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http://www.webmedcentral.com/images/Header_Logo.giftext/html2010-09-07T15:03:53+01:00http://www.webmedcentral.com/Dr. Justin T DenholmComplementary Medicine And Heavy Metal Toxicity In Australia
http://www.webmedcentral.com/article_view/535
In recent years, heavy metal toxicity related to the use of traditional Chinese and Indian herbal medications has been reported in a number of countries, including Australia. Heavy metals such as lead or mercury may be introduced into herbal medications through contaminated soil or production techniques, or may be deliberately included as a therapeutic ingredient. Particularly when consumed over prolonged periods, heavy metals have been detected in some products at levels sufficient to cause significant toxicity. Currently, these medications may be imported for personal use without licence or testing, and there is continued risk that Australians may develop heavy metal toxicity through their use.This article will review heavy metal toxicity related to herbal preparations, and argue that the current regulatory framework could be strengthened through the use of targeted public educational campaigns and the provision of free heavy metal testing for imported medications.text/html2011-12-12T15:49:07+01:00http://www.webmedcentral.com/Prof. Jayendra R GohilSanguinarine, Hydroxybutyrate Dehydrogenase and Fatigue in Epidemic Dropsy: A Retrospective Study of an Outbreak and its Control from Gujarat, India
http://www.webmedcentral.com/article_view/2118
Objective: We report an outbreak of epidemic dropsy following ingestion of cooking groundnut-oil adulterated with Argemone oil.Methods: We describe 40 patients (18 families) from three towns in Gujarat in 1998, affected with epidemic dropsy during an outbreak and its control measures. They were successfully treated with supportive measures and antioxidants. The outbreak control measures used were- active and passive surveillance, media campaigns, and action against traders.Results: Oedema, erythema, cutaneous flush, fatigue, and tachycardia were present. ESR was high. Hydroxybutyrate dehydrogenase levels (165 U/l in 33 patients), reported for the first time, showed significant rise and persisted at 1-month (128 U/l) indicating long-term cardiac toxicity. We detected in serum and urine of 25 patients, sanguinarine (2.5 and 1.4 mg/dl respectively) which at 1-month had returned to trace levels, thus confirming the consumption of oil contaminated with Argemone oil. Fatigue persisted at one month in 80%, and at six months in 38%. Groundnut oil contamination with Argemone mexicana oil was detected.Conclusion: Groundnut oil (used in cooking) contaminated with Argemone mexicana oil was the cause of epidemic dropsy. The health department controlled the outbreak with surveillance, stopping the mixing of argemone oil, and action against culprits. There were no deaths.text/html2010-08-24T20:25:08+01:00http://www.webmedcentral.com/Dr. William J MaloneyThe Death Of Cleopatra, A Medical Analysis Of The Theory Of Suicide By Naja Haje
http://www.webmedcentral.com/article_view/502
Cleopatra had been the source of mystery and intrigue throughout her life. It is imperative to remember that Cleopatra was a real human being while studying her life and, most ironically, her death. Her mythical status has been embellished throughout the past two thousand years by the numerous writers, historians, artists, and actors who have studied her life. These individuals have created a certain image of Cleopatra in the public?s consciousness which differs greatly from the once flesh-and-blood Queen of Egypt. It is of particular importance in examining her death to avoid the snares set by some of the most masterful authors (William Shakespeare), gifted artists (Guido Cagnacci) and talented actresses (Elizabeth Taylor). These are merely artistic renderings, albeit masterful ones, of what might have occurred at the scene of her death. One must remember that there are no eyewitnesses to the death of Cleopatra and her two handmaidens. There are many aspects of Cleopatra?s death which are unknown. Therefore, individuals ranging from historians of Cleopatra?s time to artists and actors of modern times have speculated as to what they think might have occurred. In analyzing the details surrounding Cleopatra?s death, one must not confuse the known facts from pure speculation or legend. The most widely accepted theory of Cleopatra?s death is that she committed suicide by an asp- specifically, the Egyptian Cobra. This theory has been promulgated throughout the past two millenia. This paper will analyze the feasibilty of such a theory by relying on the known facts- both historical and medical. I will attempt to conclude whether the legend of Cleopatra?s death by an asp has any medical and scientific plausibilty or if it is merely the product of many creative imaginations throughout the years.text/html2011-12-13T15:34:33+01:00http://www.webmedcentral.com/Ms. Marziye AmizadehEffects of Endosulfan on Human Health
http://www.webmedcentral.com/article_view/2617
Endosulfan is an organochlorine insecticide and acaracide used to control a broad range of insect and arthropod pests on a wide variety of crops in many agrosystems. Endosulfan is readily absorbed by humans via the stomach, lungs and through the skin. It can cause acute and chronic toxicity. Laboratory assays suggested more susceptibility of female than males to the lethal effects of endosulfan. Central nervous system is the main target in endosulfan toxicity. Endosulfan is a neurotoxin, haematoxin, genotoxin and nephrotoxin. Laboratory studies have also shown that there are potential carcinogenic effects. Toxicity of this insecticide on reproductive organs was confirmed. Endosulfan has been linked to congenital physical disorders, mental disabilities and deaths in farm workers and communities across the globe. Symptoms of poisoning include headaches, dizziness, nausea, vomiting, mental confusion, convulsions, hyperactivity, seizures, coma and respiratory depression, in severe cases resulting in death.text/html2016-11-26T09:58:14+01:00http://www.webmedcentral.com/Dr. Robert A Lodder4-Week Toxicity and Toxicokinetic Oral Gavage Study with Polydatin in Rats
http://www.webmedcentral.com/article_view/5231
Objective: This study determined the toxicity and toxicokinetics of polydatin when administered via oral gavage to Sprague Dawley rats daily for 4 weeks.
Background: Polydatin continues to be investigated as a potential therapy for a variety of human diseases.
Methods: Male and female Crl:CD(SD) rats were assigned to five groups, and different doses (0, 300, 600, 1200, or 3000 mg/kg/day) of polydatin were administered via oral gavage once daily for 29 days at a dose volume of 10 mL/kg. Assessment of toxicity was based on mortality, clinical observations, food consumption, body weights, ophthalmic examinations, and clinical and anatomic pathology. Blood samples were collected for toxicokinetic evaluations.
Results: All animals survived to the end of the study. Animals given polydatin at ?600 mg/kg/day exhibited lower mean body weight (?10% compared with control) and less gain in mean body weight, which correlated with decreased food consumption, compared to control rats. Several minor clinical chemistry findings were observed at ?600 mg/kg/day, but they were all of small magnitude, and were not considered adverse or toxicologically important. Polydatin related macroscopic findings included one animal with an enlarged cecum in the 1200 mg/kg/day group and 6 of 20 animals with enlarged cecums or colons in the 3000 mg/kg/day group. These findings were considered test article-related, although no microscopic correlate was present. In males given 1200 or 3000 mg/kg/day and females given 3000 mg/kg/day microscopic findings in the kidneys included tubular dilatation, hyaline droplets in the tubule cells (males only), erosion/ulceration of the transitional epithelium, acute pelvic inflammation (males only), and chronic active pelvic inflammation with hyperplasia of the transitional epithelium (females only). No marked sex differences were observed in polydatin Cmax and AUC0-24 values. No accumulation of polydatin was observed after multiple dosing.
Conclusion: The only adverse test article-related finding noted in one female given 3000 mg/kg/day was chronic active pelvic inflammation and transitional cell hyperplasia. Based on these results, the no observed adverse effect level (NOAEL) is 1200 mg/kg/day for females and 3000 mg/kg/day for males.text/html2010-10-13T10:03:17+01:00http://www.webmedcentral.com/Dr. William J MaloneyA Medical And Scientific Analysis Of Murder By Hydrogen Cyanide (prussic Acid)- Lizzie Borden\'s Preferred Method
http://www.webmedcentral.com/article_view/992
The 1892 murder of Andrew and Abby Borden has been immortalized through the generation in rhyme and verse. The savage murders have become part of the fabric of American folklore. Would-be mystery sleuths have expounded numerous theories as to who actually carried out the murders. Most theories have pointed To Andrew’s daughter, Lizzie, as being the primary subject. While others have pointed the guilty finger towards other less likely individuals. The key to the mystery can be found in the contents of a bottle which remained undisturbed on the shelf of a Fall River, MA pharmacy. Lizzie Borden had attempted to purchase prussic acid-hydrogen cyanide- the day before the murders. She was unsuccessful in this attempt and was thus driven to seek out a more reliable mode of murder.text/html2011-02-22T20:51:52+01:00http://www.webmedcentral.com/Dr. Ozgur I CanImportance Of Sampling Sites For Postmortem Evaluation Of Ethanol
http://www.webmedcentral.com/article_view/1584
Detection of ethyl alcohol and its origin in postmortem specimens is essential in terms of medico-legal aspects. It is a complicated process to determine whether alcohol has been taken in the ante-mortem period and/or originates from postmortem endogenous production.In this study, considering sampling sites and storage conditions, we aimed to develop an approach for postmortem ethyl alcohol investigations. Samples were collected from 32 cases. Blood specimens drained from the femoral vein and the vena cava inferior were put into well covered PET tubes with anti-coagulants and urine samples were put into well covered PET tubes without anti-coagulants and preserved at + 4ºC, analyzed with enzymatic immunoassay within five days of specimen collection.Scene investigations, sampling and sampling sites, specimen handling, preserving specimens and preparations before analyses are highly important for an accurate and scientific evaluation of postmortem ethyl alcohol. There were significant differences in ethyl alcohol concentrations between blood from the femoral vein and vena cava inferior and urine. Femoral vein and urine specimens seemed to be more reliable than vena cava inferior specimens.text/html2011-03-07T18:18:59+01:00http://www.webmedcentral.com/Mr. Sohel M HarsoliyaToxicity of Lps and Opa Exposure on Blood with Different Methods
http://www.webmedcentral.com/article_view/1696
BLOODBlood is considered a specialized form of connective tissue, given its origin in the bones and the presence of potential molecular fibers in the form of fibrinogen. Blood is a tissue composed of formed elements suspended in a liquid portion called plasma. Red blood cells (erythrocytes), white blood cells (leucocytes), and platelets are the three types of formed elements. Wright's stain a combination of methylene blue and eosin is commonly used to stain blood cells. Red blood cells, which contain no nucleus, are far more numerous than white blood cells, which have a nucleus (4.5 million / mm3 compared to 9 000 / mm3).It is composed of a liquid called blood plasma and blood cells suspended within the plasma. The blood cells present in blood are red blood cells (also called RBCs or erythrocytes), white blood cells (including both leukocytes and lymphocytes) and platelets (also called thrombocytes). Plasma is predominantly water containing dissolved proteins, salts and many other substances; and makes up about 55% of blood by volume. Mammals have red blood, which is bright red when oxygenated, due to hemoglobin. The most abundant cells in blood are red blood cells. These contain hemoglobin, an iron-containing protein, which facilitates transportation of oxygen by reversibly binding to this respiratory gas and greatly increasing its solubility in blood. White blood cells help to resist infections and parasites, and platelets are important in the clotting of blood. In mammals, mature red blood cells lack a nucleus and organelles. The red blood cells (together with endothelial vessel cells and other cells) are also marked by glycoproteins that define the different blood types. The proportion of blood occupied by red blood. White blood cells are part of the immune system; they destroy and remove old or aberrant cells and cellular debris, as well as attack infectious agents (pathogens) and foreign substances. Platelets are responsible for blood clotting (coagulation).There are certain membrane receptors for bacterial toxins in blood cells which act as binding sites .In plasma membrane of eukaryotic cells these are found to be Gangliosides which are sialic acid containing glycosphingolipids.Specific gangliosides have been found to bind IL-2,while others are implicated as macrophge receptors of interferon.LPS can activate macrophages and cause diverse pathophysiologic effects. Studies have shown the ability of gangliosides to alter LPS induced macrophage function,including Glucose metabolism and Fc mediated phagocytosis.(Charles S. Berenson, Herbert C. Yohe, and John L. Ryan).A red blood cell (rbc)b white blood cell (lymphocyte)c white blood cell (neutrophil)d white blood cell (eosinophil)e plasma (matrix)LPS recognition by mammalian cells occurs through a multiprotein interaction. First, a plasma protein, LPS-binding protein (LBP), binds LPS and transfers LPS monomers to CD14. CD14 is a high-affinity receptor for LPS present both as a soluble form in blood or as a glycophosphoinositol (GPI)-anchored protein on the surfaces of myeloid lineage cells. LPS signaling in cells can only occur if the transmembrane molecule TLR4 is activated. TLR4 belongs to the family of Toll-like receptors that are type 1 transmembrane proteins characterized by an extracellular domain containing multiple leucine-rich repeats, a single transmembrane domain, and an intracellular Toll/interleukin-1 (IL-1) receptor (TIR) domain. Stimulation of TLR4 by LPS activates a signaling cascade that is characterized by the production of proinflammatory cytokines and subsequent immune response. The importance of TLR4 in LPS-induced signaling is emphasized by the fact that TLR4def mice (C57BL/10ScCr), TLR4 knockout mice, and mice with a single point mutation in the TLR4 gene (C3H/HeJ) are resistant to the immunostimulatory and pathophysiologic effects of LPS (Kubes et.al, 2005). TLR4 is present in many different cell types, including dendritic cells, neutrophils, macrophages. It has also been demonstrated that ganglioside composition of LPS responsive C3H/HeN murine peritoneal macrophages is profoundly altered (Andonegui et.al, 2005).
LEUCOCYTE:Leucocytes are also known as the White blood cells in the body. Human leukocytes, when incubated with bacterial endotoxins (lipopolysaccharides, LPS) are stimulated to generate a procoagulant-tissue factor activity (TFa) (Niemetz and Morrison, 1977).This activity is associated with the lipid A region of the LPS molecule. LPS by treatment with mild alkali abrogated its capacity to stimulate TFa generation. In addition, such altered preparations of LPS partially inhibit the stimulatory effect of native LPS. Similarly, treatment of LPS (or lipid A) with the antibiotic polymyxin B substantially inhibited the stimulatory effect of LPS.They are produced and derived from a multipotent cell in the bone marrow, called hematopoietic stem cell. They are called white blood cells because when whole blood is centrifuged, these cells separate into a thin layer that is typically white in color.There are two types of leucocytes according to the presence of differently staining granules in their cytoplasm. The granulocytes (also known as polymorphonuclear leucocytes) are leucocytes with very distinctive cytoplasmic granules, e.g. neutrophils, basophils and esoniphils. The second is agranulocytes (mononuclear leucocytes), which are characterized by the lack of apparent granules, e.g. lymphocytes, monocytes and macrophages.LPS can interact with endothelial cells and it induces leucocytes sequestration to some tissues which is entirely dependent on both CD14 and TLR4 but there are also CD14-independent, TLR4-dependent endothelial cell responses. (Kubes et.al, 2005).LPS could activate peripheral blood leucocytes especially monocytes and express CD14 and CD16 and regarded as pro-inflammatory because upon stimulation produce TNF-α and also IL-10. CD14(high) CD16(+) monocytes exhibited an increased phagocytic activity and a decreased antigen presentation in comparison with CD14(dim), CD16(+). As expected, lipopolysaccharide (LPS)-stimulated CD14(dim) CD16(+) monocytes produced TNF-α but little IL-10. By contrast, LPS-stimulated CD14(high) CD16(+) subpopulation produced significantly more IL-10 than CD14(dim) CD16(+) and CD14(high) CD16(-) MO. Studies suggested that human peripheral blood CD16(+) monocytes are heterogeneous in function and consist of two subpopulations: CD14(dim) CD16(+) pro-inflammatory and CD14(high) CD16(+) with anti-inflammatory potential. In Gram-negative infections, lipopolysaccharide , can initiate a cascade of inflammatory mediators that could lead to systemic inflammation. Neutrophils play a key role in tissue injury during systemic inflammation . Recently, Toll like receptor-4 (TLR4) was found to mediate the intracellular signaling after LPS binding to CD14. (Leeuwen et.al ,2005).In contrast, other serum factors and membrane receptors have been identified which bind LPS and neutralize its toxic activity. Lipoproteins, apolipoprotein A-1, apolipoprotein B, lactoferrin, bactericidal/permeability increasing protein (BPI), soluble CD14 (sCD14) and receptors on macrophages (scavenger receptors, CD11/CD18 receptors) have all been implicated in the clearance and detoxification of LPS. (Leeuwen et.al, 2005).High-density lipoprotein (HDL) plays an important role in protecting against atherosclerosis as well as in innate immunity. Several lines of evidence showed that HDL could ameliorate the toxic effects of endotoxin or lipopolysaccharide (LPS). HDL could inhibit LPS-induced leukocyte adhesion on endothelial cells in rats. .The release of two mediators, Leukocyte Inhibiting Factor (LIF) and Tissue Factor (TF) from human mononuclear cells are described. These factors may play either beneficial effects (LIF) or noxious activities (TF liberation in certain pathological conditions). This LPS effect can be performed directly or via a lymphokine release, Platelet Slowing Factor (PSF). Interaction between LPS and platelets has also been suggested.Leukocyte adhesion is triggered by upregulation of cell surface adhesion molecules and counteracted by the shear forces of the flowing blood. Since both factors, inflammatory response and flow dynamics are severely altered during endotoxemia, the effects of endotoxin on leukocyte–endothelial interactions under different levels of shear stress in vitro.MACROPHAGESMacrophages (In Greek means: "big eaters",( makros "large" + phagein "eat") are cells within the tissues that originate from specific white blood cells called monocytes. Monocytes and macrophages are phagocytes, acting in both non-specific defense (or innate immunity) as well as specific defence (or cell-mediated immunity) of vertebrate animals. Their role is to phagocytose (engulf and then digest) cellular debris and pathogens either as stationary or mobile cells, and to stimulate lymphocytes and other immune cells to respond to the pathogen. When a monocyte enters damaged tissue through the endothelium of a blood vessel (a process known as the leukocyte adhesion cascade), it undergoes a series of changes to become a macrophage. Monocytes are attracted to a damaged site by chemical substances through chemotaxis, triggered by a range of stimuli including damaged cells, pathogens, histamine released by mast cells and basophils, and cytokines released by macrophages already at the site. One important main role of macrophage is the removal of necrotic debris and dust in the lungs and is done by. fixed macrophages, which will stay at strategic locations such as the lungs, liver, neural tissue, bone, spleen and connective tissue, where microbial invasion is likely to occur, ingesting foreign materials such as dust and pathogens, calling upon wandering macrophages if needed. They rid the body of worn-out cells and other debris and act as scavengers and act as secretory cells. The phenomenon of LPS - induced in vitro macrophage cytotoxicity has been reported by a number of investigators but has often been difficult to reproduce and to quantitate. It has been examined the effect of LPS on the ability of macrophages to ingest 51Cr-labeled, opsonized sheep erythrocytes as a method for examining the direct toxic effects of LPS on macrophages in vitro The assay was more sensitive than LPS-induced cytotoxicity, since inhibition of phagocytosis was detectable in cultures of LPS-sensitive macrophages even when cytotoxicity, assessed by trypan blue exclusion, was not. Thus, this assay represents an extremely sensitive method for analyzing the direct effects of LPS on macrophages.Macrophages play a dual role in host defence. They act as the first line of defence by mounting an inflammatory response to antigen exposure and also act as antigen presenting cells and initiate the adaptive immune response. They are also the primary infiltrating cells at the site of inflammation. Inhibition of macrophage activation is one of the possible approaches towards modulating inflammation. Both conventional and alternative approaches are being studied in this regard. Ginger, an herbal product with broad anti inflammatory actions, is used as an alternative medicine in a number of inflammatory conditions like rheumatic disorders. The effect of ginger extract on macrophage activation in the presence of LPS stimulation is studied.Lipopolysaccharide (LPS) stimulates immune responses by interacting with the membrane receptor CD14 to induce the generation of cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1, and IL-6. The mechanism by which the LPS signal is transduced from the extra cellular environment to the nuclear compartment is not well defined. Recently, an increasing amount of evidence suggests that protein tyrosine kinases especially the Src-family kinases Hck, Fgr, and Lyn, play important roles in LPS signaling.DNA DAMAGECell death can occur by either of two distinct mechanisms, necrosis or programmed cell death (apoptosis). Necrosis is a pathological process which occurs when cells are exposed to a serious physical or chemical insult. Apoptosis is a physiological and controlled process by which unwanted or useless cells are eliminated during development and other normal biological processes. Apoptosis can be detected in populations of cells or in individual cells.Apoptosis (Ptosis tosis dropping off, Greek) or “programmed cell death” in the tissues of an organism is not associated with inflammation or scarring, unlike necrosis (meaning dead, Greek). Apoptosis is a normal event that occurs both during and after development. It is an important and inevitable event in the remodeling of tissues during development and aging .This phenomenon occurs in cells injured by certain levels of toxic agents. It is also a crucial process for eliminating cancer cells. In apoptosis series of biochemical events like nuclear fragmentation, chromatin condensation and chromosomal DNA fragmentation takes place leading to alteration of cell morphology. The nuclear envelope becomes discontinuous and the DNA inside it is fragmented.In a process referred to as karyorrhexis the nucleus breaks into several discrete chromatin bodies or nucleosomal units due to the degradation of DNA.
The importance of studying apoptosis in aging and age-related disorders has been recognized by many scientists. Apoptosis may be a feature of neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and amyotropic lateral sclerosis. In most postreplicating cells the rate of apoptosis increases with age and thus may be a factor in many age-related diseases including that of the heart and kidney . Apoptosis is also thought to be responsible for the depletion of subsets of T lymphocytes , which are crucial in fighting against infections.Commonly used techniques for the estimation of apoptosisare as follows. Agarose gel electrophoresis is used to demonstrate the ladder pattern of DNA (a hallmark of apoptosis) which is generated by endonucleolytic cleavage of genomic DNA into nucleosomal size DNA of approximately 180 bases long (monomers) or oligonucleotides, which are multiples of 180 bases(oligomers). The technique usually involves a DNA isolation procedure from millions of cells and obtained results cannot be quantified. Caspase-3 quantification is used for the estimation of apoptosis in cell lysates. Both of these assays require large numbers of apoptotic cells and thus are relatively insensitive for the detection of low levels of apoptotic events.Many different methods have been devised to detect apoptosis such as The TUNEL (TdT-mediated dUTP Nick-End Labeling) analysis, ISEL (in situ end labeling), and DNA laddering analysis for the detection of fragmentation of DNA in populations of cells or in individual cells, Annexin-V analysis that measures alterations in plasma membranes, detection of apo. ptosis related proteins such p53 and Fas.Morphological estimation for apoptosis is based on cell characteristics such as chromatin condensation, formation of apoptotic bodies from one cell (each having a fragmented piece of nucleus surrounded by a viable cell membrane), shrinkage of cytoplasm, and blebbing of plasma membrane with an irregular outlineLPS can induce DNA damage by generating free radicals . among the reactive molecular species which might injure nucleic acids , superoxides and NO might be the most important ,molecular species : the former is generated by such enzymes like xanthin oxidase (XO) and NADPH oxidase , and the latter by NOS .Hydrogen peroxide ( H2O2) is also potent .biosynthesis of NO as well as superoxides generation are expressed in defense – oriented white blood cells such as macrophage and polymorphonuclear cells , endothelial cells and other tissue cell . these cells areActivated , or these enzymes are induced to produce free radical species most commonly in microbial infections . it has also been shown that activated macrophage-derived NO and its oxidative metabolite , peroxinitrile , play key roles in hepatocyte injury during inflammation , and cause subsequent DNA damage in surviving hepatocytes.The excessive production of reactive oxygen species ( ROS ) , associated with inflammation , leads to a condition of oxidative stress. Oxidative stress is a major contributing factor to the high mortality rates associated with several diseases such as endo toxic shock . this condition can be controlled to a certain degree by antioxidant therapies . immune cells use ROS in order to support their functions and therefore need adequate levels of antioxidant defenses in order to avoid the harmful effect of an excessive production of ROS . the review discusses the toxic effects of endotoxin , paying attention to immune function.Oxidative stress in cells is produced by oxygen derived species resulting from cellular metabolism and from interaction with cells of exogenous sources such as carcinogenic compounds , ionizing radiations ,and redox-cyling drugs .LPS can induce DNA damage by generating free radicals. Among the reactive molecular species which might injure nucleic acids, superoxide and NO might be the most important molecular species; the former is generated by such enzymes like xanthine oxidase (XO) and NADPH oxidase, and the latter by NOS. Hydrogen peroxide (H2O2) is also potent. Biosynthesis of NO as well as superoxide generation are expressed in defense-oriented white blood cells such as macrophage and polymorphonuclear cells, endothelial cells, and other tissue cells. These cells are activated, or these enzymes are induced to produce free radical species most commonly in microbial infections. It has also been shown that activated macrophage-derived NO and its oxidative metabolite, peroxynitrite, play key roles in hepatocyte injury during inflammation, and cause subsequent DNA damage in surviving hepatocytes. (Watanabe et.al, 2001).The excessive production of reactive oxygen species (ROS), associated with inflammation, leads to a condition of oxidative stress. Oxidative stress is a major contributing factor to the high mortality rates associated with several diseases such as endotoxic shock. This condition can be controlled to a certain degree by antioxidant therapies. Immune cells use ROS in order to support their functions and therefore need adequate levels of antioxidant defenses in order to avoid the harmful effect of an excessive production of ROS. This review discusses the toxic effects of endotoxin, paying particular attention to immune function. It continues by analyzing the mechanism to which specific cells of the immune system recognize endotoxin, and the resulting pathways leading to nuclear factor-κB activation and proinflammatory gene transcription. Focus was also given on the involvement of reactive oxygen and nitric oxide (NO) and the protective role of antioxidants. Therefore, DNA repair is regarded as one of the essential events in all life forms. There is an increasing awareness of the importance of oxidative DNA damage and its repair to human health. Thus, it becomes exceedingly important to understand, at the fundamental level, the mechanisms of oxidative DNA damage, and its processing by DNA repair enzymes as well as how unrepaired DNA lesions may lead to cytotoxicity, mutagenesis and eventually to diseases and aging. More detailed knowledge of mechanisms of DNA damage and repair might allow us to modulate DNA repair. This could lead to drug developments and clinical applications including the improvement of cancer therapy by inhibiting DNA repair in drug- or radiation-resistant tumors and/or the increase in the resistance of normal cells to DNA damage by over-expressing DNA repair genes. The role of oxidative DNA damage in chromosomal breakage in mammalian cells has been studied by focusing on genetic changes which modulate sensitivity to reactive oxygen species (ROS). These genetic changes may be inborn, as in cells from ataxia-telangiectasia (A-T) patients, or may be induced in normal cells by mutation at critical loci involved in prevention and/or repair of chromosomal damage by ROS.(Miral Dizdar). Lipopolysaccharide (LPS) causes direct pulmonary endothelial injury that can precipitate cell death. Collagen is found to be a survival factor against LPS-induced apoptosis in cultured sheep pulmonary artery endothelial cells (SPAEC) when these cells were grown in monolayer on plastic or collagen. The protective effect of collagen was not due to inactivation of LPS. It was concluded that LPS-induced apoptosis occurs in SPAEC after genotoxic damage and this process is suppressed by the extra cellular matrix.Lipopolysacchride:Lipopolysaccharide (LPS) is an endotoxin which induces a strong response from normal animal immune systems. LPS is a highly immunogenic molecule which stimulates the production of endogenous pyrogen interleukin-1 and tumor necrosis factor. Lipopolysaccharide (LPS) is a toxic component of cell walls in gram-negative bacteria and is widely present in the digestive tracts of humans and animals (Jacob et al., 1997 ). Humans are constantly exposed to low levels of LPS through infection. Gastrointestinal inflammatory diseases and excess alcohol intake are known to increase permeability of LPS from gastrointestinal tract into blood (Zhou et al., 2003 ). High levels of LPS have also been detected in women with bacterial vaginosis (Platz-Christensen et al., 1993 ). In human, Gram-negative bacterial infections are a recognized cause of fetal loss and preterm labor (Romero et al., 1988 ). Mimicking maternal infection by exposing the pregnant rodents to LPS at early gestational stages resulted in embryonic resorption and fetal death (Gendron et al., 1990 ; Ogando et al., 2003 ). Maternal LPS exposure at middle gestational stages caused fetal death and preterm delivery (Leazer et al., 2002 ). We and others found that maternal LPS exposure at late gestational stages led to fetal death, growth restriction, skeletal development retardation, and preterm labor and delivery (Buhimschi et al., 2003 ; Rivera et al., 1998 ; Xu et al., 2005 , 2006a , 2007 ).Relatively few studies have investigated LPS-induced teratogenicity. Several earlier studies found that maternal LPS exposure resulted in the development of malformed fetuses in rats (Ornoy and Altshuler, 1976 ) and golden hamsters (Collins et al., 1994 ; Lanning et al., 1983 ). Recent studies showed that subcutaneous injection of LPS led to fetal malformation including exencephaly and eye deformities (Carey et al., 2003 ; Chua et al., 2006 ). However, the exact mechanism of LPS-induced teratogenesis remains unclear.LPS function has been used for experimental research for several years due to its role in activating many transcription factors.LPS acts as the prototypical endotoxin, because it binds the CD14/TLR4/MD2 receptor complex. LPS is known to induce endotoxin shock via the production of inflammatory modulators such as Tumour necrosis factor (TNF-α) and NO. Besides being an endotoxin, LPS also possesses a powerful adjuvant activity. Previously, it has been shown that changes in the chemical composition of the lipid A domain of LPS modulate its biological activity. For example, monophosphoryl lipid A (MPL) has been shown to be a non-toxic immunostimulatory compound.
LPS induces dialation of blood vessels and this contributes to hypotension during septic shock via production of NO in the blood vessel wall which relaxes vascular smooth muscle cells (Deutz et.al, 2003).LPS stimulates the secretion of pro-inflammatory cytokines such as IL-1β. Proinflammatory cytokines such as interferon-γ, interleukin-1β, and other cytokines are modulators of the inflammatory reactions and facilitate induction of the inducible isoform of NO synthase (iNOS), thus they could mediate excessive production of NO Biosynthesis of NO as well as superoxide generation are expressed in defense-oriented white blood cells such as macrophage and polymorphonuclear cells, endothelial cells, and other tissue cells. These cells are activated by NOS induction, or these enzymes are induced to produce free radical species most commonly in microbial infections and especially when exposed to endotoxins like LPS. Besides NO it also induces the production of free radicals like hydroxyl, peroxynitrite radical. Peroxynitrite is much more reactive than NO or superoxide caused diverse chemical reactions in biological system including nitration of tyrosine residues of proteins], triggering of lipid peroxidation inactivation of aconitases inhibition of mitochondrial electron transport and oxidation of biological thiol compounds. Peroxynitrite also exerts a potent DNA cleaving activity. (Maeda and Akaike, 1998). These chemical reactions of peroxynitrite will lead to a profound biological consequence such as apoptosis, and even mutation of various cells. Once these reactive molecular species (or free radicals) are generated during the host's inflammatory responses against microbial pathogens or their products, they can induce damages to the host's DNA, and might become the cause of cancer. Agents able to neutralize the effects of LPS may be of clinical importance in therapeutics of septic shock and other inflammatory diseases.Fig. - 2 Activation of signalling pathway via LPSLipopolysaccharide (LPS)-binding protein accelerates the binding of LPS to CD14. CD14 is a 55-kD protein found as a glycosylphosphatidylinositol (GPI)-anchored protein on the surface of monocytes, macrophages, and polymorphonuclear leukocytes, and as a soluble protein in the blood. Both forms of CD14 participate in the serum-dependent responses of cells to bacterial lipopolysaccharide (LPS). While CD14 has been described as a receptor for complexes of LPS with LPS-binding protein (LBP), there has been no direct evidence showing whether a ternary complex of LPS, LBP, and CD14 is formed, or whether CD14 binds LPS directly. Alternatively, the LBP-LPS complex can be recogonized by a soluble version of CD14 binds LPS in the absence of LBP. Lipopolysaccharide (LPS)-binding protein (LBP) is a lipid transfer protein that catalyzes two distinct reactions: movement of bacterial LPS (endotoxin) from LPS micelles to soluble CD14 (sCD14) and movement of LPS from micelles to reconstituted high density lipoprotein (R-HDL) particles. Initially there is movement of LPS from LPS-sCD14 complexes to R-HDL particles. This action of LBP is catalytic, with one molecule of LBP enabling the movement of multiple LPS molecules into R-HDL. LBP-catalyzed movement of LPS from LPS-sCD14 complexes to R-HDL neutralizes the capacity of LPS to stimulate polymorphonuclear leukocytes. Findings show that LPS, complexes of LPS and rsCD14 formed in the absence of LBP or other serum proteins strongly stimulate integrin function on PMN and expression of E-selectin on endothelial cells, demonstrating that LBP is not necessary for CD14-dependent stimulation of cells. These results suggest that CD14 acts as a soluble and cell surface receptor for LPS, and that LBP may function primarily to accelerate the binding of LPS to CD14.It is likely that CD14 acts to present LPS to a distinct transmembrane receptor ie;TLR (Toll like receptor).(Wurfel et .al, 1994).OPA:OPA is 2-oxo-1-pyrrolidine acetamide and is a cyclic derivative of GABA. It is one of the racetams. OPA was first synthesized in 1964 by scientists at the Belgian pharmaceutical company UCB led by Dr Corneliu E. Giurgea. The drug was the first of the so-called nootropics ("smart drugs" or "cognitive enhancers"), that is, substances which purportedly enhance mental performance. OPA is a dietary supplement which is claimed to enhance cognition and memory, slow down brain aging, increase blood flow and oxygen to the brain, aid stroke recovery, and improve Alzheimer's, Down syndrome, dementia, and dyslexia etc. OPA appears to increase communication between the two hemispheres of the brain, and increases activity of the corpus callosum.It stimulates the central nervous system without any toxicity or addictive properties. It facilitates long-term potentiation (Molnar et al., 1994), increases neurotransmitter release from presynaptic terminals and increases the amount of neurotransmitter, particularly acetylcholine, in the brain, but does not act directly on choline transport or metabolism (Nishizaki et al, 1998). Although many direct and indirect effects of OPA have been reported, its mechanism of action remains unclear. OPA has been used successfully to treat alcoholism and alcohol withdrawal syndrome in animals and man. OPA has improved recovery from aphasia (speech impairment) after stroke, and restored various functions (use of limbs, speech, EEG, state of consciousness) in people suffering from acute and chronic cerebral ischemia (decreased brain blood flow). OPA has improved alertness, co-operation, socialization and IQ in elderly psychiatric patients suffering from ‘mild diffuse cerebral impairment. OPA is useful in the treatment of children with sickle cell disease. Studies indicate that cognition-enhancing properties of OPA are usually more pronounced in aged than in young animals. Chronic treatment of young and aged rats with OPA (300 mg/kg once daily) significantly increased membrane fluidity in some brain regions of the aged animals, but had no measurable effect on membrane fluidity in the young rats. The same treatment significantly improved active avoidance learning in the aged rats only. Nootropic drugs increase glucose uptake into anaesthetized brain and into Alzheimer’s diseased brain. It is hypothesized that the OPA sensitive cellular plasticity mechanisms may make a significant contribution to its nootropic action at the behavioral level. OPA improves mitochondrial dysfunction following oxidative stress. Studies on PC12 cells and dissociated brain cells of animals the effect of OPA on mitochondrial dysfunction following oxidative stress. OPA treatment at concentrations between 100 and 1000 mM improved mitochondrial membrane potential and ATP production of PC12 cells following oxidative stress induced by sodium nitroprusside and serum deprivation. OPA treatment (100-500 mg/kg once daily) of mice was also associated with improved mitochondrial function in dissociated brain cells. Significant improvement was mainly seen in aged animals and only less in young animals. Thus it has been proved that therapeutically relevant in vitro and in vivo concentrations of OPA are able to improve mitochondrial dysfunction associated with oxidative stress and/or aging. Mitochondrial stabilization and protection might be an important mechanism to explain many of OPA’s beneficial effects in elderly patients. OPA is an effective antimyoclonic agent useful for treatment of action myoclonus in Lance–Adams syndrome, progressive myoclonus epilepsy, Angelman syndrome, and Rett syndrome where VPA (valporate) was found to be ineffective. Chronic myoclonus is often associated with severe functional disability and is frequently intractable to currently used antiepileptic drugs.OPA at high doses s effective mainly in cases of myoclonus of cortical origin. Levetiracetam is a new antiepileptic agent, closely related to OPA and has a broad spectrum of activity including an antimyoclonic effect. It is well known that Nootropics may increase learning and memory in healthy individuals through a distinctive power to promote what has been termed hemispheric-super-connection. (S.J. Dimond et al , "Effects of nootropics" Psycopharmacol. 64, 1979 341-348).In present study we explore the sensitivity of DNA after LPS exposure at different concentrations. Effect of OPA was also investigated which could contribute in therapeutics of inflammatory diseases.COMET ASSAYSeveral man-made chemicals find their way into the environment and pose health risk to human population. These chemicals have been found to interact with the vital tissue macromolecules regulating the cellular functions leading to long lasting health disorders. Acute and chronic exposure to several of these environmental chemicals such as pesticide, metals, polycyclic aromatic hydrocarbons (PAHs), solvents etc. have been shown to produce marked toxicity at the target sites. Some of these chemicals affect the DNA, which is the carrier of inherited information and any gross change in its structure potentates serious biological changes. Hence there is a need to test the chemicals for their genotoxic potential before being released into the environment. The conventional methods for evaluating genetic damage include chromosomal aberration, micronucleus assay, sister chromatid exchanges. However these are time consuming, resource intensive and require proliferating cell population. Hence newer and more sensitive test systems have now been introduced for assessing the genotoxicity of chemicals.The single cell gel electrophoresis or comet assay is one such state-of-the-art technique for quantitating DNA damage and repair in vivo and in vitro in any eukaryotic cell and some prokaryotic cells. This technique is rapid, non-invasive, sensitive, visual and inexpensive as compared to the conventional techniques and is a powerful tool to study factors modifying mutagenicity and carcinogenicity. It has rapidly gained importance in the fields of genetic toxicology and human biomonitoring.WHAT COMET ASSAY MEASURES:Comet assay measures, double strand breaks (DSBs), single strand breaks (SSBs), alkali labile sites, oxidative DNA base damage, DNA-DNA/DNA-protein/DNA-Drug crosslinking and DNA repair.Comet assay, also known as single cell gel electrophoresis (SCGE) , is a microgel electrophoresis technique which detects DNA damage and repair at the level of individual cells.It is a quantative assay in which procedure is easy and the sensitivity is high The damage is represented by an increase of DNA fragments that have migrated out of the cell nucleus in the form of a characteristic streak similar to the tail of a comet. The DNA fragments are generated by DNA double strand breaks, single strand breaks and/or strand breaks induced by alkali-labile sites in the alkaline version of the assay. The length and fragment content of the tail is directly proportional to the amount of DNA damage .Comet assay can be conducted in exvivo , in vitro and in vivo test systems and is increasingly being used in genotoxic testing of industrial chemicals, agrochemicals and pharmaceuticals. Comet assay is rapid (results in days), simple to perform, requires small amounts of test substance (25-50 mg) and can be performed in almost any eukaryotic cells (different animal organs). Comet assay serves as an important tool in the early drug development compounds as a mechanistic and genotoxic predictorHISTORY:The comet assay and microgel electrophoresis (MGE) were first introduced by Ostling and Johanson in 1984. This was a neutral assay in which the lysis and electrophoresis were done under neutral conditions. Staining was done withfluorescent dyes like SYBR green , PI, PtBr . In present studies PI was used to stain DNA .The image obtained looked like a “comet” with a distinct head, comprising of intact DNA and a tail, consisting of damaged or broken pieces of DNA hence the name “Comet” Assay was given. The extent of DNA liberated from the head of the comet was the function of the dose of irradiation. However, in this procedure, only double strand breaks could be analyzed.The above neutral assay was modified by two groups, Singh and co-workers (1988) and Olive et al (1989). Singh et al used microgels, involving electrophoresis under highly alkaline conditions (ph>13). This enabled the DNA supercoils to get relaxed and unwind, which are then pulled out during application of electric-current which made possible the detection of single strand breaks in DNA and alkali labile sites expressed as frank single strand breaks in individual cells. This method was developed to measure low levels of strand breaks with high sensitivity.Olive and co-workers conducted the electrophoresis under neutral or mild alkaline (pH=12.3) to detect single stranded breaks. This method was optimized to detect a subpopulation of cells with varying sensitivity to drug or radiation. The technique of Singh et al was found to be one or two orders of magnitude more sensitive than the other techniques.Since then a number of advancements have greatly increased the flexibility and utility of this technique for detecting various forms of DNA damage (e.g., single- and double-strand breaks, oxidative DNA base damage, and DNA-DNA/DNA-protein/DNA-Drug crosslinking) and DNA repair in virtually any eukaryotic cell.APPLICATIONS:This assay has critically important applications in fields of toxicology ranging from aging and clinical investigations to genetic toxicology and molecular epidemiology.Major applications of the Comet assay are in the following areas:Genetic toxicology (DNA damage)In vivo & in vitro evaluation of genotoxic chemicalsDNA damage:SSB’s, DNA crosslinking, alkali labile sitesDNA repair:Strand break repairExcision repairEco-toxicology: the assay has been used to monitor soil and aquatic toxicologyNutritionBio-monitoring genotoxicityEnvironmental biomonitoringEvaluation of genotoxic pollutants from hazardous waste sitesHypoxia assessmentHuman epidemiologyFor assessing levels of DNA damage in occupationally, clinically and environmentally exposed individuals or in evaluating the differences in DNA repair competency among control and exposed individuals.(a) Sperm bank(b) Blood bank(c) Monitoring Radio- and chemo- therapy in cancer patientsThe assay can be performed on a variety of samples which can be obtained as a single cell population e.g. peripheral blood lymphocytes, nasal and buccal epithelium from clinically or occupationally exposed human population and for in vitro studies on cell lines e.g. CHO, V79, mouse lymphoma or cultured human lymphocytes and bone marrow cells. Both DNA damage and repair studies can be conducted. Also a variety of information related to genetic toxicology, human epidemiology, patients undergoing radio/chemo- therapy, ageing and nutrition can be obtained. The assay has been used for environmental biomonitoring and has utilized earthworms, fishes, mollusks exposed to polluted environments.ADVANTAGES:There are many advantages of the comet assay, some of which are:it is a non-invasive techniqueit requires counting of 50-100 cells per individual / treatment group, through a computerised image analysis software gives a robust statisticsthat virtually any eukaryotic cell population is amenable to analysisits sensitivity (1 break in 1010 daltons) for detecting DNA damage and repairresults obtained in a few hours compared to conventional cytogenetics techniques which take a few dayssingle strand breaks (SSB’s) and alkali labile lesions (capable of being transformed into SSB’s under alkaline conditions) in the DNA of individual cells can be assessedonly few microlitres of blood (5-10?l), nasal & buccal mucosal cells, epithelial cells, male germ cells, fine needle biopsy, etc. required human studies.text/html2011-11-18T16:51:29+01:00http://www.webmedcentral.com/Dr. Sayed M MarashiHydroxyethyl Starch, Golden Remedy in Acute Aluminum Phosphide Poisoning Treatment: A Case Report
http://www.webmedcentral.com/article_view/2491
High mortality rate in acute aluminum phosphide toxicity is now a threat in developing countries. After exposure to air or acidic medium of stomach, phosphine gas released. This toxin rapidly causes a multisystem toxicity.Severe hypotension, cardiac dysrhythmias,thirst, tachypnea, and severe metabolic acidosis are significant symptoms.Autopsy examinations, point to extravasation of fluid into the third space. Besides to its consequences as intravascular volume expanders, hydroxyethylstarch solution is a colloid volume expander and reduces the extra vascular leakage ofalbumin and fluids. As sever hypotension and cardiovascular collapse, are common causes of death in this context, hydroxyethyl starch can be resuscitative in this toxicity.text/html2011-12-19T15:33:13+01:00http://www.webmedcentral.com/Prof. Rachid RouabhiInfluence of Nickel on Growth, Movement Speed, Respiratory Metabolism, and Biochemical Parameters of Paramecium sp.
http://www.webmedcentral.com/article_view/2676
Living things require different concentrations of metals such as iron, Cu and Zn, whose consumption is crucial for the metabolism, large amounts of these metals induces a phenomenon called Metalo-toxicity.This study is intended to investigate thechronic toxicity of nickel on specie of freshwater ciliatesParamecium sp. After exposing standard culture to a soluble compound of nickel (NiCl2.6H2O) at three selected concentrations 15, 30 and 60 ppm in strictly controlled conditions of temperature, light and darkness.The results show an inhibitory effect of Ni on the growth and mobility of protozoa according the time.The determination of biochemical parameters level (protein and carbohydrates) shows an increase in these parameters compared with controls contrarily to the lipids level where there is a decrease compared to the control.It is noted that the concentration of 60 ppm of Ni increases the rate of these parameters unless the other two concentrations.Effect of nickel "Ni" on the respiratory metabolism showed inhibition of O2 consumption in concentrations 15 and 60 ppm in contrast to the 30 ppm concentration where there is a stimulation of respiration.text/html2012-01-26T19:17:32+01:00http://www.webmedcentral.com/Dr. Csaba VargaSolid-Phase Environmental Genotoxicity: In Vivo Veritas!
http://www.webmedcentral.com/article_view/2932
Specific genotoxicity of solid particles are discussed by using three different examples. Carcinogenic asbestos fibres have primary genotoxic effects as well, that can be studied in in vitro studies. Nevertheless, demonstration of their mesothelioma inducing effect is only possible in in vivo studies. Their carrier function seems to be essential for the biological activity. Carbon nanotubes do not show any genotoxic effects, but lack of their carcinogenicity is still debated. The size distribution is close to asbestos fibres and fibrils, after all, their biological behaviour are rather different. Medicinal muds used in balneotherapy and medical wellness - consisting of suspensions- cause dermal exposure of patients. Some kinds of these muds may have genotoxicity but probably not the particles themselves, rather their extractable chemical fractions. Ethical aspects of environmental health studies on particles are also discussed.text/html2012-09-18T12:58:10+01:00http://www.webmedcentral.com/Dr. Akio HiuraAnalysis of DNA Extracted From the Trigeminal Ganglion Cells After Neonatal Capsaicin Treatment by Agarose Gel Electrophoresis
http://www.webmedcentral.com/article_view/3708
The aim of this study was to examine whether the neonatal injection of capsaicin induces DNA ladder formation, as an indicator of apoptosis, in the rat trigeminal ganglion (TG). The DNA extracted from the TGs after treatment with capsaicin (50 mg/kg) at 2 days of age exhibited diffuse DNA fragmentation instead of “ladder formation”, as determined by agarose gel electrophoresis. In contrast, clear DNA ladder formation was induced in human osteosarcoma cells treated with okadaic acid (OA) at concentrations of 10 and 20 nM. These results suggest that capsaicin cannot induce apoptosis of TG neurons sufficient for detectable DNA ladder formation. Thus, it is conceivable that capsaicin mainly causes necrosis rather than apoptosis in rodent primary sensory neurons.text/html2013-03-06T12:35:57+01:00http://www.webmedcentral.com/Prof. Rakesh SharmaPhysical Basis of Gadolinium Induced Skin Nephrofibrosis: Testing by Gadolinium-Protein Targeting Assay and Iron Oxide Nanoparticle Based Magnetic Resonance Microscopy
http://www.webmedcentral.com/article_view/3089
Gadolinium based MRI contrast agents are functional and cationic morphometric markers but toxic to cause undefined fibrosis in skin and kidney damage. Magnetic Resonance Microimaging of rat skin and kidney was used first time to identify the physical factors modulating the gadolinium Omniscan® induced fibrosis by protein targeting.Hypothesis: Gadolinium contrast agent containing less chelated endogenous ions target Gd-protein interactions in both epidermal thickening of skin with result of dermatopathy and renal basement membrane proteins with result of nephrofibrosis. Materials and Methods: Gadolinium contrast agent was injected in rat animal. 500 MHz MR imaging was done to visualize fibrosis in gadolinium treated animals. In other alternative method to enhance the MR image contrast, cationic superparamagnetic iron oxide magnetoferritin (SPIOM) was injected in rat to target basement membrane(in rat kidney and different skin structures including epidermis glycolipids and dermis proteins. After MRI imaging, excised rat skin and kidneys tissues were imaged by ex vivo 900 MHz MR microimaging to confirm renal fibrosis and skin epidermis thickening. Results: Phantom showed change in magnetic resonance signal intensity dependence upon protein and GdIII concentration. Stereotactic arrangement of coordinate bonds between GdIII-ligand and protein was associated with relaxivities. The proton density weighted images visualized micro details of skin structures and nephron territories while T2 weighted images showed better contrast of tissue structures in both skin and kidney. The Gadolinium further enhanced the image contrast and targeted the proteins in renal basement membrane and viable proteins in epidermis. SPIOM enhanced the tissue contrast due to dephasing effect caused by SPIOM on structural changes in nephron and epidermis. Conclusion: Tissue membrane protein and chelate ligand group binding with gadolinium biophysical interaction at molecular level may develop fibrosis and dermatopathy. SPIOM injection improved the dephased image contrast of different structures in both skin and nephrons. The epidermis thickening and nephrofibrosis changes may be associated with nephrogenic systemic fibrosis or fibrosing dermatopathy.Key words: Skin, Kidney, MRI, 500 MHz NMR, 21 Tesla MR microscopy, Spectroscopy, Gadolinium, Nephrogenic systemic fibrosis.text/html2013-04-08T12:26:32+01:00http://www.webmedcentral.com/Ms. Mohammadali Ziaei MadbuniRisk Assessment Process of Amitraz on Environment and Human Health
http://www.webmedcentral.com/article_view/4121
Amitraz is the common name for N'-(2,4-dimethylphenyl)-N-[[(2,4-dimethylphenyl) imino] methyl]-N-methylmethanimidamide. Amitraz is a triazapentadiene compound, a member of the amidine chemical family. It is an insecticide and acaricide used to control red spider mites, leaf miners, scale insects, and aphids. On cotton it is used to control bollworms, white fly, and leaf worms. On animals it is used to control ticks, mites, lice and other animal pests. The EPA classifies Amitraz as Class III - slightly toxic. Amitraz is slightly toxic to mammals if ingested orally. The dose of Amitraz that is lethal to half of the test animals that ingest it is called the median lethal dose, or the LD50. The oral LD50 is 523- 800 mg/kg for amitraz in rats. The oral LD50 is greater than 1,600 mg/kg for mice. Dermal exposure results in an LD50 of greater than 1,600 mg/kg for rats and greater than 200 mg/kg for rabbits. The Lethal Concentration 50 or LC50 is the concentration of the chemical in air or water that kills half of the experimental animals exposed to it. The inhalation LC50 (6 hours) of amitraz for rats is 65 mg/l of air. Amitraz is not a skin irritant and does not sensitize skin. At high doses, amitraz can reduce the function of the hypothalamus, which helps regulate the metabolism by controlling hormone release in the body. A daily dose of 200 mg of amitraz per kilogram of body weight for ten weeks causes decreased growth and food consumption.text/html2018-06-05T05:26:36+01:00http://www.webmedcentral.com/Dr. Robert A LodderA Novel Statistical Approach to NOAEL: QBEST Applied to Dosing of Ellagic Acid
http://www.webmedcentral.com/article_view/5451
QBEST, a novel statistical method, can be applied to the problem of estimating the No Observed Adverse Effect Level (NOAEL) of a New Molecular Entity (NME) in order to anticipate a safe starting dose for beginning clinical trials. The NOAEL from QBEST (called the QNOAEL) can be calculated using multiple disparate studies in the literature and/or from the lab. The QNOAEL is similar in some ways to the Benchmark dose (BMD) and is superior to the BMD in others. The Benchmark Dose Method is currently widely used in toxicological research.
Results are used in a simulation based on nonparametric cluster analysis methods to calculate confidence levels on the difference between the Effect and the No Effect studies. The QNOAEL simulation generates an intuitive curve that is comparable to the dose-response curve. The NOAEL of ellagic acid (EA) will be calculated for clinical trials of its use as a component therapeutic agent (in BSN476) for treating Chikungunya infections. This will be the first published application of QBEST to the problem of NOAEL determination. The specific aims of the proposed study are to evaluate the accuracy and precision of the QBEST Simulation and QNOAEL compared to the Benchmark Dose Method, and to calculate the QNOAEL of EA for BSN476 Drug Development.