Mark K. Wax, MD, FACS, FRCSC

• Professor, Otolaryngology/Head and Neck Surgery
• Professor, Oral and Maxillofacial Surgery
• Program Director
• Director, Microvascular Reconstruction
• Coordinator, Education, AAOHNS(F)
• Department of Otolaryngology/Head and Neck Surgery
• Oregon Health Sciences University
• Portland, Oregon

Investigation of pyrrolizidine alkaloids and their N-oxides in commercial comfrey-containing products and botanical materials by liquid chromatography electrospray ionization mass spectrometry fungus testing lab purchase sporanox with a visa. Pharmacological characterisation of the plant sesquiterpenes polygodial and drimanial as vanilloid receptor agonists fungus gnats larvae buy 100 mg sporanox with visa. A sensitive monoclonal antibody-based enzyme-linked immunosorbent assay to quantify Parietaria judaica major allergens antifungal ingredients order sporanox 100 mg with visa, Par j1 and Par j2 fungus gnats on plants buy cheapest sporanox and sporanox. Clinical and pathological aspects of experimental oleander (Nerium oleander) toxicosis in sheep fungus contagious best 100mg sporanox. A review of Silybum marianum (milk thistle) as a treatment for alcoholic liver disease fungus gnats in peace lily quality 100mg sporanox. Medical Toxicology of Natural Substances: Foods, Fungi, Medicinal Herbs, Plants and Venomous Animals. Structure and functions of channel-forming peptides: magainins, cecropins, melittin and alamethicin. Isolation of the major component in white snakeroot that is toxic after microsomal activation: possible explanation of sporadic toxicity of white snakeroot plants and extracts. Class I chitinases as potential panallergens involved in the latex-fruit syndrome. A genome-wide search for quantitative trait loci contributing to variations in seasonal pollen reactivity. Life-threatening interaction between complementary medicines: cyanide toxicity following ingestion of amygdalin and vitamin C. Ultrasound studies of the effects of certain poisonous plants on uterine function and fetal development in livestock. Snake venom disintegrins: novel dimeric disintegrins and structural diversification by disulfide bond engineering. Characterization and some properties of the venom gland extract of a theridiid spider (Steatoda paykulliana) frequently mistaken for black widow spider (Latrodectus tredecimguttatus). Tick saliva inhibits differentiation, maturation and function of murine bone-marrow derived dendritic cells. Anticholinergic toxicity from night-shade berry poisoning responsive to physostigmine. A novel neurotoxin, cobrotoxin b, from Naja naja atra venom: purification, characterization and gene organization. Bugs as drugs, part two: worms, leeches, scorpions, snails, ticks, centipedes and spiders. Isolation and quantification of tuliposides and tulipalins in tulips (Tulipa) by high-performance liquid chromatography. Novel peptides from assassin bugs (Hemiptera: Reduviidae): isolation, chemical and biological characterization. An ergot alkaloid biosynthesis gene and clustered hypothetical genes from Aspergillus fumigatus. The localization of paralysis toxin in granules and nuclei of prefed female Rhipicephalus evertsi evertsi tick salivary gland cells. Salp25D, an Ixodes scapularis antioxidant, is 1 of 14 immunodominant antigens in engorged tick salivary glands. Structure and other chemical characterizations of gila toxin, a lethal toxin from lizard venom. Capsaicin-induced depolarisation of mitochondria in dorsal root ganglion neurons is enhanced by vanilloid receptors. Pokeweed anitviral protein: its cytotoxicity mechanism and applications in plant disease resistance. Mass spectrometry in toxinology: a 21st-century technology for the study of biopolymers from venoms. Use of ribosome-inactivating proteins from Sambusus for the construction of immunotoxins and conjugates for cancer therapy. Comparison of nicotinic receptor binding and biotransformation of coniine in the rat and chick. Cloning of a salivary gland metalloprotease and characterization of gelatinase and fibrino(gen)lytic activities in the saliva of the lyme disease tick vector Ixodes scapularis. From genome to "venome": molecular origin and evolution of the snake venom proteome inferred from phylogenetic analysis of toxin sequences and related body proteins. Augmenting the efficacy of immunotoxins and other targeted protein toxins by endosomal escape enhancers. Mucuna pruriens seed extract pretreatment protects against cardiorespiratory and neuromuscular depressant effects of Naja sputatrix (Javan spitting cobra) venom in rats. The development of Byetta (exenatide) from the venom of the Gila monster as an anti-diabetic agent. Implications of C-5, C-6 unsaturation as a key structural factor in steroidal alkaloid-induced mammalian teratogenesis. Occupational respiratory allergic disease induced by Passiflora alata and Rhamnus purshiana. Isolierung von Willardiin [3-(1-uracyl)-l-alanin] aus den samen von Acacia millefolia, Acacia lemmoni und Mimosa asperata. Isolation, purification and pharmacodynamics of a toxin from the venom of centipede, Scolopendra subspinipes dehaani Brandt. Impact of occupational and inhalant allergy on rhinitis-specific quality of life in employees of bell pepper greenhouses in the Netherlands. An investigation of the irritant and allergenic properties of daffodils (Narcissus pseudonarcissus, Amaryllidaceae): a review of daffodil dermatitis. In vitro ruminal disappearance of fumonisin B1 and its effects on in vitro dry matter disappearance. The ergot alkaloid gene cluster in Claviceps purpurea: extension of the cluster sequence and intra species evolution. Usnic acid-induced necrosis of cultured mouse hepatocytes: inhibition of mitochondrial function and oxidative stress. Black widow spider alpha-latrotoxin: a presynaptic neurotoxin that shares structural homology with the glycogen-like peptide-1 family of insulin secretagogic hormones. Post-translational modification: a two dimensional strategy for molecular diversity of Conus peptides. Peptides for the New Millennium: Proceedings of the Sixteenth American Peptide Symposium. Species differences in the hepatic microsomal enzyme metabolism of the pyrrolizidine alkaloids. Correlation between quantal secretion and vesicle loss at the frog neuromuscular junction. Amatoxin-a(s), a naturally occurring organophosphate, is an irreversible active site-directed inhibitor of acetylcholinesterase (E. Profound neonatal congestive heart failure caused by maternal consumption of blue cohosh herbal medication. Inhibition of coagulation activation and inflammation by a novel factor Xa inhibitor synthesized from the earthworm Eisenia andrei. Enrichment and function of urushiol (poison ivy)specific T lymphocytes in lesions of allergic contact dermatitis to urushiol. Myopathy in cattle induced by alkaloid extracts from Thermopsis montana, Laburnum anagyroides and a Lupinus sp. Suspected buttercup (Ranunculus bulbosus) toxicosis with secondary photosensitization in a Charolais heifer. Hyaluronidases, a neglected class of glycosidases from snake venom: beyond a spreading factor. Detecting potential teratogenic alkaloids from blue cohosh rhizomes using an in vitro rat embryo culture. Ovine copper poisoning and Pteridium aquilinumassociated bovine urinary bladder tumor in Korea. Excitement ahead: structure, function and mechanism of snake venom phospholipase A2 enzymes. Structural analysis of the glycoprotein allergen Hev b 4 from natural rubber latex by mass spectrometry. Production of isodomoic acids A and B as major toxin components of a pennate diatom Nitzschia navis-varingica. Biochemistry, toxicology and ecology of the venom of the spider Cupiennius salei (Ctenidae). Mimosine blocks cell cycle progression by chelating iron in asynchronous human breast cancer cells. In the picture: disulfide-poor conopeptides, a class of pharmacologically interesting compounds. Anemonin, from Clematis crassifolia, potent and selective inducible nitric oxide synthase inhibitor. Effects of Cassia obtusifolia (sicklepod) extracts and anthraquinones on muscle mitochondrial function. Putting the brakes on snake venom evolution: the unique molecular evolutionary patterns of Aipysurus eydouxii (marbled sea snake) phospholipase A2 toxins. Biochemistry of hemlock (Conium maculatum) alkaloids and their acute and chronic toxicity in livestock: a review. Structural determinants for the action of grayanotoxin in D1 S4-S5 and D4 S4-S5 intracellular linkers of sodium channel alpha-subunits. Purification and characterization of apyrase from the tick, Ornithodoros savignyi. Experimental evidence for toxic damage induced by a dimeric anthracenon: diast T-514 (peroxisome A2). Contact dermatitis due to Euphorbia pulcherrima Willd, simulating a phototoxic reaction. Non-enzymatic proteins from snake venoms: a gold mine of pharmacological tools and drug leads. The toxicosis of Embellisia fungi from locoweed (Oxytropis lambertii) is similar to locoweed toxicosis in rats. Venom apparatus and toxicity of the centipede Ethmostigmus rubripes (Chilopoda, Scolopendridae). Primary structure and properties of helothermine, a peptide toxin that blocks ryanodine receptors. Helothermine, a lizard venom toxin, inhibits calcium current in cerebellar granules. New view on crotamine, a small basic polypeptide myotoxin from South American rattlesnake venom. Clinical and immunologic features of systemic contact dermatitis from ingestion of Rhus (Toxicodendron). Plant-derived abrin-a induces apoptosis in cultured leukemic cell lines by different mechanisms. Conus venom peptides, receptor and ion channel targets and drug design: 50 million years of neuropharmacology. Calcium channel diversity and neurotransmitter release: the -conotoxins and -agatoxins. The necrotic venom of the brown recluse spider induces dysregulated endothelial cell-dependent neutrophil activation. Mimosine attenuates serine hydroxymethyltransferase transcription by chelating zinc. Effective dose in cattle of toxic alkaloids from tall larkspur (Delphinium barberi). Snake postsynaptic neurotoxins: gene structure, phylogeny and applications in research and therapy. A new age for biomedical applications of ribosome inactivating proteins: from bioconjugate to nanoconstructs. Snake venom metalloproteases- structure and function of catalytic and disintegrin domains. Nicotinic toxicity from tincture of blue cohosh (Caulophyllum thalictroides) used as an abortifacient. Distribution of the carcinogenic terpene ptaquiloside in bracken fronds, rhizomes (Pteridium aquilinum), and litter in Denmark. Schistosoma mansoni proteins attenuate gastrointestinal motility disturbances during experimental colitis in mice. Anti-diarrheal mechanism of the traditional remedy Uzara via reduction of active chloride secretion. Molecular structure, polymorphism, and toxicity of lantadene A, the pentacyclic triterpenoid from the hepatotoxic plant Latana camara. Efficacy, routine effectiveness, and safety of horse chestnut seed extract in the treatment of chronic venous insufficiency. Purification and characterization of two classes of neurotoxins from the funnel web spider Agelenopsis aperta.

We certainly know of the requirement for the expression of critical cell surface markers by the sperm that facilitate the normal binding of the sperm to the egg surface membrane anti yeast antifungal shampoo buy sporanox discount. Lastly fungus gnats kill order sporanox 100 mg fast delivery, there is the potential for effects in the male to induce paternally mediated developmental toxicity in the embryo/fetus fungus gnats hydro order sporanox 100 mg without prescription. While this is not a common occurrence fungi quiz cheap 100 mg sporanox overnight delivery, it has been documented with one or two specific chemicals fungus malassezia buy sporanox 100 mg without a prescription. The number of known environmental chemicals that produce adverse responses in human males is not large antifungal medication list generic 100 mg sporanox. All of these have been shown to induce effects in rodents and especially the rat, although there may be differences in sensitivity based on dose. However, this does not imply that all chemicals known to produce injury in the rats would indeed show toxicity in humans. A transverse section of a tubule covering one cycle of the epithelium will contain cellar representatives at different stages of maturity from successive waves. Diagram of the 14 stages of spermatogenesis of the rat testis (after Leblond and Clermont, 1952). Posttesticular Processes Following the release of mature spermatids from the seminiferous epithelium, the extraneous cytoplasm and organelles form the residual body that is phagocytosed by the Sertoli cell and move from the periphery of the tubule to its base. These nonmotile sperm are moved along the tubules by a peristaltic-like action of the myoepithelial cells of the tubule and eventually emptied into the rete testis. In rodents, but not humans, a large blood plexus forms over the rete (which is close to the surface and near the pole of the testis) where fluid exchange can take place. The efferent ducts then empty into the caput (head) of the epididymis that is a single highly coiled tube derived from the Wolffian duct in utero. The epididymis can be divided into three anatomical portions: the caput, corpus (body), and cauda (tail), which has a changing chemical environment and fluid composition from the efferent ducts through to the cauda. The sperm undergo maturation in the caput and corpus and begin to acquire motility, whereas the cauda is principally used for sperm storage, although expression of some critical surface markers does occur that are involved in the process of fertilization. In humans, the passage of sperm takes approximately 6 days and is longer in rats (~10 days). During the movement along the epididymal, tubule fluid is removed by active transport and this stage of the process is one that can be interfered with by toxicants resulting in an inappropriate environment for normal sperm development. The physiology and anatomy of these organs vary widely among mammalian species, with the rodent having a clear lobular pattern to the prostate that is not seen in humans. These organs are predominantly glandular/secretory in nature and produce much of the seminal plasma for the ejaculation of sperm to survive within the female reproductive tract. The seminal plasma contains many nutrients for sperm motion as well as distinct proteins and ion content. For example, a diminution in energy substrates can affect sperm motion characteristics. These "accessory sex organs" are androgen dependent for their function and/or development and are frequently recorded in toxicity studies as indicators of androgen action. Semen volume varies considerably among species, ranging from relatively small (1 to 10 mL: in humans) to much larger (~500 mL in boars). Parasympathetic nerve stimulation results in dilatation of the arterioles of the penis, which initiates an erection. Erectile tissue of the penis engorges with blood, veins are compressed to block outflow, and the turgor of the organ increases. In the human, afferent impulses from the genitalia and descending tracts, which mediate erections in response to erotic psychic stimuli, reach the integrating centers in the lumbar segments of the spinal cord. The efferent fibers are located in the pelvic splanchnic nerves (Andersson and Wagner, 1995). Emission is the movement of the semen into the urethra; ejaculation is the propulsion of the semen out of the urethra at the time of orgasm. Afferent pathways involve fibers from receptors in the glans penis that reach the spinal cord through the internal pudendal nerves. Emission is a sympathetic response produced by contraction of the smooth muscle of the vas deferens and seminal vesicles. Semen is ejaculated out of the urethra by contraction of the bulbocavernosus muscle. The spinal reflex centers for this portion of the reflex are in the upper sacral and lowest lumbar segments of the spinal cord; the motor pathways traverse the first to third sacral roots of the internal pudendal nerves. Little is known concerning the effects of chemicals on erection or ejaculation (Woods, 1984). Pesticides, particularly the organophosphates, are known to affect neuroendocrine processes involved in erection and ejaculation. Many drugs act on the autonomic nervous system and affect potency (Table 21-5) (see also Buchanan and Davis, 1984; Stevenson and Umstead, 1984; Keene and Davies, 1999). Impotence, the failure to obtain or sustain an erection, is rarely of endocrine origin; more often, the cause is psychological. The occurrence of nocturnal or early-morning erections implies that the neurological and circulatory pathways involved in attaining an erection are intact and suggests the possibility of a psychological cause. In the rat, prenatal exposure to the antiandrogenic fungicide, vinclozolin, induces a significant reduction of erections at all dose levels during the ex copula penile reflex tests in male offspring (Colbert et al. The earliest studies using a 10-week dosing regimen (5 day/week by gavage in corn oil) reported effects at 6 mg/kg/day (Linder et al. Foster (1989) showed that 5-day dosing with 5 mg/kg/day produced a minimal-to-moderate testicular lesion within 2 weeks and with 10 mg/kg/day a moderate-to-severe lesion. Testicular weight remained reduced for many weeks after the treatment period with significant dose-related effects on fertility (measured by pregnancy rate and implantation success). Detailed electron microscopic evaluation has shown initial lesions to be present in the Sertoli cells of the testis, which results rapidly in germ cell apoptosis and death. The earliest features of these studies after a single dose (250 or 500 mg/kg/ day) were that there are Sertoli cell vacuoles and swollen germ cell mitochondria, followed by (or concurrent with) a breakdown of the membrane between the Sertoli cell and the pachytene spermatocyte in a spermatogenic stage-specific manner. This is followed quickly (within hours) by the death of (probably those) pachytene spermatocytes (Foster et al. As with other testis toxicants, higher doses produce a more widespread lesion involving other cell types (Foster et al. Effect of m-dinitrobenzene on percentage of females pregnant in a serial mating study design. Effect of ethylene glycol monomethyl ether (or its metabolite methoxyacetic acid) 24 hours after a single oral dose (100 mg/kg/d). The lesion is not characteristic of a low-androgen testicular lesion, and reduced accessory sex organ weights are not a prominent feature associated with the early testicular pathology. Theperiodofreceptivity begins at the onset of the dark phase of their light cycle, terminating later in the evening before the next stage of the cycle, defined as estrus, which is typically characterized by the display of a vaginal lavage of mostly cornified epithelial cells. During mating, the female rat displays proceptive behaviors like ear wiggling and darting to induce the male to mount, and when mounted the female is "receptive" displaying a lordosis posture characterized by a raised head and tail and fully arched back. In experienced male rats, the latency to the first mount is usually on a few seconds, but inexperienced males may take much longer. When the male rat mounts the lordosing female, he will display a single pelvic thrust that may or may not result in intromission of the penis into the vagina. Within a few seconds, the male mounts again and this series continues until the male ejaculates. During this period, the male produces a 22 kHz vocalization, during which the female does not display proceptive behaviors (Porter et al. At the beginning of the second series, the male dislodges the copulatory plug, formed from the seminal secretions. The copulatory plug normally fits close to the cervix, and it is necessary to facilitate sperm entry into the uterus. It is not unusual to find seven to eight copulatory plugs in the breeding cage the day aftermating(Grayetal. Ifmatingdoesnotoccur,thenthe brief rise in serum progesterone declines by the next day. Cervix the mucosa of the uterine cervix does not undergo cyclic desquamation, but there are regular changes in the cervical mucus. Estrogen, which makes the mucus thinner and more alkaline, promotes the survival and transport of sperm. The mucus is thinnest at the time of ovulation and dries in an arborizing, fernlike pattern on a slide. After ovulation and during pregnancy, it becomes thick and fails to form the fern pattern. Disruptions of the cervix may be expressed as disorders of differentiation (including neoplasia), disturbed secretion, and incompetence. Once sperm fusion has occurred, a "zona block" is initiated to prevent any further sperm entering through the zona pellucida and fusing with the oocyte membrane. The precise mechanisms of how this occurs have not been fully elucidated (Hoodbhoy and Dean, 2004). Implantation can only occur when the embryo reaches the blastocyst stage and gains implantation competency and the uterus, through steroid hormone-dependent changes, attains a receptive state. This reciprocal interaction must occur between the blastocyst and uterus together with an increase in uterine vascular permeability at the site of blastocyst attachment. There are four stages that comprise early implantation in mammals: (1) apposition and adhesion of the blastocyst to the uterine lumen, (2) penetration of the epithelium, (3) decidualization of the stromal cells, and (4) trophoblastic invasion into the stromal vasculature. The molecular understanding of these physiological events is far from complete, with data being generated mainly from studies in the mouse that have indicated through gene ablation in the uterus, a number of critical factors and cytokines involved in implantation; however, a number of these critical gene products. Another important aspect of the implantation process common to many species (and offering an experimental tool to study implantation) is the embryonic diapause (or delayed implantation) evolved as a strategy to ensure proper implantation timing depending on environmental conditions (see review by Lopes et al. The regulation of this phenomenon varies widely between species ranging from photoperiod through hormonal or nutritional influences. The layers of cells become cornified and can be readily identified in vaginal smears. Progesterone stimulation produces thick mucus and the epithelium proliferates, becoming infiltrated with leukocytes. Analysis of vaginal fluid or cytological studies of desquamated vaginal cells (quantitative cytochemistry) normally reflects ovarian function. Vaginal sampling of cells and fluid might offer a reliable and easily available external monitor of internal function and dysfunction. In mammals, the oocyte is surrounded by two layers: an outer layer of cumulus cells and an inner layer of extracellular matrix termed the zona pellucida (see the review by Hoodbhoy and Dean, 2004). To reach the oocyte, the sperm must penetrate both layers that require high motility, the release of sperm enzymes and the presence of proteins that will facilitate binding of the sperm to the oocyte. Moreover, once fertilization has occurred, mechanisms must be in place to prevent the binding of further sperm to the fertilized oocyte (the zygote). To facilitate these activities, sperm must be capacitated (Hunter and Rodriguez-Martinez, 2004) and the secretion of enzymes (hyaluronidases) allows the sperm to penetrate through the cumulus cells to the zona pellucida. This special extracellular matrix is composed of three glycoproteins and cell surface factors that cause the sperm to release the secretory enzymes present in the acrosome via binding to the specific carbohydrates present in this matrix. There are a huge number of different placental types exhibited by eutherian mammals that exhibit differences in both structure and endocrinology, including significant difference between the major experimental animal species and humans (see reviews by Malassine et al. Pigs, horses, and donkeys have an epitheliochorial type of placenta, whereas sheep, goats, and cows have a syndesmochorial type of placenta. Among the various species, the number of maternal and fetal cell layers ranges from six. Primates, including humans, have three layers of cells in the placenta that a substance must pass across. The blastocysts of most mammalian species implant about day 6 or 7 following fertilization. At this stage, the differentiation of the embryonic and extraembryonic (trophoblastic) tissues is apparent. Trophoblastic tissue differentiates into cytotrophoblast and syncytiotrophoblast cells. The syncytiotrophoblast cells produce chorionic gonadotropin, chorionic growth hormones, placental lactogen, estrogen, and progesterone, which are needed to achieve independence from the ovary in maintaining the pregnancy. Rapid proliferation of the cytotrophoblast serves to anchor the growing placenta to the maternal tissue. The developing placenta consists of proliferating trophoblasts, which expand rapidly and infiltrate the maternal vascular channels. Shortly after implantation, the syncytiotrophoblast is bathed by maternal venous blood, which supplies nutrients and permits an exchange of gases. Histotrophic nutrition involves yolk sac circulation; hemotrophic nutrition involves the placenta. Placental circulation is established quite early in women and primates and relatively much later in rodents and rabbits. One of the major differences in endocrine placental function between humans and rodents is in the production and regulation of progesterone necessary for the maintenance of pregnancy. In the rodent, the corpus luteum in the ovary has to produce progesterone throughout gestation and is regulated initially by pituitary prolactin secretion and then around midway through gestation by placental lactogens produced by the trophoblast. Thereissufficientprogesterone produced by the trophoblast after 8 weeks of gestation in humans to maintain pregnancy even in cases of ovariectomy. Generally, the placenta is quite impermeable to chemicals/ drugs with molecular weights of 1000 Da or more. Placental permeability to a chemical is affected by placental characteristics including thickness, surface area, carrier systems, and lipid-protein concentration of the membranes. The inherent characteristics of the chemical itself such as its degree of ionization, lipid solubility, protein binding, and molecular size also affect its transport across the placenta. Various transporter families have also been identified in the placenta and can contribute to the passage of xenobiotics across the placenta (see Chap. If sperm transport, fertilization, or implantation is blocked, then the mated female is "pseudopregnant" for about 10 to 13 days (Swingle et al.

Sensitivity to apoptosis signal fungus beetle ffxi order 100 mg sporanox otc, clearance rate fungus haematodes buy sporanox 100mg overnight delivery, and ultrastructure of Fas ligand-induced apoptosis in in vivo adult cardiac cells anti yeast juice order generic sporanox on line. Morphological and morphometric investigation of cardiac lesions after chronic administration of methamphetamine in rats antifungal azoles cost of sporanox. Cardiac hypertrophy is not a required compensatory response to short-term pressure overload fungus gnats cannabis coco purchase sporanox without prescription. Inhibition of the slow inward current and the time-dependent outward current of mammalian ventricular muscle by gentamicin antifungal for thrush purchase sporanox with a mastercard. Mechanistic investigation of imatinibinduced cardiac toxicity and the involvement of c-Abl kinase. Atherogenic properties of phenothiazine drugs manifesting in cultured cells of the human aortic intima. Historical perspective on the pathology of myocardial ischemia/reperfusion injury. Thyroid hormones differentially affect sarcoplasmic reticulum function in rat atria and ventricles. Apoptotic and necrotic myocyte cell deaths are independent contributing variables of infarct size in rats. Suppression by metallothionein of doxorubicin-induced cardiomyocyte apoptosis through inhibition of P38 mitogen-activated protein kinases. Metallothionein inhibits myocardial apoptosis in copper-deficient mice: role of atrial natriuretic peptide. Myocardial oxidative stress and toxicity induced by acute ethanol exposure in mice. Reverse remodeling and enhanced inotropic reserve from the cardiac support device in experimental cardiac failure. Polyamines mediate androgenic stimulation of calcium fluxes and membrane transport in rat heart myocytes. Overexpression of tumor necrosis factor-alpha activates both anti- and pro-apoptotic pathways in the myocardium. Endogenous tumor necrosis factor protects the adult cardiac myocyte against ischemicinduced apoptosis in a murine model of acute myocardial infarction. Early changes in left ventricular function in chronic asymptomatic alcoholics: relation to the duration of heavy drinking. Roles of the mammalian mitochondrial fission and fusion mediators Fis1, Drp1, and Opa1 in apoptosis. Ablation of telomerase and telomere loss leads to cardiac dilatation and heart failure associated with p53 upregulation. Cardiac cell toxicity induced by 4-hydroperoxycyclophosphamide is modulated by glutathione. Rapid transition of cardiac myocytes from hyperplasia to hypertrophy during postnatal development. Monensin toxicosis in the domestic bovine calf: a large animal model of cardiac dysfunction. Inhibition of L-type Ca2+ channel current in rat ventricular myocytes by terfenadine. Oxidative and non-oxidative mechanisms in the inactivation of cardiac mitochondrial electron transport chain components by doxorubicin. The function of zinc metallothionein: a link between cellular zinc and redox state. Regulation of expression of contractile proteins with cardiac hypertrophy and failure. Echocardiographic abnormalities in chronic alcoholics with and without overt congestive heart failure. Phenotypic spectrum caused by transgenic overexpression of activated Akt in the heart. Role of primary response genes in generating cellular responses to growth factors. Induction by p-hydrazinobenzoic acid hydrochloride of the cultivated mushroom Agaricus bisporus. Effects of myosin heavy chain isoform switching on Ca2+-activated tension development in single adult cardiac myocytes. Downregulation of the Na(+)creatine cotransporter in failing human myocardium and in experimental heart failure. Telomerase reverse transcriptase promotes cardiac muscle cell proliferation, hypertrophy, and survival. Episodic exposure to fine particulate air pollution decreases circulating levels of endothelial progenitor cells. Review of cardiovascular effects of fluoxetine, a selective serotonin reuptake inhibitor, compared to tricyclic antidepressants. Arteriosclerotic plaque development is "promoted" by polynuclear aromatic hydrocarbons. Alcoholic cardiomyopathy: incidence, clinical characteristics, and pathophysiology. Comparison of the fluoroquinolones based on pharmacokinetic and pharmacodynamic parameters. Doxorubicin induces senescence and impairs function of human cardiac progenitor cells. Effects of chronic ethanol administration on free radical defence in rat myocardium. Cardiac arrhythmias and antiarrhythmic drugs: recent advances in our understanding of mechanism. Role of hypoxia-induced bax translocation and cytochrome c release in reoxygenation injury. Kinetic, thermodynamic, and developmental consequences of deleting creatine kinase isoenzymes from the heart. Daunorubicin-induced apoptosis in rat cardiac myocytes is inhibited by dexrazoxane. Sodium- and calcium-dependent steps in the mechanism of neonatal rat cardiac myocyte killing by ionophores. Disruption of mitochondrial calcium homeostasis following chronic doxorubicin administration. Cardiovascular risk associated with celecoxib in a clinical trual for colorectal adenoma prevntion. Microvascular and mitochondrial dysfunction in the female F1 generation after gestational TiO2 nanoparticle exposure. Long-term air pollution exposure and acceleration of atherosclerosis and vascular inflammation in an animal model. Time course of the apoptotic cascade and effects of caspase inhibitors in adult rat ventricular cardiomyocytes. In vivo vascular damage, leukocyte activation and inflammatory response induced by beta-amyloid. Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension. Exposure to traffic and left ventricular mass and function: the Multi-Ethnic Study of Atherosclerosis. Clinical, clinicopathologic, and pathologic alterations in acute monensin toxicosis in cattle. Effect of intravenous aminophylline on plasma levels of catecholamines and related cardiovascular and metabolic responses in man. Metallothionein inhibits doxorubicininduced mitochondrial cytochrome c release and caspase-3 activation in cardiomyocytes. Alcohol-induced myocardial fibrosis in metallothionein-null mice: prevention by zinc supplementation. Cardiac muscle cell hypertrophy and apoptosis induced by distinct members of the p38 mitogen-activated protein kinase family. Are myocardial fibrosis and diastolic dysfunction reversible in hypertensive heart disease Absence of pressure overload induced myocardial hypertrophy after conditional inactivation of Galphaq/Galpha11 in cardiomyocytes. Cytoprotective role of Ca2+-activated K+ channels in the cardiac inner mitochondrial membrane. Lead perturbs the regulation of spontaneous release of tissue plasminogen activator and plasminogen activator inhibitor-1 from vascular smooth muscle cells and fibroblasts in culture. Reperfusion-activated Akt kinase prevents apoptosis in transgenic mouse hearts overexpressing insulin-like growth factor-1. Apoptosis in relevant clinical situations: contribution of apoptosis in myocardial infarction. Tissue-specific pattern of stress kinase activation in ischemic/reperfused heart and kidney. High-glucose stimulation increases reactive oxygen species production through the calcium and mitogen-activated protein kinase-mediated activation of mitochondrial fission. Mitochondrial fission mediates high glucose-induced cell death through elevated production of reactive oxygen species. Cumulative and irreversible cardiac mitochondrial dysfunction induced by doxorubicin. Propofol-induced alterations in myocardial beta-adrenoceptor binding and responsiveness. Calcineurin plays a critical role in the development of pressure overload-induced cardiac hypertrophy. Although substantial reduction in the reported incidence has occurred in recent years due to better workplace environments and personal protective equipment, further improvements in prevention and management are clearly needed. Skin conditions resulting from occupational or consumer exposures not resulting in lost work are poorly recorded. Previously, inhalation exposures were thought to produce the most risk to workers, with skin exposure being only a secondary pathway. The new notations utilize these categories to designate hazard specific skin exposures, and have incorporated standardized criteria to allow for consistency in how chemicals are designated. Determining the hazard potential of a particular chemical is based upon physicochemical properties of the substance, toxicokinetic studies, epidemiological data, in vitro or in vivo laboratory testing, and in silico computational predictions. Its biochemical properties allow it to perform a myriad of functions beyond that of barrier. Physiologically, the skin participates directly in thermal, electrolyte, hormonal, metabolic, antimicrobial, and immune regulation. Rather than merely repelling noxious agents, the skin may react to them with a variety of defensive mechanisms preventing widespread cutaneous and/or internal injuries. If an insult is severe or sufficiently intense to overwhelm the protective function of the skin, acute or chronic injury manifests in various ways. The specific presentation depends upon a variety of intrinsic and extrinsic factors (Belsito, 1989) including body site, duration of exposure, other environmental conditions, and the physicochemical properties of the insult (Table 19-1). In addition, epidermal appendages (hair follicles, sebaceous glands, and eccrine glands) span the epidermis and embed into the dermis. In thickness, the dermis comprises approximately 90% of the skin, and largely has a supportive function. It has a high content of collagen and elastin secreted by fibroblasts, thus providing the skin with resilience and elasticity. Separating the dermis from underlying tissues is a layer of fat (adipocytes), whose accumulation of lipids has a cushioning and thermoregulatory action. The blood supply to the epidermis originates in the capillaries located in the rete ridges at the dermoepidermal junction. Capillaries also supply the bulbs of the hair follicles and the secretory cells of the sebaceous and eccrine glands. The ducts from the eccrine glands carry a dilute salt solution to the surface of the skin, where its evaporation provides thermoregulation. The interfollicular epidermis is stratified squamous epithelium consisting primarily of keratinocytes. These cells are tightly attached to each other by desmosomes and to the basement membrane by hemidesmosomes. Melanocytes, whose melanin granules give the skin its color, are interspersed among the basal cells and distributed in the papillae of hair follicles. Migrating through the epidermis are numerous Langerhans cells, which are dendritic, antigen presenting cells involved in the immune response of skin to foreign xenobiotics. When a basal cell divides, one of the progeny detaches from the basal lamina and migrates upwards. As cells move toward the skin surface, they undergo a programmed terminal differentiation, gradually expressing new protein markers, and accumulating keratin proteins. These keratins form insoluble intermediate filaments, which account for nearly 40% of the total cellular protein in the spinous layer of the epidermis. At the granular layer of the epidermis, keratinocytes undergo a striking morphological transformation, becoming flattened and increasing in volume nearly 40-fold. Lipid granules fuse with the plasma membrane at the granular layer/stratum corneum interface, filling the intercellular spaces of the stratum corneum with lipid, as opposed to the aqueous intercellular environment of the underlying viable epidermis. These surface lipids perform a variety of defensive functions, both in preventing diffusion of water and ions out of the body, and preventing access of toxicants and bacteria into the skin (Elias, 2005). Meanwhile, the plasma membranes of the now moribund keratinocytes become permeable, lose their reducing environment, and undergo extensive disulfide bonding of the keratin proteins.

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The lifelong exposure of both males and females in the F1 generation fungus gnats damage cheap sporanox 100 mg line, which allows one to detect effects induced in utero fungus roses buy sporanox 100mg free shipping, during lactation fungus gnats diatomaceous earth buy sporanox online now, or from direct exposure after puberty fungus eye discount 100mg sporanox visa, can confound the identification of when the effect was induced fungus gnats walls cheap sporanox 100 mg otc. In studies fungus underarm buy 100 mg sporanox amex, where the dosing period normally is terminated near birth or at weaning, precludes misinterpretation of the developmental origin of reproductiveeffects. Testing should be tailored based on the pharmacological activity demonstrated in T1S. Collins, 2006 for specific study descriptions) although any permutation or specific design is open to the investigator to explore specific toxicity based on the pharmacology of the drug tested. Males can be necropsied for the endpoints noted above for the multigeneration studies after pregnancy has been confirmed, and for the pregnant females, necropsy takes place any time after mid-gestation. As with the multigeneration study, reproductive and target organs are weighed and examined histologically, sperm parameters are assessed in males and in females, the uterine implantation sites and ovarian corpora lutea are counted, as well as live and dead embryos. In this study design, the selection of the dosing regimen for males has been based on pragmatism in attempting to shorten the study, rather than the biology of spermatogenesis in the test species (as employed in the multigeneration study). It is thought that the majority of chemicals that might affect the male should be detectable (by histology) after 4 weeks exposure; however, there are a number of exceptions to this notion. One of the significant advantages of the pharmaceutical guideline approach is that the investigator is encouraged to tailor their testing protocols to reflect the best science and available knowledge. One potential disadvantage is that the basic approach does represent a theoretical "gap" as some chemicals may not manifest a testis histological lesion in 4 weeks and also there is a potential disassociation of structure (testis histology and sperm parameters) from function (male breeding performance). Aftercessationofexposure, selected offspring (one male and one female per litter) are raised to adulthood and then mated to assess reproductive competence. In addition, sensory function, reflexes, motor activity, learning, and memory are also evaluated. This study tests for enhanced toxicity relative to that noted in pregnant females and unlike the previous two studies is normally conducted in two species (typically the rat and rabbit). At necropsy, dams are observed for any affected organs and corpora lutea are counted. Live and dead fetuses are counted and examined for external, visceral, and skeletal abnormalities. In the evaluation of prenatal developmental toxicity for a pesticide or other chemical. The tool is used in a tiered manner consisting of three sections: (1) methods applicable to all datasets, (2) approaches applicable only to datasets without evidence of reproductive and developmental toxicity, and (3) approaches applicable to datasets with positive indications of reproductive and/or developmental toxicity. This integration would provide one of three summary risk conclusions that would be applied to the drug label namely-(1) not anticipated to produce reproductive and/or developmental effects above the background incidence for humans when used in accordance with the dosing information on the product label; (2) the drug may increase the incidence of adverse reproductive and/or developmental events, or (3) that the drug is expected to increase the incidence of adverse reproductive and/or developmental effects in humans when used according to the product label. However, there has been significant interest in the safe use of pharmaceuticals in pediatric populations, and unlike the more standard reproductive and developmental studies, specific studies on juvenile animals are usually performed on a case-by-case basis. Newer Guidelines and Approaches the International Life Sciences Institute sponsored a new endeavor looking at how agricultural chemicals might be assessed for toxicity, including reproductive toxicity in a proposed life stage approach (Cooper et al. This approach incorporated many of the changes made more recently to testing guidelines (including extra endocrine-related endpoints) and attempted to streamline the testing of agrochemicals for toxicity. The life stages protocol was one of a tiered set of proposed studies, such that all data available could be incorporated into the study design and interpretation of the data. The approach was very laudable, in that it proposed (unfortunately only as an option) incorporation of toxicokinetic data generated during pregnancy and lactation into the study design, as has long been required in drug testing, to aid study design and data interpretation. In addition, endpoints evaluating (at least to some degree) developmental neurotoxicity and developmental immunotoxicity would be measured as a standard, rather than as a triggered option. Its major aim was to reduce the number of animals required and increase the information available on young animals. The study would seek to be a substitute for the current multigeneration study in most instances. The proposal does offer the opportunity to undertake a classical multigeneration study in a second tier, but only if an adverse event was found in the Tier 1 study. Thus, a negative in the extended one-generation study could mean a halt to testing for reproductive toxicity. Estimates are made of the standard litter parameters and reproductive performance of the F0 parents, but in this design the study halts at the weaning of the F1 offspring and no estimate is made of effects on adult F1 offspring, or on the ability of this generation to reproduce. This study design provides critical information on parental reproductive effects, but has very limited information on the offspring aside from pup number, growth, and survival to weaning, and thus has limited utility in the estimation of transgenerational effects, or postnatal reproductive consequences. It is proposed to be used for all chemicals (not just pesticides), where a much reduced toxicity database is likely to be available. As our knowledge of critical windows of exposure has increased, particularly with the increased focus on chemicals that may have endocrine-like activity, the last 15 years has shown the need for a study where there has been a larger focus on the evaluation of potential postnatal adverse outcomes. Thus, there have been updates to standard designs to incorporate more functional endpoints. For example, in an evaluation of prenatal developmental toxicity, every fetus is examined for potential abnormalities (typically ~250 fetuses per group) whereas in the multigeneration study, only one male and female pup per litter from a minimum of 20 litters is examined at adulthood for adverse pathological events. Before embarking on such a study, it would be customary to undertake a preliminary study that evaluated target organ toxicity (for a conventional cancer study, this would be the 90-day toxicity study) and enabled suitable dose levels to be selected for the cancer bioassay. It became apparent that this basic design could easily be adapted to provide more detailed information on reproduction and development, as well as all the necessary information to select dose levels for the cancer study. Thus, there would be a gain in information on a greater array of toxicity endpoints and maximize the utility of the animals that had already been produced and raised to weaning, such that the other, "stand-alone" reproduction and developmental toxicity studies would not be required. At weaning (usually postnatal day 21 in the rat), the offspring would be continued to be administered the test article at the same dose level as their respective dam and are subsequently assigned to a number of different cohorts that can be considered as interchangeable "cassettes" that can be included, or not, based on the objectives of the study, or other available information. Justpriortoexpecteddelivery,aCesareansectionwould be performed on the pregnant dams for a standard evaluation of external, visceral, and skeletal abnormalities of the fetuses. Power curves for the detection of offspring abnormalities with low background incidence (20 litters, 0% background). Thepregnant dams would be allowed to deliver their litters and raise them to weaning. On a specific case basis, other cassettes could be added, or substituted, in the protocol, including an assessment of developmental immunotoxicity and/or developmental neurotoxicity, using other standard guideline protocols. The study would normally be conducted in the rat with a sufficient number of time-mated animals acquired to ensure a minimum of 20 litters per dose group with normally three dose levels, plus a vehicle control. A major addition will be the information achieved on prenatal developmental toxicity. The teratology and littering cohorts of animals allow the evaluation of fertility and fecundity and importantly, to maintain the relationship between structural changes in the reproductive organs and functional outcomes in the same animals. In addition, the design will be able to maintain a 10-week exposure period prior to mating of the F1 animals to ensure that any potential male germ cell effects could be reflected in a functional outcome. Some of these issues include: (1) a truncated exposure period before breeding the F0 animals that will only produce functional effects in males if the chemical under investigation affects epididymal sperm; (2) a failure to routinely breed F1 animals and so not provide a full characterization of this unique exposure group; (3) the employment of internal triggers to make decisions on when breeding of the F1 generation, or utilization of specific cohorts of animals, will occur. In particular, the triggers to be employed do not take into account the timing for the production of data from the various components of the study, to make informed decisions on whether to apply triggers, or not; (4) the adverse structural changes will not be related to functional outcomes in the same animals if the triggers are not applied correctly; and (5) the developmental neurotoxicity cohort is underpowered with only 10 animals/sex/group evaluated and has no assessment of learning and memory. However, there is built-in redundancy in the number and type of endpoints evaluated in these studies that could indicate male, female, or effects on both sexes during testing. The following examples give an outline of the types of endpoints evaluated typically in rat multigeneration studies (the species most commonly used for reproductive toxicity evaluations). For example, did histological changes at one dose level become decrements in litter size and then reductions in fertility at higher dose levels in any generation Likewise, findings in an F1 generation animal may (or may not) be reproduced in F2 offspring. For example, effects in the F1 generation on reproductive parameters may have resulted in the selection out of sensitive animals in the population, thus not producing F2 offspring for subsequent evaluation. The first primary indication of a decrement in reproduction is obtained from the inspection of litter parameters from a breeding and determination of any functional effects. Thus, it is normal to inspect for various treatment groups versus the control, the number of fertile pairings, the mean litter size, pup weight at birth (small litters tend to have higher pup weights), and the sex ratio (to determine if there is a selective effect on any one sex). In the parental females, there should also be an evaluation of potential maternal toxicity that may or may not impact on the reproductive performance of these animals; these measures are crude and usually restricted to body weight, food consumption, and clinicalsigns. Chemicals with progestin-like activity may also produce midgestational bleeding observable on the fur/or in the cage. These data are not as definitive for pre- versus postimplantation loss as in the developmental toxicity study because the female will begin to cycle around postnatal day 15 and have representative corpora lutea from both the pregnancy and the new ovarian cycle(s). Some care needs to be used in the impact of other toxicity on these pubertal parameters, and it is usual to normalize based on bodyweight. However, timing of puberty should not be normalized by body weight at acquisition of puberty (since a delay will invariably mean that the females are larger compared to controls and vice versa for acceleration). Instead, it is more likely that the investigator would employ weight at weaning as a covariate in the analysis of these pubertal endpoints. As the female matures, estimates will be made of estrous cyclicity particularly if they are normal or abnormal (a rat normally has a 4- to 5-day cycle) and the duration of the cycles. Vaginal smears are also noted during mating, and the presence of a sperm positive smear would indicate a successful mating that provides at least some surrogate of normal reproductive behavior from the breeding pair. At necropsy of the adult F1 female, weights and histopathology would be undertaken on critical organs. Histopathology of the ovary is not straightforward and some guidelines require the evaluation of primordial follicle counts in step sections of the ovary. However, such an examination provides only limited information on one type of follicle and it is essential that the pathologists make their evaluation with regard to the normal expected patterns of the different follicular types (from primordial to antral) and when necessary undertake quantitative analysis to confirm an effect on ovarian follicular development. In the parental males, similar types of evaluation are available to the investigator with regard to potential parental toxicity. Decreases in fertile pairings and litter size may be equally applicable for the detection of a male effect. The presence of a sperm positive smear in the female is indicative that the male has successfully mounted and mated with the female (note the presence of a copulatory plug is not the same because these may be formed from accessory sex organ fluids in the absence of sperm). Males going through puberty can be estimated using the date of balanopreputial separation of the penis as an index. This androgen-dependent endpoint in the male is also corrected for growth, but the same caveats used for the female around normalization of data would apply to this male measurement. Decrements of ~10% body weight are normally without significant effect on male or female puberty indices (Carney et al. As the male matures and is bred with a female, observation of the precoital interval (the time between pairing and evidence of mating) can indicate treatmentrelated effects on mating performance or behavior. However, it should be noted that if the female is at a random stage of estrus when introduced to the male, she may not allow mating until estrus is attained. Thus, delays of more than 4 to 5 days in precoital interval should be carefully examined. Once a pregnancy has been achieved and there is no requirement for further matings, the parental male is necropsied and organ weights and histological examination conducted usually of the testis, epididymis, prostate, seminal vesicles, and pituitary (and perhaps adrenal as for the female as another steroidogenic organ). Although quantitative analysis of stage frequency is rarely required (and not useful in longer term studies), the noting of specific stages that may show a predilection for injury is most helpful, as is an appreciation of the different cellular associations within the seminiferous tubule, which is essential in the detection of more subtle testicular effects. At necropsy, a number of quantitative estimates can be made of sperm production and function. These can include testicular spermatid counts following homogenization (this endpoint entails destruction of one testis and has to be balanced with the information obtained from histopathology). A sperm sample is also taken from the vas or cauda epididymis for examination of sperm concentration, motility, and morphology, which can be examined using manual methods. More often, computer-assisted sperm analysis is used to evaluate these sperm endpoints and in addition further parameters can be collected, such as forward progressive motility, which is believed more closely related to fertility. Frequently, whole cauda epididymal sperm counts are also evaluated and normalized by weight. Evaluation of male and female offspring follows the schema outlined above for adults and for animals going through puberty. In the normal male rat fetus, the presence of androgen around gestation day 17 causes the anlagen for the nipples to undergo apoptosis and thus males are born without nipples whereas females have the full complement of 12. The presence of an antiandrogen in males or an androgen in females would upset this balance to produce nipple retention in the males and a reduced number in the females reflective of the androgen status of these animals at critical periods of development. Some assessment must also be made of general growth of the offspring (usually bodyweight). For example, a selective effect during in utero exposure of F1 on the mammary gland would show the F1 population as being normal with regard to reproduction, but when the F1 animal becomes a parent, it cannot raise the F2 adequately because of a mammary effect. In this instance, there would be a more profound influence on the F2 than the F1 litters. There may also be an increase in the severity of the type of lesion with the full constellation of the effects only noted at the highest dose level. Thus, for example, a single compound may produce a subtle effect on testis histology at low-dose levels. As the dose level increases, this lesion may become more severe, with pathology noted in the epididymis, which in turn may affect semen parameters that result in a decrease in litter size and as the dose increases further, to a reduction in the number of fertile pairs. Thus, there is a continuum of effects, that may be shown by a chemical producing reproductive toxicity that are interrelated and become important in selecting appropriate effect dose levels and therefore those exposures that maybe without effect. Effects of the androgenic growth promoter 17-beta-trenbolone on fecundity and reproductive endocrinology of the fathead minnow. Temporal changes in biological responses and uncertainty in assessing risks of endocrine-disrupting chemicals: insights from intensive time-course studies with fish. Consistency Across Generations the F0 reproductive parameters can differ markedly from those noted in the F1 and similarly from the F2 generation in a multigeneration study. Because exposure in a multigeneration study typically starts with the F0 generation as young adults, critical periods of reproductive development have already taken place. In the F1 generation where exposure is from conception to adulthood, when these animals were bred at the same dose, only 19/20 pairings resulted in a litter and thus the effects on reproduction were significantly enhanced in the F1 generation and illustrate the importance of breeding the F1 animals to detect functional effects on the offspring due to in utero exposure. However, since one normally only takes one male and female from each litter to generate the F1 and F2 parents, it is distinctly possible that a selection bias can exist. Conceptevaluation:anassay for receptor-mediated and biochemical antiestrogens using pubertal rats.