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Terms modified by First Line Selected AbstractsNeutrophils display biphasic relationship between migration and substrate stiffnessCYTOSKELETON, Issue 6 2009Kimberly M. Stroka Abstract Neutrophils are one type of migrating cell in the body's innate immune system and are the first line of defense against inflammation or infection. While extensive work exists on the effect of adhesive proteins on neutrophil motility, little is known about how neutrophil motility is affected by the mechanical properties of their physical environment. This study investigated the effects of substrate stiffness on the morphology, random motility coefficient, track speed (v), spreading area, and distribution of turning angles of neutrophils during chemokinesis. Human neutrophils were plated onto polyacrylamide gels of varying stiffness, ranging from 3 to 13 kPa, and coated with the extracellular matrix protein fibronectin, and timelapse images were taken with phase contrast microscopy. Our results show a biphasic behavior between neutrophil motility and substrate stiffness, with the optimum stiffness for motility depending on the concentration of fibronectin on the surface of the gel. On 100 ,g/mL fibronectin, the optimum stiffness is 4 kPa (v = 6.9 ± 0.6 ,m/min) while on 10 ,g/mL fibronectin, the optimum stiffness increases to 7 kPa (v = 4.5 ± 2.0 ,m/min). This biphasic behavior most likely arises because neutrophils on soft gels are less adherent, preventing production of traction forces, while neutrophils on stiff gels adhere strongly, resulting in decreased migration. At intermediate stiffness, however, neutrophils can attain optimal motility as a function of extracellular matrix coating. Cell Motil. Cytoskeleton 2009. © 2009 Wiley-Liss, Inc. [source] How does premenstrual dysphoric disorder relate to depression and anxiety disorders?DEPRESSION AND ANXIETY, Issue 3 2003Mikael Landén M.D., Ph.D. Abstract Premenstrual dysphoric disorder (PMDD) is a severe variant of premenstrual syndrome that afflicts approximately 5% of all women of fertile age. The hallmark of this condition is the surfacing of symptoms during the luteal phase of the menstrual cycle, and the disappearance of symptoms shortly after the onset of menstruation. Whereas many researchers have emphasized the similarities between PMDD and anxiety disorders, and in particular panic disorder, others have suggested that PMDD should be regarded as a variant of depression. Supporting both these notions, the treatment of choice for PMDD, the serotonin reuptake inhibitors (SRIs), is also first line of treatment for depression and for most anxiety disorders. In this review, the relationship between PMDD on the one hand, and anxiety and depression on the other, is being discussed. Our conclusion is that PMDD is neither a variant of depression nor an anxiety disorder, but a distinct diagnostic entity, with irritability and affect lability rather than depressed mood or anxiety as most characteristic features. The clinical profile of SRIs when used for PMDD, including a short onset of action, suggests that this effect is mediated by other serotonergic synapses than the antidepressant and anti-anxiety effects of these drugs. Although we hence suggest that PMDD should be regarded as a distinct entity, it should be emphasized that this disorder does display intriguing similarities with other conditions, and in particular with panic disorder, which should be the subject of further studies. Also, the possibility that there are subtypes of PMDD more closely related to depression, or anxiety disorders, than the most common form of the syndrome, should not be excluded. Depression and Anxiety 17:122,129, 2003. © 2003 Wiley-Liss, Inc. [source] Diagnostic value of needle aspiration cytology (NAC) in the assessment of palpable inguinal lymph nodes: A study of 210 casesDIAGNOSTIC CYTOPATHOLOGY, Issue 4 2003F.I.A.C., Raj K. Gupta M.D. Abstract The aim of this study was to evaluate the diagnostic value of needle aspiration cytology (NAC) in the assessment of palpable inguinal lymph nodes, which were analyzed in 210 cases. NAC in all the cases were performed by the conventional aspiration method and cytologic examination was done on site after staining smears with the Papanicolaou method. In addition, Diff-Quik-stained air-dried smears, Papanicolaou-stained fixed smears, and filter preparations from needle washings and hematoxylin-eosin-stained sections of cell blocks were studied. The NAC diagnosis was supported by examining cell blocks in 92/210 cases which showed a reliable histologic architecture; further support was also obtained with a tissue biopsy in 9/12 cases of inflammatory lesions, 7/7 cases with a suspicious diagnosis, 20/26 cases of melanomas, 15/15 cases of lymphomas, and/or a comparison with the primary tumor in other cases of metastatic tumors. Additionally, immunoperoxidase and/or histochemical stains were done. Twelve cases were diagnosed as inflammatory lesions and 88 cases were regarded as negative (normal cellular elements n = 40; reactive elements n = 48). In 58 cases a variety of metastatic tumors were diagnosed (melanoma n = 26; others n = 32) and in 15 cases a diagnosis of lymphoma was made. Seven cases were diagnosed as suspicious of malignancy and 30 cases were unsatisfactory due to scanty/acellular samples (despite 2,3 repeat samplings). However, in five of these malignant tumors were later found on a biopsy which was done due to a persistent and continued enlargement of lymph node(s). The sensitivity was 91.7%, specificity 98.2%, positive predictive value (PPV) 97.7.%, and negative predictive value (NPV) was 95.45%. Based on our study we feel that NAC as a first line of investigation is not only useful in the diagnosis of lesions in inguinal lymph nodes, but can also help in deciding on an appropriate management. Also, histologic architecture from cell blocks can be correlated with cytology and such material can be used for histochemical and immunomarker studies. Diagn. Cytopathol. 2003;28:175,180. © 2003 Wiley-Liss, Inc. [source] Evolution and development of gastropod larval shell morphology: experimental evidence for mechanical defense and repairEVOLUTION AND DEVELOPMENT, Issue 1 2001Carole S. Hickman SUMMARY The structural diversity of gastropod veliger larvae offers an instructive counterpoint to the view of larval forms as conservative archetypes. Larval structure, function, and development are fine-tuned for survival in the plankton. Accordingly, the study of larval adaptation provides an important perspective for evolutionary-developmental biology as an integrated science. Patterns of breakage and repair in the field, as well as patterns of breakage in arranged encounters with zooplankton under laboratory conditions, are two powerful sources of data on the adaptive significance of morphological and microsculptural features of the gastropod larval shell. Shells of the planktonic veliger larvae of the caenogastropod Nassarius paupertus[Gould] preserve multiple repaired breaks, attributed to unsuccessful zooplankton predators. In culture, larvae isolated from concentrated zooplankton samples rapidly repaired broken apertural margins and restored the "ideal" apertural form, in which an elaborate projection or "beak" covers the head of the swimming veliger. When individuals with repaired apertures were reintroduced to a concentrated mixture of potential zooplankton predators, the repaired margins were rapidly chipped and broken back. The projecting beak of the larval shell is the first line of mechanical defense, covering the larval head and mouth and potentially the most vulnerable part of the shell to breakage. Patterns of mechanical failure show that spiral ridges do reinforce the beak and retard breakage. The capacity for rapid shell repair and regeneration, and the evolution of features that resist or retard mechanical damage, may play a more prominent role than previously thought in enhancing the ability of larvae to survive in the plankton. [source] Amoebal pathogens as emerging causal agents of pneumoniaFEMS MICROBIOLOGY REVIEWS, Issue 3 2010Frédéric Lamoth Abstract Despite using modern microbiological diagnostic approaches, the aetiological agents of pneumonia remain unidentified in about 50% of cases. Some bacteria that grow poorly or not at all in axenic media used in routine clinical bacteriology laboratory but which can develop inside amoebae may be the agents of these lower respiratory tract infections (RTIs) of unexplained aetiology. Such amoebae-resisting bacteria, which coevolved with amoebae to resist their microbicidal machinery, may have developed virulence traits that help them survive within human macrophages, i.e. the first line of innate immune defence in the lung. We review here the current evidence for the emerging pathogenic role of various amoebae-resisting microorganisms as agents of RTIs in humans. Specifically, we discuss the emerging pathogenic roles of Legionella -like amoebal pathogens, novel Chlamydiae (Parachlamydia acanthamoebae, Simkania negevensis), waterborne mycobacteria and Bradyrhizobiaceae (Bosea and Afipia spp.). [source] Low dose radiotherapy in indolent lymphomas, enough is enough,HEMATOLOGICAL ONCOLOGY, Issue 2 2009R. L. M. Haas MD. Abstract Follicular lymphomas, as a prototype of all indolent lymphomas, are exquisitely radiation sensitive. This review paper highlights the clinical presentation of this lymphoma entity. Literature data are presented on first line curative irradiation in stage I and II patients, low-dose total body irradiation (TBI) in stage III and IV patients in first line and low-dose IF-RT (involved field radiotherapy) in patients with relapse. The clinical aspects of 2,×,2,Gy IF-RT in follicular lymphoma (FL) are presented as well as the in vivo imaging of the apoptotic cell death underlying the clinical response. Finally, by gene expression profiling, possible molecular-biological pathways are described involved in the low dose irradiation of FL. Copyright © 2009 John Wiley & Sons, Ltd. [source] Guidelines for the treatment of chronic hepatitis and cirrhosis due to hepatitis B virus infection for the fiscal year 2008 in JapanHEPATOLOGY RESEARCH, Issue 1 2010Hiromitsu Kumada In the 2008 guidelines for the treatment of patients with cirrhosis, who are infected with hepatitis B virus (HBV), the main goal is to normalize levels of alanine and aspartate aminotransferases by eliminating HBV or reducing viral loads. In patients with compensated cirrhosis, the clearance of HBV from serum is aimed for by entecavir, as the main resort, for histological improvement toward the prevention of hepatocellular carcinoma (HCC). In patients with decompensated cirrhosis, by contrast, meticulous therapeutic strategies are adopted for the reversal to compensation, toward the eventual goal of decreasing the risk of HCC. For maintaining liver function and preventing HCC, branched chain amino acids and nutrient supplements are applied, in addition to conventional liver supportive therapies. For patients with chronic hepatitis B, separate guidelines are applied to those younger than 35 years and those aged 35 years or older. Even for patients with chronic hepatitis who are negative for hepatitis e antigen (HBeAg), but who harbor HBV DNA in titers of 7 log copies/mL or more, a "drug-free state" is aimed for by sequential treatment with interferon (IFN) plus entecavir as the first line. For patients with chronic hepatitis B aged 35 years or older, who are HBeAg-negative and carry HBV DNA in titers of less than 7 log copies/mL, long-term IFN for 24,48 weeks is adopted anew. To HBeAg-negative patients who have either or both platelet counts of less than 150 × 103/mm3 and less than 7 log copies of HBV DNA, also, long-term IFN for 24,48 weeks is indicated. [source] The liver as a crucial organ in the first line of host defense: the roles of Kupffer cells, natural killer (NK) cells and NK1.1 Ag+ T cells in T helper 1 immune responsesIMMUNOLOGICAL REVIEWS, Issue 1 2000Shuhji Seki Summary: The liver remains a hematopoietic organ after birth and can produce all leukocyte lineages from resident hematopoietic stem cells. Hepatocytes produce acute phase proteins and complement in bacterial infections. Liver Kupffer cells are activated by various bacterial stimuli, including bacterial lipopolysaccharide (LPS) and bacterial superantigens, and produce interleukin (IL)-12. IL-12 and other monokines (IL-18 etc.) produced by Kupffer cells activate liver natural killer (NK) cells and NK1.1 Ag+ T cells to produce interferon-g and thereby acquire cytotoxicity against tumors and microbe-infected cells. These liver leukocytes and the T helper 1 immune responses induced by them thus play a crucial role in the first line of defense against bacterial infections and hematogenous tumor metastases. However, if this defense system is inadequately activated, shock associated with multiple organ failure takes place. Activated liver NK1.1 Ag+ T cells and NK cells also cause hepatocyte injury. NK1.1 Ag+ T cells and another T-cell subset with an intermediate T-cell receptor, CD122+CD8+ T cells, can develop independently of thymic epithelial cells. Liver NK cells and NK1.1 Ag+ T cells physiologically develop in situ from their precursors, presumably due to bacterial antigens brought from the intestine via the portal vein. NK cells activated by bacterial superantigens or LPS are also probably involved in the vascular endothelial injury in Kawasaki disease. [source] Dissecting innate immunity by germline mutagenesisIMMUNOLOGY, Issue 4 2008Sophie Rutschmann Summary The innate arm of our immune system is the first line of defence against infections. In addition, it is believed to drive adaptive immune responses, which help fight pathogens and provide long-term memory. As such, the innate immune system is instrumental for protection against pathogens that would otherwise destroy their host. Although our understanding of the innate immune components involved in pathogen sensing and fighting is improving, it is still limited. This is particularly exemplified by increased documentation of innate immune deficiencies in humans that often result in high and recurrent susceptibility to infections or even death, without the genetic cause being evident. To provide further insight into the mechanisms by which pathogen sensing and eradication occur, several strategies can be used. The current review focuses on the forward genetic approaches that have been used to dissect innate immunity in the fruit fly and the mouse. For both animal models, forward genetics has been instrumental in the deciphering of innate immunity and has greatly improved our understanding of how we respond to invading pathogens. [source] Functional characterization of human natural killer cells responding to Mycobacterium bovis bacille Calmette-GuérinIMMUNOLOGY, Issue 1 2004Semih Esin Summary The kinetics of activation and induction of several effector functions of human natural killer (NK) cells in response to Mycobacterium bovis bacille Calmette-Guérin (BCG) were investigated. Owing to the central role of monocytes/macrophages (MM) in the initiation and maintenance of the immune response to pathogens, two different experimental culture conditions were analysed. In the first, monocyte-depleted nylon wool non-adherent (NW) cells from healthy donors were stimulated with autologous MM preinfected with BCG (intracellular BCG). In the second, the NW cells were directly incubated with BCG, which was therefore extracellular. In the presence of MM, CD4+ T lymphocytes were the cell subset mainly expressing the activation marker, CD25, and proliferating with a peak after 7 days of culture. In contrast, in response to extracellular BCG, the peak of the proliferative response was observed after 6 days of stimulation, and CD56+ CD3, cells (NK cells) were the cell subset preferentially involved. Such proliferation of NK cells did not require a prior sensitization to mycobacterial antigens, and appeared to be dependent upon contact between cell populations and bacteria. Following stimulation with extracellular BCG, the majority of interferon-, (IFN-,)-producing cells were NK cells, with a peak IFN-, production at 24,30 hr. Interleukin (IL)-2 and IL-4 were not detectable in NK cells or in CD3+ T lymphocytes at any time tested. IL-12 was not detectable in the culture supernatant of NW cells stimulated with extracellular BCG. Compared to the non-stimulated NW cells, the NW cells incubated for 16,20 hr with BCG induced the highest levels of expression of apoptotic/death marker on the NK-sensitive K562 cell line. BCG also induced expression of the activation marker, CD25, and proliferation, IFN-, production and cytotoxic activity, on negatively selected CD56+ CD3, cells. Altogether, the results of this study demonstrate that extracellular mycobacteria activate several NK-cell functions and suggest a possible alternative mechanism of NK-cell activation as the first line of defence against mycobacterial infections. [source] Host's innate immune response to fungal and bacterial agents in vitro: up-regulation of interleukin-15 gene expression resulting in enhanced natural killer cell activityIMMUNOLOGY, Issue 2 2003Phay Tran Summary Natural killer (NK) cells play an important role in the first line of defence against viral infections. We have shown earlier that exposure of human peripheral blood mononuclear cells (PBMC) to viruses results in rapid up-regulation of NK cell activity via interleukin-15 (IL-15) induction, and that this mechanism curtails viral infection in vitro. By using Candida albicans, Escherichia coli and Staphylococcus aureus, we now show here that exposure of PBMC to fungi and bacteria also results in an immediate increase of NK cytotoxicity. Reverse transcriptase,polymerase chain reaction and Western blot analyses as well as the use of antibodies against different cytokines revealed that IL-15 induction played a predominant role in this NK activation. These results indicate that IL-15 is also involved in the innate immune response against fungal and bacterial agents. [source] Ageing and the neutrophil: no appetite for killing?IMMUNOLOGY, Issue 4 2000S. Butcher Summary In the armoury of the immune system developed to combat the various micro-organisms that could invade the host, the neutrophil forms the first line of defence against rapidly dividing bacteria and fungi. However, as humans age they become more susceptible to infection with these microbes and this has been ascribed to a decline in immune status, termed immune senescence. Here we summarize the literature specifically concerning the attenuation of neutrophil function with age and the possible mechanisms underlying their reduced response to infectious agents. [source] Tumour-associated macrophages and melanoma tumourigenesis: integrating the complexityINTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY, Issue 3 2006Mahmoud R. Hussein Summary When the body discovers a tumour cell (foreign antigen), several kinds of mechanisms and cells operate in what is called an immune response. The latter has evolved into two mechanisms: non-specific immunity and specific immunity, which are closely linked to and influence each other. The former represents the first line of defence against neoplastic cells. The adaptive (specific) immunity is orchestrated by antigen-specific T and B lymphocytes. The effector cells of innate immunity include granulocytes, macrophages and natural killer cells. Among these cells, macrophages represent the most important part of innate immunity against tumours. Tumour-associated macrophages (TAMs) are important antigen-presenting cells and as such an understanding of their interactions with tumour cells gives insights into novel therapeutic strategies. In tumours, the effect of TAMs is the outcome of their two concomitantly competing interactions: tumour growth reduction and tumour growth promotion. The macrophage (TAMs) content of melanoma ranges from 0 to 30% and their density increases with increasing tumour thickness. The melanoma cells and TAMs seem to interact with each other through the release of soluble factors that either prevent or enhance tumour growth. For instance, syngeneic macrophages from tumour-bearing mice can inhibit melanoma growth in the nude mice more than the control macrophages. Alternatively, metastatic B16 melanoma cells can produce some macrophage cytotoxic substances that help tumour cells not only escape the host immunosurveillance system but also prevent distant metastasis. Together, these observations suggest opposing effects for these soluble factors in melanoma. To date, little is available in the literature about the interactions between TAMs and melanoma cells. This viewpoint not only tries to examine these interactions but also provides relevant speculations. [source] Cautious response of inexperienced birds to conventional signal of stronger threatJOURNAL OF AVIAN BIOLOGY, Issue 6 2007Tomasz S. Osiejuk Several studies demonstrated that bird song functions as a first line of territorial defence. The efficiency of deterring rivals depends strongly on the strategy of singing used (e.g. alternating/overlapping singing, singing with low/high rate, matching song type of a rival or singing different type). Causes of between males variation during countersinging are still not fully understood, especially when different signals have similar production costs and their meaning is assigned by arbitrary convention (conventional signalling). We tested whether an oscine bird with small repertoire size, the ortolan bunting Emberiza hortulana, differentiate strategy of responding to song of an intruder in relation to its age and threat value of signals. We performed playback experiments to measure response of second year (SY) and after second year (ASY) males to a song of low (eventual variety singing) and high (immediate variety singing) threat value. We found substantial differences in response to playback, which were related both to the type of stimuli used and age of responding males. Both SY and ASY males gave more calls than songs in response to immediate variety playback, which suggest stronger vocal response to the signal of higher threat value. Approaching loudspeaker was similar for both age classes when lower threat value signal was played back, while simultaneously SY males clearly avoided approaching loudspeaker when stronger threat values signal was played back. We conclude that ortolan bunting differentiate response to signal of different threat value and that the strength of response depends on the age of a male. This study provides experimental evidence that age of receiver affects its response to a territorial intruder. It also demonstrates that observed in many studies variation in response to playback may be an effect of age differences between males, which rarely is controlled. [source] The antioxidant capacity of salivaJOURNAL OF CLINICAL PERIODONTOLOGY, Issue 3 2002M. Battino Abstract Background/aims: Saliva, a heterogeneous fluid comprising proteins, glycoproteins, electrolytes, small organic molecules and compounds transported from the blood, constantly bathes the teeth and oral mucosa. It acts as a cleansing solution, an ion reservoir, a lubricant and a buffer. In addition to its other host-protective properties, saliva could constitute a first line of defence against free radical-mediated oxidative stress, since the process of mastication and digestion of ingested foods promotes a variety of reactions, including lipid peroxidation. Moreover, during gingival inflammation, gingival crevicular fluid flow increases the change of saliva composition with products from the inflammatory response; this, in turn, could have some rôle in controlling and/or modulating oxidative damages in the oral cavity. This is the reason why the antioxidant capacity of saliva has led to increasing interest, and the development of techniques suitable for saliva antioxidant evaluation. Materials and Methods: Here, we review the current peer-reviewed literature concerning the nature and characteristics of free radicals, reactive oxygen species, oxidants, pro-oxidants and antioxidants in saliva, especially pro-oxidant and antioxidant features, as well as current methods for assessing the antioxidant capacity of saliva. Results and Conclusions: In the last decade, several methods have been developed for assaying the antioxidant activity of saliva, indicating an increasing interest of researchers and clinicians. Unfortunately, systematic studies of saliva are still lacking, even in healthy populations. Zusammenfassung Hintergrund/Zielsetzung: Der Speichel, eine heterogene Flüssigkeit bestehend aus Proteinen, Glykoproteinen, Elektrolyten, kleinen organischen Molekülen und Bestandteilen aus dem Blut, umspült andauernd Zähne und Mundschleimhäute. Er wirkt als Reinigungslösung, Reservoir für Ionen, als Schmiermittel und als Puffer. Zusätzlich zu seinen anderen Abwehreigenschaften könnte der Speichel eine erste Verteidigungslinie gegen durch freie Radikal verursachten oxidativen Stress sein, da der Prozess der Nahrungszerkleinerung und -verdauung eine Vielzahl von Reaktionen auslöst einschließlich der Lipidperoxidation. Darüber hinaus erhöht sich während gingivaler Entzündung der Sulkusflüssigkeitsfluss und verändert die Zusammensetzung des Speichels durch Produkte der Entzündungsreaktion. Dies könnte eine Rolle bei der Kontrolle und/oder Beeinflussung oxidativer Schäden in der Mundhöhle spielen. Dies sind die Gründe dafür, warum die antioxidative Kapazität des Speichels zu einem wachsenden Interesse und zur Entwicklung von Techniken geführt hat, die die Bestimmung der antioxidativen Kapazität des Speichels erlauben. Material und Methoden: In diesem Übersichtsartikel wird die akutelle Literatur hinsichtlich der Natur und Charakteristika freier Radikale, reaktiver Sauerstoffarten, Oxidantien, Prooxidantien und Antioxidantien im Speichel, insbesondere Eigenschaften der Pro- und Antioxidantien sowie aktuelle Methoden zur Bestimmung der antioxidative Kapazität des Speichels, dargestellt. Ergebnisse/Schlussfolgerungen: Während des vergangenen Jahrzehnts wurden mehrere Methoden für die Bestimmung der antioxidativen Kapazität des Speichels entwickelt, was für ein wachsendes wissenschaftliches und klinisches Interesse spricht. Unglücklicherweise fehlen noch systematische Studien zum Speichel selbst für gesunde Kollektive. Résumé Origine/but: La salive, fluide hétérogène constitué de protéines, de glycoprotéines, d'électrolytes, de petites molécules organiques et de composés transportés du sang, baigne constamment les dents et les muqueuses buccales. Elle agit comme une solution nettoyante, comme réservoir d'ions, comme lubrifiant et comme tampon. En plus de ces propriétés protectrices pour l'hôte, la salive pourrait constituer une première ligne de défense contre le stress oxydatif dû aux radicaux libres puisque le processus de mastication et de digestion des nourritures ingérées induit une variété de réactions, telle la peroxidation des lipides. De plus, pendant l'inflammation gingivale, le flux gingival sulculaire augmente et altère la compositon de la salive par les produits de la réponse inflammatoire. Cela, à son tour, pourrait avoir un rôle dans le contrôle ou la modulation des dommages oxydatifs dans la cavité buccale. C'est la raison pour laquelle la capacité antioxydant de la salive a connu un intérêt croissant et le développement de techniques fiables pour l'évaluation des antioxydants salivaires. Matériaux et méthodes: Ici, nous passons en revue de façon concise la littérature actuelle concernant la nature et les caractéristiques des radicaux libres, des espèces réactives à l'oxygène, des oxydants, des pro-oxydants et des antioxydants dans la salive, particulièrement les caractéristiques pro-oxydante et antioxydante et les méthodes actuelles de mise en évidence des capacités antioxydantes de la salive. Résultats et conclusions: Lors de la dernière décade, plusieurs méthodes ont été développées pour tester l'activité antioxydante de la salive, ce qui prouve un intérêt grandissant des chercheurs et des cliniciens. Malheureusement, des études systématiques sur la salive manquent même pour les populations saines. [source] Purification and characterization of a 630 kDa bacterial killing metalloprotease (KilC) isolated from plaice Pleuronectes platessa (L.), epidermal mucusJOURNAL OF FISH DISEASES, Issue 5 2008T Tvete Abstract Antibacterial chemicals in the mucus of fish such as lysozyme, lectins, peptides and proteases provide an efficient first line of defence against pathogens. This study shows that there are at least three antibacterial proteins in plaice skin mucus in addition to lysozyme. One of these proteins is responsible for approximately 74% of the antibacterial activity and is a 630 kDa protease complex designated KilC (bacterial killing metalloprotease C). Purified KilC kills the bacteria Staphylococcus aureus, Escherichia coli, Bacillus subtilis and Pseudomonas aeruginosa efficiently. The protease activity of KilC is dependent upon the divalent cation Mg2+ and shows pH dual optima of 5.0 and 8.0. The enzyme has a temperature optimum of 25 °C and is made up of at least five different sized peptides. Studies with protease inhibitors show that the catalytic site of KilC may be cysteine- or serine protease-like. KilC may kill bacterial cells by acting directly upon the bacteria or by producing low molecular weight bioactive compounds such as peptides. [source] Aggregation kinetics of recombinant human FVIII (rFVIII)JOURNAL OF PHARMACEUTICAL SCIENCES, Issue 9 2005Karthik Ramani Abstract The physical phenomenon of aggregation can have profound impact on the stability of therapeutic proteins. This study focuses on the aggregation behavior of recombinant human FVIII (rFVIII), a multi-domain protein used as the first line of therapy for hemophilia A, a bleeding disorder caused by the deficiency or dysfunction of factor VIII (FVIII). Thermal denaturation of rFVIII was investigated using circular dichroism (CD) spectroscopy and size exclusion chromatography (SEC). The dependence of unfolding on heating rate indicated that the thermal denaturation of the protein was at least partly under kinetic control. The data was interpreted in terms of a simple two-state kinetic model, , where k is a first-order kinetic constant that changes with temperature, as given by the Arrhenius equation. Analysis of the data in terms of the above scheme suggested that under the experimental conditions used in this study, the rate-controlling step in the aggregation of rFVIII may be a unimolecular reaction involving conformational changes. © 2005 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 94:2023,2029, 2005 [source] Melatonin in the duodenal lumen is a potent stimulant of mucosal bicarbonate secretionJOURNAL OF PINEAL RESEARCH, Issue 4 2003Markus Sjöblom Abstract: Melatonin, originating from intestinal enterochromaffin cells, mediates vagal and sympathetic neural stimulation of the HCO secretion by the duodenal mucosa. This alkaline secretion is considered the first line of mucosal defense against hydrochloric acid discharged from the stomach. We have studied whether luminally applied melatonin stimulates the protective secretion and whether a melatonin pathway is involved in acid-induced stimulation of the secretion. Rats were anaesthetized (Inactin®) and a 12-mm segment of proximal duodenum with an intact blood supply was cannulated in situ. Mucosal HCO secretion (pH-stat) and the mean arterial blood pressure were continuously recorded. Luminal melatonin at a concentration of 1.0 ,m increased (P < 0.05) the secretion from 7.20 ± 1.35 to 13.20 ± 1.51 ,Eq/cm/hr. The MT2 selective antagonist luzindole (600 nmol/kg, i.v.) had no effect on basal HCO secretion, but inhibited (P < 0.05) secretion stimulated by luminal melatonin. Hexamethonium (10 mg/kg i.v. followed by continuous i.v. infusion at a rate of 10 mg/kg/hr), abolishes neurally mediated rises in secretion and also inhibited (P < 0.05) the stimulation by luminal melatonin. Exposure of the lumen to acid containing perfusate (pH 2.0) for 5 min increased (P < 0.05) the HCO secretion from 5.85 ± 0.82 to 12.35 ± 1.51 ,Eq/cm/hr, and luzindole significantly inhibited (P < 0.05) this rise in secretion. The study thus demonstrates that luminal melatonin is a potent stimulant of duodenal HCO secretion and, furthermore, strongly suggests melatonin as an important mediator of acid-induced secretion. [source] Upregulation of Serotonin Transporter by Alcohol in Human Dendritic Cells: Possible Implication in Neuroimmune DeregulationALCOHOLISM, Issue 10 2009Dakshayani Kadiyala Babu Background:, Alcohol is the most widely abused substance and its chronic consumption causes neurobehavioral disorders. It has been shown that alcohol affects the function of immune cells. Dendritic cells (DC) serve as the first line of defense against infections and are known to accumulate neurotransmitters such as 5-hydroxytryptamine (5-HT). The enzyme monoamine oxidase-A (MAO-A) degrades 5-HT that is associated with clinical depression and other neurological disorders. 5-HT is selectively transported into neurons through the serotonin transporter (SERT), which is a member of the sodium- and chloride-dependent neurotransmitter transporter (SLC6) family. SERT also serves as a receptor for psychostimulant recreational drugs. It has been demonstrated that several drugs of abuse such as amphetamine and cocaine inhibit the SERT expression; however, the role of alcohol is yet to be elucidated. We hypothesize that alcohol can modulate SERT and MAO-A expression in DC, leading to reciprocal downregulation of 5-HT in extracellular medium. Methods:, Dendritic cells were treated with different concentrations (0.05% to 0.2%v/v) of alcohol for 24,72 hours and processed for SERT and MAO-A expression using Q-PCR and Western blots analysis. In addition, SERT function in DC treated with alcohol both in the presence and absence of imipramine, a SERT inhibitor was measured using 4-[4-(dimethylamino)styryl]-1-methylpyridinium iodide uptake assay. 5-HT levels in culture supernatant and intracellular 5-hydroxy indole acetic acid (5-HIAA) and cyclic AMP were also quantitated using ELISA. Results:, Dendritic cells treated with 0.1% alcohol for 24 hours showed significant upregulation of SERT and MAO-A expression compared with untreated DC. We also observed that 0.1% alcohol enhanced the function of SERT and decreased extracellular 5-HT levels compared with untreated DC cultures, and this was associated with the elevation of intracellular 5-HIAA and cyclic AMP levels. Conclusions:, Our study suggests that alcohol upregulates SERT and MAO-A by elevating cyclic AMP, which may lead to decreased concentration of 5-HT in the extracellular medium. As 5-HT is a major neurotransmitter and an inflammatory mediator, its alcohol-mediated depletion may cause both neurological and immunological deregulation. [source] Alcohol Stimulates Ciliary Motility of Isolated Airway Axonemes Through a Nitric Oxide, Cyclase, and Cyclic Nucleotide-Dependent Kinase MechanismALCOHOLISM, Issue 4 2009Joseph H. Sisson Background:, Lung mucociliary clearance provides the first line of defense from lung infections and is impaired in individuals who consume heavy amounts of alcohol. Previous studies have demonstrated that this alcohol-induced ciliary dysfunction occurs through impairment of nitric oxide (NO) and cyclic nucleotide-dependent kinase-signaling pathways in lung airway ciliated epithelial cells. Recent studies have established that all key elements of this alcohol-driven signaling pathway co-localize to the apical surface of the ciliated cells with the basal bodies. These findings led us to hypothesize that alcohol activates the cilia stimulation pathway at the organelle level. To test this hypothesis we performed experiments exposing isolated demembranated cilia (isolated axonemes) to alcohol and studied the effect of alcohol-stimulated ciliary motility on the pathways involved with isolated axoneme activation. Methods:, Isolated demembranated cilia were prepared from bovine trachea and activated with adenosine triphosphate. Ciliary beat frequency, NO production, adenylyl and guanylyl cyclase activities, cAMP- and cGMP-dependent kinase activities were measured following exposure to biologically relevant concentrations of alcohol. Results:, Alcohol rapidly stimulated axoneme beating 40% above baseline at very low concentrations of alcohol (1 to 10 mM). This activation was specific to ethanol, required the synthesis of NO, the activation of soluble adenylyl cyclase (sAC), and the activation of both cAMP- and cGMP-dependent kinases (PKA and PKG), all of which were present in the isolated organelle preparation. Conclusions:, Alcohol rapidly and sequentially activates the eNOS,NO,GC,cGMP,PKG and sAC,cAMP, PKA dual signaling pathways in isolated airway axonemes. These findings indicate a direct effect of alcohol on airway cilia organelle function and fully recapitulate the alcohol-driven activation of cilia known to exist in vivo and in intact lung ciliated cells in vitro following brief moderate alcohol exposure. Furthermore, these findings indicate that airway cilia are exquisitely sensitive to the effects of alcohol and substantiate a key role for alcohol in the alterations of mucociliary clearance associated with even low levels of alcohol intake. We speculate that this same axoneme-based alcohol activation pathway is down regulated following long-term high alcohol exposure and that the isolated axoneme preparation provides an excellent model for studying the mechanism of alcohol-mediated cilia dysfunction. [source] In Utero Ethanol Exposure Impairs Defenses Against Experimental Group B Streptococcus in the Term Guinea Pig LungALCOHOLISM, Issue 2 2009Theresa W. Gauthier Background:, The effects of fetal alcohol exposure on the risks of neonatal lung injury and infection remain under investigation. The resident alveolar macrophage (AM) is the first line of immune defense against pulmonary infections. In utero ethanol (ETOH) exposure deranges the function of both premature and term guinea pig AM. We hypothesized that fetal ETOH exposure would increase the risk of pulmonary infection in vivo. Methods:, We developed a novel in vivo model of group B Streptococcus (GBS) pneumonia using our established guinea pig model of fetal ETOH exposure. Timed-pregnant guinea pigs were pair fed ±ETOH and some were supplemented with the glutathione (GSH) precursor S -adenosyl-methionine (SAM-e). Term pups were given GBS intratracheally while some were pretreated with inhaled GSH prior to the experimental GBS. Neonatal lung and whole blood were evaluated for GBS while isolated AM were evaluated using fluorescent microscopy for GBS phagocytosis. Results:, Ethanol-exposed pups demonstrated increased lung infection and sepsis while AM phagocytosis of GBS was deficient compared with control. When SAM-e was added to the maternal diet containing ETOH, neonatal lung and systemic infection from GBS was attenuated and AM phagocytosis was improved. Inhaled GSH therapy prior to GBS similarly protected the ETOH-exposed pup from lung and systemic infection. Conclusions:, In utero ETOH exposure impaired the neonatal lung's defense against experimental GBS, while maintaining GSH availability protected the ETOH-exposed lung. This study suggested that fetal alcohol exposure deranges the neonatal lung's defense against bacterial infection, and support further investigations into the potential therapeutic role for exogenous GSH to augment neonatal AM function. [source] Reduction of Perforin, Granzyme B, and Cytokine Interferon , by Ethanol in Male Fischer 344 RatsALCOHOLISM, Issue 4 2003Madhavi Dokur Background: Chronic alcohol consumption can impair the immune system and predispose individuals to an increased risk of cancer and infection. Natural killer (NK) cells are the first line of defense against viral, bacterial, and fungal infections and play an important role in cellular resistance to malignancy and tumor metastasis. We have shown previously that ethanol administration suppresses NK cell cytolytic activity in male Fischer rats. This study analyzed the effects of ethanol on perforin, granzyme B, and the cytokine interferon (IFN)-,, factors that modulate NK cell cytolytic activity, to understand the molecular mechanism involved in ethanol's suppression of NK cell activity. Methods: A group of male Fischer rats was fed an ethanol-containing diet (8.7% v/v), whereas a control group was pair-fed an isocaloric diet. At the end of 2 weeks, animals were decapitated, and spleen tissues were immediately removed and used for analysis of NK cell cytolytic activity, perforin, granzyme B, and IFN-, messenger RNA (mRNA) or protein levels. The mRNA levels of perforin, granzyme B, and IFN-, were evaluated by quantitative real-time polymerase chain reaction, and protein levels of these factors were analyzed by Western blot, enzyme-linked immunosorbent assay, or enzymatic activity assay. Results: Ethanol reduced the NK cell cytolytic activity and decreased the mRNA expression of perforin, granzyme B, and IFN-, in ethanol-fed animals when compared with pair-fed animals. Ethanol also significantly reduced the protein levels of perforin and IFN-, and the enzyme activity of granzyme B in alcohol-fed animals as compared with pair-fed animals. Conclusions: These data suggest that chronic ethanol consumption may suppress NK cell cytolytic activity in male Fischer rats by decreasing the production, activity, or both of granzyme B, perforin, and IFN-,. [source] European Federation of Neurological Societies/Peripheral Nerve Society Guideline, on management of multifocal motor neuropathy.JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM, Issue 1 2006Report of a joint task force of the European Federation of Neurological Societies, the Peripheral Nerve Society Abstract Background: Several diagnostic criteria for multifocal motor neuropathy (MMN) have been proposed in recent years, and a beneficial effect of intravenous immunoglobulin (IVIg) and various other immunomodulatory drugs has been suggested in several trials and uncontrolled studies. Objectives: The aim of this guideline was to prepare consensus guidelines on the definition, investigation, and treatment of MMN. Methods: Disease experts and a representative of patients considered references retrieved from MEDLINE and the Cochrane Library in July 2004 and prepared statements that were agreed in an iterative fashion. Recommendations: The Task Force agreed on good practice points to define clinical and electrophysiological diagnostic criteria for MMN and investigations to be considered. The principal recommendations and good practice points were as follows: (1) IVIg (2 g/kg given over 2,5 days) should be considered as the first line of treatment (level A recommendation) when disability is sufficiently severe to warrant treatment; (2) corticosteroids are not recommended (good practice point); (3) if initial treatment with IVIg is effective, repeated IVIg treatment should be considered (level C recommendation). The frequency of IVIg maintenance therapy should be guided by the individual response (good practice point). Typical treatment regimens are 1 g/kg every 2,4 weeks or 2 g/kg every 4,8 weeks (good practice point); (4) if IVIg is not (or not sufficiently) effective, then immunosuppressive treatment may be considered. Cyclophosphamide, cyclosporine, azathioprine, interferon-,1a, or rituximab are possible agents (good practice point); and (5) toxicity makes cyclophosphamide a less desirable option (good practice point). [source] Surgery for biliary atresiaLIVER INTERNATIONAL, Issue 3 2001Ryoji Ohi Abstract: Although the prognosis of biliary atresia has been improved in recent years, particularly in the era of liver transplantation, hepatic portoenterostomy, e.g., the Kasai operation, is still the first line of surgical treatment. Successful hepatic portoenterostomy depends on early diagnosis and operation, adequate operative technique, prevention of postoperative cholangitis, and precise postoperative management. The pathophysiology of the liver and of the intrahepatic bile ducts in this disease is still controversial. [source] Segmental Pulmonary Vein Ablation: Success Rates with and without Exclusion of Areas Adjacent to the EsophagusPACING AND CLINICAL ELECTROPHYSIOLOGY, Issue 6 2008KLAUS KETTERING M.D. Background: Catheter ablation has become the first line of therapy in patients with symptomatic recurrent, drug-refractory atrial fibrillation (AF). The occurrence of an atrioesophageal fistula is a rare but serious complication after AF-ablation procedures. This risk is even present during segmental pulmonary vein (PV) ablation procedures because the esophagus does frequently have a very close anatomical relationship to the right or left PV ostia. The aim of the present study was to analyze whether the exclusion of areas adjacent to the esophagus does have a significant effect on the success rates after segmental pulmonary vein ablation procedures. Methods: Forty-three consecutive patients with symptomatic paroxysmal AF were enrolled in this study. In all patients, a segmental PV ablation procedure was performed. The procedures were facilitated by a 3D real-time visualization of the circumferential mapping catheter placed in the pulmonary veins using the NavXÔ system (St. Jude Medical, St. Paul, MN, USA; open irrigated tip ablation catheter; 43°C; 30 W). In 21 patients, a complete ostial PV isolation was attempted regardless of the anatomical relationship between the ablation sites and the esophagus (group A). In the remaining 22 patients, the esophagus was marked by a stomach tube and areas adjacent to the esophagus were excluded from the ablation procedure (group B). After discharge, patients were scheduled for repeated visits at the arrhythmia clinic at 1, 3, and 6 months after the ablation procedure. Results: The segmental pulmonary vein ablation procedure could be performed as planned in all patients. In group A, all pulmonary veins could be isolated successfully in 14 out of 21 patients (67%). A mean number of 3.7 pulmonary veins (SD ± 0.5 PVs) were isolated per patient. The main reasons for an incomplete PV isolation were: small diameter of the PVs, side branches close to the ostium, or poorly accessible PV ostia. In group B, all PVs could be isolated successfully in only 12 out of 22 patients (55%; P = 0.54). A mean number of 3.2 PVs (SD ± 0.9 PVs) were isolated per patient (P = 0.05). This was mostly due to a close anatomical relationship to the esophagus. The ablation strategy had to be modified in 16/22 patients in group B because of a close anatomical relationship between the left (n = 10) or right (n = 6) PV ostia and the esophagus. After 3 months, the percentage of patients free from an AF recurrence was not significantly different between the two groups (90% vs 95%; P = 0.61). After 6 months, there was no significant difference between the success rates either (81% vs 82%; P = 1.0). There were no major complications in both groups. Conclusions: The exclusion of areas adjacent to the esophagus results in a moderately higher percentage of incompletely isolated PVs. However, it does not have a significant effect on the AF recurrence rate during short-term and mid-term follow-up. [source] an algorithmic approach. (Jefferson Headache Center, Thomas Jefferson University, Philadelphia, PA) Neurology 2000;55:S46,S52.PAIN PRACTICE, Issue 2 2001Stephen D. Silberstein This article provided practical suggestions for treating migraine pain. It covered an overall wellness program including exercise, rest, good nutrition, and avoidance of headache triggers. The authors pointed out that simple analgesics or nonsteroidal anti-inflammatory drugs are often the first line of attack with combinations of analgesics and ergotamine preparations representing the second-line of attack for patients with infrequent attacks. For patients unlikely to respond to simpler treatments, other options were provided. Patients suggested for preventive therapy were those with 3 or more days of headache-related disability per month or with headache refractory to acute treatment. [source] Recognition profiles of microsporidian Encephalitozoon cuniculi polar tube protein 1 with human immunoglobulin M antibodiesPARASITE IMMUNOLOGY, Issue 1 2008K. FURUYA SUMMARY Microsporidian Encephalitozoon cuniculi has a unique organelle called a polar tube (PT), the extrusion of which is absolutely required to invade a host cell. We recently detected anti- E. cuniculi PT immunoglobulin (Ig) M antibodies in sera from many healthy individuals. The present one-dimensional (1-D) immunoblot analysis predominantly detected a band at 52 kDa in all of the examined human sera with anti-PT IgM. The use of mouse monoclonal antibody confirmed that the 52-kDa band detected in 1-D immunoblots was an antigen derived from the PT, which represents a glycoprotein nature. In addition, from changes in the immunoreactivity of the 52-kDa band before and after treatment with NaOH, we determined that the 24 human serum samples with anti-PT IgM activities could be roughly grouped into three types: (i) sera containing antibodies against only a saccharic determinant (n = 3); (ii) sera containing antibodies against only a proteinic determinant (n = 11); and (iii) sera showing dual recognition of saccharic and proteinic determinants (n = 10). Further two-dimensional (2-D) immunoblot analysis followed by proteomic analysis confirmed that human sera with anti-PT IgM reacted with E. cuniculi polar tube protein 1 (PTP1). Such circulating IgM antibodies may be important in the first line of defence against E. cuniculi infection. [source] Local early induced resistance of plants as the first line of defence against bacteria,PEST MANAGEMENT SCIENCE (FORMERLY: PESTICIDE SCIENCE), Issue 4 2003Zoltán Klement Abstract This paper is an overview of a non-specific local early induced resistance (EIR) mechanism, distinct from the incompatible-specific hypersensitive reaction (HR). We have shown that the local induced resistance (LIR) described earlier is not a single and uniform response to pathogen infection, because an early (EIR) and a late form can be distinguished. EIR operates from 3,6,h post-inoculation (hpi) until about 20,hpi, and is inhibited by a short heat-shock or the eukaryotic protein synthesis inhibitor, cycloheximide. In contrast, LIR, which corresponds to the induced resistance forms discovered earlier, requires more time (about 24,h) and intensive illumination to develop, and is effective for a longer period. EIR develops parallel with HR and is sometimes able to prevent it when the induction time of HR is longer than the time required for the development of EIR. It seems that EIR inhibits the metabolism of bacteria and the activity of hrp genes which otherwise are required for the induction of HR. In a compatible host,pathogen relationship the effect of EIR fails to take place. The rapid development of EIR is greatly influenced by temperature and the physiological state of the plant. EIR activates the accumulation of hydrogen peroxide at the bacterial attachment, expressing new peroxidase isoenzymes in the initiated plant tissue. It seems that this is a native general local defence mechanism which can localise foreign organisms even at the penetration site. © 2003 Society of Chemical Industry [source] The phytochemical profile and identification of main phenolic compounds from the leaf exudate of Aloe secundiflora by high-performance liquid chromatography,mass spectroscopyPHYTOCHEMICAL ANALYSIS, Issue 2 2003Waihenya Rebecca Abstract The phytochemical profile of Aloe secundiflora (Aloeaceae) and the identity of eight major compounds, including the two main constituents, have been determined from the leaf exudate of this ethnoveterinary used species from Kenya and Tanzania. Analytical HPLC-MS studies of the exudate have revealed that it comprises a mixture of phenolic compounds, mainly anthrones (aloenin, aloenin B, isobarbaloin, barbaloin and other aloin derivatives), chromones and phenylpyrones with a low content of polysaccharides and aliphatic compounds. The high percentage of anthrones in the exudate could provide a first line of evidence for the use of the plant in ethnoveterinary practices. Copyright © 2003 John Wiley & Sons, Ltd. [source] Ascorbic acid, a familiar small molecule intertwined in the response of plants to ozone, pathogens, and the onset of senescencePLANT CELL & ENVIRONMENT, Issue 8 2004P. L. CONKLIN ABSTRACT Ascorbic acid is a well-known antioxidant and cellular reductant with an intimate and complex role in the response of plants to ozone. It is clear from a number of studies that sensitivity to ozone is correlated with total ascorbic acid levels, and that a first line of defence against the reactive oxygen species generated in the apoplastic space by ozone is ascorbic acid. For activity, ascorbic acid must be in the fully reduced state. Therefore, both the rate of ascorbic acid synthesis and recycling via dehydroascorbate and monodehydroascorbate reductases are critical in the maintenance of a high ascorbic acid redox state. Active transport of ascorbic acid across the plasma membrane is necessary to achieve reduction of oxidized ascorbic acid by cytoplasm-localized reductases. It has been known for some time that the chlorotic lesions produced by exposure to ozone are not unlike lesions produced by the hypersensitive response to avirulent pathogen attack. Surprisingly, activation of a defence gene-signalling network by both ozone and pathogens is influenced by the level of ascorbic acid. Indeed, in addition to acting simply as an antioxidant in the apoplastic space, ascorbic acid appears to be involved in a complex phytohormone-mediated signalling network that ties together ozone and pathogen responses and influences the onset of senescence. [source] | |||||||||||||||||||||||||||||||||||||