Andrea H. S. Loewen, MD, FRCP(C)

  • Department of Medicine and Department of
  • Physiology and Biophysics, Faculty of Medicine,
  • University of Calgary, Canada

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Biological and Computational Techniques to Identify Mitochondrial Toxicants 215 Salimi birth control for women costa buy drospirenone 3.03 mg online, A. Toxicity of lithium on isolated heart mitochondria and cardiomyocyte: A justification for its cardiotoxic adverse effect. A mechanism of S(1,2,3,4,4pentachloro1,3 butadienyl)lcysteine toxicity to rabbit renal proximal tubules. Cellular toxicity of bromobenzene and bromobenzene metabolites to rabbit proximal tubules: the role and mechanism of 2bromohydroquinone. Selective toxicity of apigenin on cancerous hepatocytes by directly targeting their mitochondria. Fusaric acid induces mitochondrial stress in human hepatocellular carcinoma (HepG2) cells. Toxicophore exploration as a screening technology for drug design and discovery: Techniques, scope and limitations. Labeling of cell membranes and compartments for live cell fluorescence microscopy. Boar spermatozoa successfully predict mitochondrial modes of toxicity: Implications for drug toxicity testing and the 3R principles. Statininduced muscle necrosis in the rat: Distribution, development, and fibre selectivity. Mitochondrial toxicity assessment in industry: A decade of technology development and insight. Highthroughput respirometric assay identifies predictive toxicophore of mitochondrial injury. Mechanism of cisplatin proximal tubule toxicity revealed by integrating transcriptomics, proteomics, metabolomics and biokinetics. Luminescent sensing and imaging of oxygen: Fierce competition to the clark electrode. Autophagy plays an important role in sunitinibmediated cell death in H9c2 cardiac muscle cells. Thus, although the final outcome may be cell death for many, if not most, of these *Both authors share first authorship insults, mechanistically, mitochondrial damage is not a uniform stereotypic process. Especially with respect to potential (therapeutic) countermeasures, it is a prerequisite to understand the specific mode of action of diverse mitochondriotoxic conditions. This is one main focus of "mitochondrial toxicology," an emerging research field that aims at unraveling the mechanisms of mitochondriotoxic insults and their cellular and systemic consequences and at finding potential remedies. Due to their organspecific tasks, mitochondria from diverse tissues vary considerably in their molecular composition (Fleischer et al. Therefore, one key issue of mitochondrial toxicology is to determine such- potentially tissuespecific-toxic modes of action. A tissuespecific mode of mitochondrial impairments may appear as unintended side effect of diverse pharmaceuticals.

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The role of human carboxylesterases in drug metabolism: have we overlooked their importance Statininduced coenzyme Q10 depletion: clinical consequences and therapeutic implications in skeletal and myocardial myopathies birth control methods national womens health information center discount 3.03 mg drospirenone amex. Supercomplex assembly determines electron flux in the mitochondrial electron transport chain. Targeted disruption of the alpha isoform of the peroxisome proliferatoractivated receptor gene in mice results in abolishment of the pleiotropic effects of peroxisome proliferators. Missense mutation of the CoQ2 gene causes defects of bioenergetics and defects of bioenergetics and de novo pyrimidine synthesis. Metabolic control analysis and threshold effect in oxidative phosphorylation: implications for mitochondrial pathologies. Fenofibrate in the treatment of dyslipidemia: a review of the data as they relate to the new suprabioavailable tablet formulation. Reversible atorvastatinassociated external ophthalmoplegia, anti acetylcholine receptor antibodies, and ataxia. Glucuronidation of statins in animals and humans: a novel mechanism of statin lactonization. Mechanism of clofibrate hepatoxicity: mitochondrial damage and oxidative stress in hepatocytes. Diagnosis and therapy in neuromuscular disorders: diagnosis and new treatments in mitochondrial disease. How increased oxidative stress promotes longevity and metabolic health: the concept of mitochondrial hormesis (mitohormesis). Simvastatin triggers mitochondriainduced Ca2+ signalling alteration in skeletal muscle. Muscle mitochondrial metabolism and calcium signaling impairment in patients treated with statins. Statin induced myotoxicity: the lactone forms are more potent than the acid forms in human skeletal muscle cells in vitro. Statinassociate muscle symptoms: impact on statin therapyEuropean Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management. Plasma concentrations and bioavailability of clofibric acid from its calcium salt in humans. Statins enhance peroxisome proliferatoractivated receptor gamma coactivator1alpha activity to regulate energy metabolism. Inhibition of selenoprotein synthesis by selenocysteine Trna(Ser)Ser lacking isopentenyladenosine.

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Why does the measles vaccine pose risks for immunocompromised contacts of vaccinated children Treatment Supportive therapy birth control for women 70s outfit 3.03 mg drospirenone purchase, ribavirin, vitamin A, and antibodies against the virus. Distinct reddening of facial skin that resembles the result of a slap is characteristic of this parvovirus-caused disease. Now that we have examined some bacterial and viral diseases of the skin, we turn our attention to fungal diseases of the skin, hair, and nails. Mycoses (fungal diseases) are traditionally classified according to the locations within the body that they affect. Physicians classify mycoses as superficial (on the surface), cutaneous (in the skin), subcutaneous (in the hypodermis and muscles), or systemic (affecting numerous systems). Superficial and cutaneous mycoses of the hair, nails, and skin are generally not life threatening, though they may cause chronic or recurring diseases. Surface mycoses are acquired by direct contact with the hyphae or spores of opportunistic fungi. However, fluorescence under ultraviolet is not a definitive diagnosis, because some other fungi also fluoresce. Superficial Malassezia infections are treated topically with solutions of ciclopirox or antifungal imidazoles, such as ketoconazole shampoos. Alternatively, topical applications of zinc pyrithione, selenium sulfide lotions, or propylene glycol solutions can be used. Oral therapy with ketoconazole may be required to treat extensive infections and infections that do not respond to topical treatments. The skin takes months to regain its normal pigmentation following successful treatment. This condition, which typically occurs on the trunk, shoulders, and arms, and rarely on the face and neck, is called versicolor in reference to the variable pigmentation seen in affected individuals. Pathogenesis and Epidemiology Superficial fungi produce keratinase, an enzyme that dissolves keratin. These fungi do not penetrate living tissues and do not trigger immune responses, which differentiates them from the cutaneous and subcutaneous pathogens (discussed shortly). Transmission of the fungi of pityriasis onto the surface of the skin is usually mediated via shared hairbrushes and combs, and several members of a family may be infected at the same time. Adolescents are more likely to be afflicted, possibly as a result of increased sebum production related to hormonal changes. They are caused by dermatophytes, which are fungi that grow on skin, nails, and hair and invade the body, where they stimulate cell-mediated immune responses that damage deeper tissues.

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Note that all cells birth control yes or no 3.03 mg drospirenone order overnight delivery, no matter their type, stain almost the same color with a simple stain because only one dye is used. Microorganisms are spread in liquid across the surface of a slide using a circular motion. In contrast, anionic dyes, for example, eosin, bind to positively charged molecules, such as some amino acids. Anionic chromophores are also called acidic dyes because they stain alkaline structures and work best in acidic (low pH) environments. Positively charged, cationic chromophores are called basic dyes because they combine with and stain acidic structures; further, they work best under basic (higher pH) conditions. In microbiology, basic dyes are used more commonly than acidic dyes because most cells are negatively charged. Some stains do not form bonds with cellular chemicals but rather function because of their solubility characteristics. For example, Sudan black selectively stains membranes because it is lipid soluble and accumulates in phospholipid bilayers. Differential Stains Most stains used in microbiology are differential stains, which use more than one dye so that different cells, chemicals, or structures can be distinguished when microscopically examined. Common differential stains are the Gram stain, the acidfast stain, the endospore stain, Gomori methenamine silver stain, and hematoxylin and eosin stain. Gram Stain In 1884, the Danish scientist Hans Christian Gram developed the most frequently used differential stain, which now bears his name. The Gram stain differentiates between two large groups of microorganisms: purple-staining Gram-positive cells and pink-staining Gram-negative cells. Typically, a Gram stain is the first step a medical laboratory scientist performs to identify bacterial pathogens. Simple stains are composed of a single basic dye, such as crystal violet, safranin, or methylene blue. They are "simple" Staining 109 Gram-positive and Gram-negative colorless bacteria. This solution, which acts as a decolorizing agent, breaks down the thin cell wall of Gram-negative cells, allowing the stain and mordant to be washed away; these Gram-negative cells are now colorless. Although all types of cells may absorb safranin, the resulting pink color is masked by the darker purple dye already in Grampositive cells. After this step, Gram-negative cells now appear pink, whereas Gram-positive cells remain purple. Older Gram-positive cells bleach more easily than younger cells and can therefore appear pink, which makes them appear to be Gram-negative cells. In a three-step variation, safranin dissolved in ethanol simultaneously decolorizes and counterstains.

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As long as rifampin is present birth control patch xulane effectiveness 3.03 mg drospirenone purchase with visa, cells with such a mutation have an advantage over cells without the mutation, and the population evolves resistance to rifampin. If they occurred often, organisms could not live or effectively reproduce themselves. Here we consider three categories of repair: direct repair, single-strand repair, and repair of double-strand damage. An example of direct repair is base-excision repair in which one of several enzymes recognizes a specific incorrect base and removes and replaces only that base. Another form of direct repair is the repair of pyrimidine dimers by so-called light repair. The repair enzyme distinguishes the original strand from the new strand because the original strand is methylated. An example is nucleotide-excision repair (sometimes called dark repair because it can correct a pyrimidine dimer without using light). Another type of single-strand repair is mismatch repair, which is a repair mechanism that corrects errors produced during replication. How does the mismatch repair system determine which of the two strands is in error If it chose randomly, 50% of the time it would choose the wrong strand and introduce mutations. Mutagen induces mutations If a cell does not successfully repair a mutation, it and its descendants are called mutants. In contrast, cells normally found in nature (in the wild) are called wild-type cells. Scientists distinguish mutants from wild-type cells by observing or testing for altered phenotypes. Because mutations are rare and nonfatal mutations are even rarer, mutants can easily be "lost in the crowd. Penicillin-resistant mutants indistinguishable from nonmutants Positive Selection Positive selection involves selecting a mutant by eliminating wild-type phenotypes. Assume, for example, that researchers want to isolate penicillin-resistant bacterial mutants from a liquid culture. To do so, they spread the liquid medium, which contains mostly penicillin-sensitive cells but also the few penicillin-resistant mutants, onto a medium that includes penicillin. While the researchers are isolating mutants, they can also determine the rate of mutation by comparing the number of mutant colonies formed after use of the mutagen with the number formed before treatment. Only mutants that are resistant to penicillin can survive on the plate containing this antibiotic. Obviously, if a researcher attempts to grow tryptophan auxotrophs on media lacking tryptophan, it will not be possible; the bacteria will die because tryptophan is a necessary amino acid for proper synthesis of proteins. Therefore, to isolate such auxotrophs, scientists can use a technique called negative (indirect) Greek auxein, meaning "to increase," and trophe, meaning "nutrition.

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Now that we have studied the terminology and general principles of microbial control and biosafety levels birth control pills 30 mcg estrogen generic 3.03 mg drospirenone otc, we turn our attention to the actual physical and chemical agents available to scientists, medical personnel, and the general public to control microbial growth. Physical methods of microbial control include exposure of the microbes to extremes of heat and cold, desiccation, filtration, osmotic pressure, and radiation. High temperatures denature proteins, interfere with the integrity of cytoplasmic membranes and cell walls, and disrupt the function and structure of nucleic acids. Heat can be used for sterilization, in which case all cells and viruses are deactivated, or for commercial preparation of canned goods. In so-called commercial sterilization, hyperthermophilic prokaryotes remain viable but are harmless because they cannot grow at the normal (room) temperatures in which canned foods are stored. Though microorganisms vary in their susceptibility to heat, it can be an important agent of microbial control. As a result, scientists have developed concepts and terminology to convey these differences in susceptibility. Thermal death point is the lowest temperature that kills all cells in a broth in 10 minutes, and thermal death time is the time it takes to completely sterilize a particular volume of liquid at a set temperature. The standard in food processing is to apply heat such that a population of 1012 C. Moist Heat Moist heat (which is commonly used to disinfect, sanitize, sterilize, and pasteurize) kills cells by denaturing proteins and destroying cytoplasmic membranes. Moist heat is more effective in microbial control than dry heat because water is a better conductor of heat than air. The first method we consider for controlling microbes using moist heat is boiling. Boiling Boiling kills the vegetative cells of bacteria and fungi, the trophozoites of protozoa, and most viruses within 10 minutes at sea level. It is impossible to boil something more quickly simply by applying more heat; the added heat is carried away by the escaping steam. Further, it is important to realize that at higher elevations, water boils at lower temperatures because atmospheric pressure is lower; thus, a longer boiling time is required in Denver than in Los Angeles to get the same antimicrobial effect. Bacterial endospores, protozoan cysts, and some viruses (such as hepatitis viruses) can survive boiling at sea level for many minutes or even hours.

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The dikaryon undergoes mitosis and cell division to produce a hypha composed of dikaryotic cells birth control for women ltd chicago buy drospirenone 3.03 mg without a prescription. Eventually, nuclei of opposite mating types within the dikaryons fuse to form diploid nuclei that then undergo meiosis and cytokinesis to form four haploid cells lined up within an ascus. The four haploid cells may each undergo mitosis and cytokinesis to form eight haploid ascospores. The asci open to release their ascospores, which germinate to produce either a + or a - hypha. That fungal sphere, an aspergilloma, had started as a single spore of an ascomycete fungus Aspergilloma called Aspergillus. The mold had formed the mass of fungal hyphae that was invading the airways of his lung and slowly killing him. Such bronchopulmonary aspergillosis is a rare but increasingly frequent pathogen of immunocompromised people. Besides his difficulty in breathing, fever, and chest pain, Matt most hated coughing up wads of bloody mucus-as if he were expelling the very fabric of his life. Soon the signs and symptoms of invasive aspergillosis would be his-extreme tiredness, excessive weakness, severe headaches, and delirium. The sheer terror of knowing his brain was being pierced by thin hyphal threads, digesting his personality away, was almost more than Matt could stand. A medical miracle in the form of a new antifungal drug (voriconazole) brought Matt back to life. The invasive mold was defeated, and Matt returned home grateful, aware that life is precious and hopeful that no more spores floated his way. Why is a powerful drug like voriconazole effective against fungi but relatively harmless to humans Aspergillus can also infect humans (see Emerging Disease Case Study: Aspergillosis). Aspreviouslynoted,anotherascomycete, the pink bread mold Neurospora, has been an important tool in genetics and biochemistry. Many ascomycetes partner with green algae or cyanobacteria to form lichens (discussed in more detailshortly). Poisonous mushrooms are sometimes called toadstools, but there is no sure way to always distinguish an edible "mushroom" from a poisonous "toadstool" except by eating them-a truly risky practice! Basidiospores disperse in the wind and germinate in suitable, moist environments to form small haploid hyphae that have either + or - nuclei. Most basidiomycetes are important decomposers that digest chemicals such as cellulose and lignin in dead plants and return nutrients to the soil. Other basidiomycetes are rusts and smuts, which attack crop plants, causing millions of dollars of damage each year. The most coveted include Tuber melanosporum, a black truffle that is also known as the "black diamond," and Tuber magnatum, a white truffle that can sell for $10,000 per pound! Because truffles are very difficult to find, truffle hunters often use pigs and dogs trained to sniff them out.

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The overlay graph shows the amount of precipitate formed versus the amount of antigen present birth control for women 80s 3.03 mg drospirenone order overnight delivery. If the researcher is examining a serum for the presence of antibodies, then one well is filled with a solution of antigen and the other with the serum. Such an immunodiffusion test has been used to indicate exposure to complex mixtures of antigens from pathogens such as fungi. Agar (a) Zone of antigen excess Zone of optimal precipitation Zone of antibody excess Well containing four different antigens Lines of immune precipitation Well containing a mixture of antibodies, each reacting to a different antigen Turbidimetric and Nephelometric Tests Turbidimetry and nephelometry are automated methods that measure the cloudiness of a solution, as occurs when antibodies and antigens are mixed together. As noted previously, when the concentrations of antibodies and antigens are optimal, the initial cloudiness is followed by precipitation. In turbidimetry, a light detector measures the amount of light passing through a solution, whereas in nephelometry, a machine measures the amount of light reflected from the antigen-antibody complexes within the solution. Medical laboratory scientists use these methods to quantify the amounts of proteins, such as antibodies and complement, in serum. The artist has used color for the antigen, antibodies, and line of precipitation to clarify what happens, but in reality antigens and antibodies are colorless, and lines of precipitation are off-white. Why did only three lines of precipitation occur when the antigen well contained four antigens The difference between agglutination and precipitation is that agglutination involves the clumping of insoluble particles, whereas precipitation involves the aggregation of soluble molecules. Agglutination reactions are sometimes easier to see and interpret with the unaided eye. Serial dilutions of serum are added to wells containing a constant amount of antigen. At lower serum dilutions (higher concentrations of antibody), agglutination occurs; at higher serum dilutions, antibody concentration is too low to produce agglutination. Another use of agglutination is in a type of test that determines the concentration of antibodies in a clinical sample. Although the simple detection of antibodies is sufficient for many purposes, it is often more desirable to measure the amount of antibodies in serum. Eventually, the antibodies in the serum become so dilute that they can no longer cause agglutination. The highest dilution of serum giving a positive reaction is a titer, which is expressed as a ratio reflecting the dilution. Where the antibodies react with the surface antigens, the blood cells can be seen to agglutinate, or clump together. What is the blood type of the person whose blood was used in this hemagglutination reaction Neutralization tests work because antibodies can neutralize the biological activity of many pathogens and their toxins. For example, combining antibodies against tetanus toxin with a sample of tetanus toxin renders the sample harmless to mice because the antibodies have reacted with and neutralized the toxin.

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