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Modulation of red cell mass by neocytolysis in space and on Earth.

Astronauts predictably experience anemia after return from space. Upon entering microgravity, the blood volume in the extremities pools centrally and plasma volume decreases, causing plethora and erythropoietin suppression. There ensues neocytolysis, selective hemolysis of the youngest circulating red cells, allowing rapid adaptation to the space environment but becoming maladaptive on re-entry to a gravitational field. The existence of this physiologic control process was confirmed in polycythemic high-altitude dwellers transported to sea level. Pathologic neocytolysis contributes to the anemia of renal failure. Understanding the process has implications for optimizing erythropoietin-dosing schedules and the therapy of other human disorders. Human and rodent models of neocytolysis are being created to help find out how interactions between endothelial cells, reticuloendothelial phagocytes and young erythrocytes are altered, and to shed light on the expression of surface adhesion molecules underlying this process. Thus, unraveling a problem for space travelers has uncovered a physiologic process controlling the red cell mass that can be applied to human disorders on Earth.

Anemia, Hemolytic↗

Neuropeptide Y inhibits ion secretion in intestinal epithelium by reducing chloride and potassium conductance.

Neuropeptide Y (NPY) is probably the most abundant neuropeptide, with a plethora of central as well as peripheral effects, including its proabsorptive action in the gastro-intestinal tract. The effects of NPY on electrical parameters related to three different pathways stimulating ion secretion were investigated using the human intestinal cell line HT29cl.19A. Transepithelial potential and resistance were measured with the preparation maintained in a horizontal Ussing chamber, allowing simultaneous measurement of the membrane potential and determination of the fractional resistance of the apical cell membrane. It was found that application of NPY, after the adenylyl-cyclase-activating drug forskolin, resulted in complete inhibition of forskolin-induced effects within approximately 20 min. The secretion stimulated by adenosine appeared to be insensitive to NPY. The acetylcholine analogue carbachol stimulates ion secretion by increasing intracellular free calcium concentrations ([Ca2+]i) which activates the basolateral potassium (K+) conductance. NPY caused 50% inhibition of the effect of carbachol. Measurements of [Ca2+]i showed that NPY inhibited the carbachol-induced rise in [Ca2+]i, which correlates with the reduced activation of basolateral K+ channels. From this study we conclude that NPY inhibits cAMP-stimulated as well as Ca2+-stimulated secretion via a reduction in the apical Cl- and basolateral K+ conductance. This double effect makes NPY an effective proabsorptive peptide.

Adenosine↗

Cellular regulation of islet hormone secretion by the incretin hormone glucagon-like peptide 1.

Glucagon-like peptide 1 is a gastrointestinally derived hormone with profound effects on nutrient-induced pancreatic hormone release. GLP-1 modulates insulin, glucagon and somatostatin secretion by binding to guanine nucleotide binding protein-coupled receptors resulting in the activation of adenylate cyclase and generation of cyclic adenosine monophosphate (cAMP). In the B-cell, cAMP, via activation of protein kinase A, interacts with a plethora of signal transduction processes including ion channel activity, intracellular Ca2+ handling and exocytosis of the insulin-containing granules. The stimulatory action of GLP-1 on insulin secretion, contrary to that of the currently used hypoglycaemic sulphonylureas, is glucose dependent and requires the presence of normal or elevated concentrations of the sugar. For this reason, GLP-1 attracts much interest as a possible novel principle for the treatment of human type-2 diabetes. Here we review the actions of GLP-1 on islet cell function and attempt to integrate current knowledge into a working model for the control of pancreatic hormone secretion.

Animals↗

Photoreceptors in Arabidopsis thaliana: light perception, signal transduction and entrainment of the endogenous clock.

To keep track of fluctuations in spectral composition and intensity of incoming sunlight, plants engage a plethora of photosensory pigments. Absorption of light by these photoreceptors sets in motion signaling cascades that ultimately influence the plant's physiology. Many light-controlled processes are based on modulation of gene activity in response to changes in irradiation. The molecular basis of this regulation and the downstream components transducing signals from the photoreceptors are not fully understood yet, but recent evidence suggests that some of those routes are rather short. The phytochrome photoreceptors have been found to influence light-responsive promoters by direct contact with transcription factors. Additionally, the cryptochrome blue-light receptors directly interact with a key repressor of photomorphogenesis, suggesting that light activation of photoreceptors could initiate photomorphogenesis through posttranslational regulation. This review focuses on recent insights into photosensory transduction mechanisms as well as on our current understanding of light entrainment of the endogenous clock.

Arabidopsis↗

The anatomy and innervation of the mammalian pineal gland.

The parenchymal cells of the mammalian pineal gland are the hormone-producing pinealocytes and the interstitial cells. In addition, perivascular phagocytes are present. The phagocytes share antigenic properties with microglial and antigen-presenting cells. In certain species, the pineal gland also contains neurons and/or neuron-like peptidergic cells. The peptidergic cells might influence the pinealocyte by a paracrine secretion of the peptide. Nerve fibers innervating the mammalian pineal gland originate from perikarya located in the sympathetic superior cervical ganglion and the parasympathetic sphenopalatine and otic ganglia. The sympathetic nerve fibers contain norepinephrine and neuropeptide Y as neurotransmitters. The parasympathetic nerve fibers contain vasoactive intestinal peptide and peptide histidine isoleucine. Recently, neurons in the trigeminal ganglion, containing substance P, calcitonin gene-related peptide, and pituitary adenylate cyclase-activating peptide, have been shown to project to the mammalian pineal gland. Finally, nerve fibers originating from perikarya located in the brain containing, for example, GABA, orexin, serotonin, histamine, oxytocin, and vasopressin innervate the pineal gland directly via the pineal stalk. Biochemical studies have demonstrated numerous receptors on the pinealocyte cell membrane, which are able to bind the neurotransmitters located in the pinealopetal nerve fibers. These findings indicate that the mammalian pinealocyte can be influenced by a plethora of neurotransmitters.

Animals↗

Localization of glutamate receptors at a complex synapse. The mammalian photoreceptor synapse.

A key feature of signal processing in the mammalian retina is parallel processing, where the segregation of visual information, e.g., brightness, darkness, and color, starts at the first synapse in the retina, the photoreceptor synapse. These various aspects are transmitted in parallel from the input neurons of the retina, the photoreceptor cells, through the interconnecting bipolar cells, to the output neurons, the ganglion cells. The photoreceptors and bipolar cells release a single excitatory neurotransmitter, glutamate, at their synapses. This parsimony is contrasted by the expression of a plethora of glutamate receptors, receptor subunits, and isoforms. The detailed knowledge of the synaptic distribution of glutamate receptors thus is of major importance in understanding the mechanisms of retinal signal processing. This review intends to highlight recent studies on the distribution of glutamate receptors at the photoreceptor synapses of the mammalian retina.

Animals↗

Dedicated minimally invasive surgery suites increase operating room efficiency.

BACKGROUND: The rapid adoption of laparoscopic surgery since the late 1980s added tremendous complexity into the operating room (OR) environment. For each case, a plethora of additional equipment-including monitors, video equipment, wiring, tubing, and cords-had to be set up, prolonging OR turnover time and decreasing OR efficiency. In 1993, the concept of designated minimally invasive surgery (MIS) suites was introduced. MIS suites integrated monitors and video equipment into the OR on ceiling-mounted columns and moved the controls to a centralized nursing station. The overall effect of this innovation on OR efficiency has not been measured. METHODS: Five RNs with varying degrees of MIS experience were instructed on video setup and put-away criteria and then timed while performing a set of standardized tasks. Each set of tasks was performed twice using a standardized surgery model. Differences in setup and put-away times between MIS suites and standard ORs were tested using the t-test for paired comparisons. RESULTS: The mean +/- standard deviation (SD) video setup times were 27.9 +/- 5.3 sec (MIS) and 254.3 +/- 54.0 sec (standard); the put-away times were 19.8 +/- 2.7 sec (MIS) and 222.3 +/- 26.0 sec (standard). The mean difference +/- standard error (SE) in both the setup (226.4 +/- 16.9 sec, p = 0.0001) and put-away times (202.5 +/- 8.6, p = 0.0001) were large and statistically significant. CONCLUSION: Using a simulation model, we have demonstrated that the use of a MIS suite reduces video setup and put-away time significantly, with the potential for significant associated cost savings. This provides just one justification for the high cost of building such "ORs of the future."

Cost-Benefit Analysis↗

A case of unfulfilled expectations. Cytokines in idiopathic minimal lesion nephrotic syndrome.

Idiopathic minimal lesion nephrotic syndrome (IMLNS) was proposed to be a disorder of T-cell dysfunction by Shalhoub in 1974. The mechanisms by which T-cells increase glomerular permeability have remained elusive (and unproven). There is evidence that IMLNS may be due to a circulating factor released from activated T-cells. In recent years, efforts have been made to identify this pathogenetic cytokine as well as to understand the mechanism(s) for the increased release of this factor. This review attempts to critically analyze the available published data. Using different methodologies, investigators have focused on the production of cytokines in patients with IMLNS during relapse and remission. This has resulted in a plethora of data without definitive conclusions. The pathogenetic cytokine has not been identified, and it is questionable whether there is a Th2 dominance in IMLNS. The review of the available data illustrates the difficulties encountered when one is studying the cytokine secretory pattern in patients with IMLNS. Differences in patient population, type of cells studies, sample preservation, and methodology used to measure cytokines are some of the factors that could account for the disparity of observed results.

Capillary Permeability↗

Alport syndromes: phenotypic heterogeneity of progressive hereditary nephritis.

Alport syndrome is a primary genetic disease of basement membranes, manifested clinically as a progressive nephropathy variably associated with sensorineural deafness and a plethora of ocular abnormalities. The long-recognized phenotypic heterogeneity of Alport syndrome may be considered on several levels, including basement membrane biochemistry, basement membrane ultrastructure, the natural history of the nephropathy, and the occurrence of extrarenal abnormalities. This review discusses the possible molecular bases for the heterogeneity. The discussion draws upon recent insights into the molecular genetics of Alport syndrome, and the biochemistry of normal and Alport syndrome basement membranes, in order to provide a framework for understanding the variable renal and extrarenal manifestations of the disease.

Disease Progression↗

Molecular and clinical aspects of iron homeostasis: From anemia to hemochromatosis.

The discovery in recent years of a plethora of new genes whose products are implicated in iron homeostasis has led to rapid expansion of our knowledge in the field of iron metabolism and its underlying complex regulation in both health and disease. Abnormalities of iron metabolism are among the most common disorders encountered in practical medicine and may have significant negative impact on physical condition and life expectancy. Basic insights into the principles of iron homeostasis and the pathophysiological and clinical consequences of iron overload, iron deficiency and misdistribution are thus of crucial importance in modern medicine. This review summarizes our current understanding of human iron metabolism and focuses on the clinically relevant features of hereditary and secondary hemochromatosis, iron deficiency anemia, anemia of chronic disease and anemia of critical illness. The interconnections between iron metabolism and immunity are also addressed, in as much as they may affect the risk and course of infections and malignancies.

Adolescent↗

Danish version of the Oswestry Disability Index for patients with low back pain. Part 1: Cross-cultural adaptation, reliability and validity in two different populations.

Over the past 10 years, a plethora of back-specific patient-orientated outcome measures have appeared in the literature. Standardisation has been advocated by an expert panel of researchers proposing a core set of instruments. Of the condition-specific questionnaires the Oswestry Disability Index (ODI) is recommended for use with low back pain (LBP) patients. To date, no Danish version of the ODI exists which has been cross-culturally adapted, validated and published in the peer-reviewed literature. A cross-cultural adaptation and validation of the ODI for the Danish language was carried out according to established guidelines: 233 patients [half of the patients were seen in the primary sector (PrS) and half in the secondary sector (SeS) of the Danish health care system] with LBP and/or leg pain completed a questionnaire booklet at baseline, 1 day or 1 week and 8 weeks follow-up. The booklet contained the Danish version of the ODI, along with the Roland Morris Disability Questionnaire, the LBP Rating Scale, the SF36 (physical function and bodily pain scales) and a global pain rating. For the ODI test-retest analysis (93 stable patients) resulted in an intraclass correlation coefficient of 0.91, a mean difference of 0.8 and 95% limits of agreements of - 11.5 to + 13. Thus, a worsening greater than 12 points and improvement greater than 13 points can be considered a "real" change above the measurement error. A substantial floor effect was found in PrS patients (14.1%). The ODI showed satisfactory cross-sectional discriminant validity when compared to the external measures. Concurrent validity of the ODI revealed: (a) a 10% and 21% lower ODI score compared to the disability and pain measures, respectively, (b) a poorer differentiation of patient disabilities and (c) an acceptable individual ODI score level compared to the external measures. Longitudinal external construct validity showed moderate correlations (range 0.56-0.78). We conclude that the Danish version of the ODI is both a valid and reliable outcome instrument in two LBP patient populations. The ODI is probably most appropriate for use in SeS patients.

Adolescent↗

Applications and current challenges of proteomic approaches, focusing on two-dimensional electrophoresis.

Since the formulation of the concept of "proteomics" in 1995, a plethora of proteomic technologies have been developed in order to study proteomes of tissues, cells and organelles. The powerful new technologies enabled by proteomic approaches have lead to the application of these methods to an exponentially increasing variety of biological questions for highly complex protein mixtures. Continuous technical optimization allows for an ever-increasing sensitivity of proteomic techniques. In this review, a brief overview of currently available proteomic techniques and their applications is given, followed by a more detailed description of advantages and technical challenges of two-dimensional electrophoresis (2-DE). Some solutions to circumvent currently encountered technical difficulties for 2-DE analyses are proposed.

Animals↗

Improvement of Erdheim-Chester disease in two patients by sequential treatment with vinblastine and mycophenolate mofetil.

Erdheim-Chester disease (ECD) is a rare non-Langerhans' form of histiocytosis with a plethora of different clinical manifestations owing to multiple organ involvement. We report two patients who presented initially with different clinical symptoms. The presenting complaint of the first patient was bone pain, predominantly in the legs, whereas in the other patient the initial symptoms were related to obstruction of both ureters, as in idiopathic retroperitoneal fibrosis. Ultimately, ECD was diagnosed in both patients by the occurrence of both pathognomonic manifestations, the histologic presence of non-Langerhans' histiocytes in bone biopsies, and osteosclerotic lesions of the long bones. Because the extraosseous manifestations progressed and a single application of corticosteroids was ineffective, sequential treatment with vinblastine and mycophenolate mofetil, together with prednisolone, was started. At follow-up respectively 15 and 16 months after the start of treatment a beneficial effect was noted in both patients. These cases illustrate the clinical spectrum of ECD, detail the pathognomonic manifestations of this rare disease, emphasize the need to consider ECD as an uncommon but important differential diagnosis in patients with arthralgias or systemic fibrosis, and give the first evidence for a new treatment option.

Antineoplastic Agents, Phytogenic↗

HBV and HCV infection, polyarteritis nodosa and mixed cryoglobulinaemia: a case report.

HCV infection has been associated with a broad spectrum of extrahepatic manifestations. In some of these, such as mixed cryoglobulinaemia (MC), the association is firmly established, whereas in others, such as polyarteritis nodosa (PAN), it is anecdotal; in fact, in this disorder the importance of the association is controversial, since it seems to be related to the frequent coinfection of HBV and HCV. The pathogenesis of MC and PAN is far from clear, but recent developments have added a plethora of information on the mechanisms underlying these disorders. Although both could be induced by a viral infection, the pathophysiological processes underlying the two diseases are different. We describe the occurrence in the same patient of HBV-related PAN and HCV-related MC.

Cryoglobulinemia↗

Clues to the immunopathogenesis of multiple sclerosis by investigating untreated patients during the very early stage of disease.

Plethora of abnormalities of the immune system has been described in multiple sclerosis (MS). They include a number of myelin antigens (e.g. MBP, MOG, PLP, MAG), the presence of reactive T cells in blood and, further enriched, in the cerebrospinal fluid (CSF), large numbers of B cells in the CSF secreting antibodies of multiple but unknown specificities, an increase of mononuclear cells (MNC) expressing and secreting both pro- and anti-inflammatory cytokines, including Th1 cytokines interferon-gamma (IFN-gamma) and interleukin (IL)-6, the Th2 related IL-4 and IL-10, and the Th3-driven TGF-beta, elevated numbers of MNC in both blood and CSF expressing a spectrum of metalloproteinases and their inhibitors, as well as many other aberrations. However, no consistent patterns have emerged that relate any, of these findings to clinical variables such as exacerbations, duration of disease, disability, or lesions in the central nervous system (CNS) detected at magnetic resonance imaging. In order to elucidate the relevance of these immunological abnormalities in the pathogenesis of MS, my colleagues and I studied patients with acute monosymptomatic optic neuritis (ON) and compared them with patients with clinically definite MS (CDMS). The patients have not been treated and have not received corticosteroids or interferon-beta. When comparing these two groups, we were unable to identify any differences in any of the variables mentioned. Thus, very early MS, as represented by ON, shows the same full-blown pattern of immunological abnormalities seen in CDMS. Furthermore, a complete epitope spread affecting MBP, MOG, PLP, MAG and other myelin components is already present in ON. Whether any of these alterations play a pathogenetic role is still unsettled.

Brain↗

Marine sponges as pharmacy.

Marine sponges have been considered as a gold mine during the past 50 years, with respect to the diversity of their secondary metabolites. The biological effects of new metabolites from sponges have been reported in hundreds of scientific papers, and they are reviewed here. Sponges have the potential to provide future drugs against important diseases, such as cancer, a range of viral diseases, malaria, and inflammations. Although the molecular mode of action of most metabolites is still unclear, for a substantial number of compounds the mechanisms by which they interfere with the pathogenesis of a wide range of diseases have been reported. This knowledge is one of the key factors necessary to transform bioactive compounds into medicines. Sponges produce a plethora of chemical compounds with widely varying carbon skeletons, which have been found to interfere with pathogenesis at many different points. The fact that a particular disease can be fought at different points increases the chance of developing selective drugs for specific targets.

Animals↗

Prognostic implications of hMLH1 and p53 immunohistochemical status in right-sided colon cancer.

PURPOSE: Extensive research into the molecular biology of colorectal cancer has identified a plethora of molecular markers reputed to provide independent prognostic information. p53 mutational status has been associated with both improved and reduced survival; however, tumors expressing a particular phenotype associated with defective mismatch repair consistently do better. This study was designed to examine site-specific survival implications of p53 and mismatch repair status. METHODS: Mismatch repair (hMLH1 and hMSH2) and p53 status was investigated immunohistochemically in 111 proximal colon cancers along with tumor TNM stage, grade, and extramural vascular invasion. Fisher's exact test was used to assess categoric data; univariate and multivariate models compared survival between the respective tumor phenotypes. RESULTS: Thirty-two percent of tumors showed loss of expression of hMLH1 and in a multivariate analysis were associated with a significant survival advantage after adjustment for tumor stage, p53 status, and extramural vascular invasion (hazard ratio, 0.29; 95 percent confidence interval, 0.1-0.87; P = 0.027). Only two tumors showed loss of expression of hMSH2, which was not related further to survival. Aberrant p53 expression was detected in 39 percent of tumors. Such expression was found to be associated with a significantly reduced survival in univariate analysis (P = 0.037, log-rank test) but not in a multivariate model. Subgroup analysis showed no association between survival and p53 expression in mismatch repair proficient tumors. CONCLUSIONS: Loss of hMLH1 expression is an independent predicator of improved survival in this series and perhaps the underlying cause of the observed survival difference associated with p53 expression.

Adaptor Proteins, Signal Transducing↗

[Psychotherapy in a tax-financed sectorized health care system--a happy ending or disaster for English patients?].

Compared to other European countries' health systems, the NHS is very different. Finance by taxes, standards set by frameworks and statutory bodies to monitor nationwide the outcome, are virtually unknown on the Continent. For the patients there are considerable differences in how they are referred to psychotherapy and receive their treatment based on guaranteed standards. Health professionals identified with the NHS have to cope with a plethora of government directives.

Cost Control↗