparison with data from previous studies suggested that dissolution was a greater limitation to bioavailability than lutein ester hydrolysis because an oil-solubilized unesterified lutein preparation, given at 0.5 micro mol/kg body, resulted in greater mean peak concentrations and AUC compared with either the unesterified or lutein diester formulations used in our study. In conclusion, the lutein diester formulation poses no impediment to lutein bioavailability at the doses tested, but formulation dissolution is an important factor in lutein bioavailability and should be evaluated before a supplement and dose are selected for use in clinical trials.

Adult↗
PubMed2000

Anticonvulsants (antineuropathics) for neuropathic pain syndromes.

Our knowledge about the pathogenesis of neuropathic pain has grown significantly during last two decades. Basic research with animal models of neuropathic pain and human clinical trials with neuropathic pain have accumulated solid evidence that a number of pathophysiologic and biochemical changes take place in the nervous system at a peripheral or central level as a result of the insult or disease. Many similarities between the pathophysiologic phenomena observed in some epilepsy models and neuropathic pain models justify the rationale for the use of anticonvulsant drugs in the symptomatic management of neuropathic pain disorders. Carbamazepine (CBZ) was the first representative from this class of drugs to be studied in clinical trials. It has been used for the treatment of neuropathic pain syndromes, in particular, trigeminal neuralgia (TN), for the longest time of any of the drugs in this class. Results from clinical trials support the use of CBZ in the treatment of TN, painful diabetic neuropathy, and postherpetic neuralgia. The use of CBZ was not studied for complex regional pain syndrome, phantom limb pain, and other neuropathic conditions, however. Phenytoin was the first anticonvulsant to be used as an antinociceptive agent, but based on clinical trials, there is no evidence for its efficacy in relieving neuropathic pain. Newer anticonvulsants have marked a new era in the treatment of neuropathic pain, with clinical trials of higher quality standards. Gabapentin (GBP) has most clearly demonstrated an analgesic effect for the treatment of neuropathic pain, specifically for the treatment of painful diabetic neuropathy and postherpetic neuralgia. Gabapentin has a favorable side effects profile, and based on the results of these studies, it should be considered a first-line treatment for neuropathic pain. Gabapentin mechanisms of action are still not thoroughly defined, but GBP is effective in relieving indexes of allodynia and hyperalgesia in animal models. It still remains to be seen whether GBP is as effective in other painful disorders. One small clinical trial with lamotrigine demonstrated improved pain control in TN. Evidence in support of the efficacy of anticonvulsant drugs in the treatment of neuropathic pain continues to evolve, and benefits have been clearly demonstrated in the case of GBP and CBZ. More advances in our understanding of the mechanisms underlying neuropathic pain syndromes should further our opportunities to establish the role of anticonvulsants in the treatment of neuropathic pain.

Anticonvulsants↗
PubMed1990

Pathogenesis and significance of abnormal nonepileptiform rhythms in the EEG.

In this article the present state of knowledge of physiological mechanisms underlying nonepileptiform EEG abnormalities is reviewed. Focal and widespread slow waves, background activity abnormalities, and bursts of rhythmic slow activity are discussed. Clinical and experimental data accumulated over the past four decades suggest that polymorphic slow activity is generated in cerebral cortex by layers of pyramidal cells and is probably due to partial deafferentation from subcortical areas. Unilateral background activity changes are probably due to thalamic dysfunction, and bilateral paroxysmal slow activity is due to abnormal thalamocortical circuits combined with cortical pathology. The fact that pathologic slow-wave phenomena are longer in duration than the average postsynaptic potential is also discussed.

Alpha Rhythm↗