Steven J. Kalbfl eisch, MD, FACC

  • Medical Director of Cardiac Electrophysiology
  • Professor of Clinical Medicine
  • Cardiovascular Medicine
  • The Ohio State University Medical Center
  • Columbus, Ohio

Changes in yolk platelet pH during Xenopus laevis development correlate with yolk utilization hiv infection by needle stick order 800mg zovirax visa. Yolk platelets in Xenopus oocytes maintain an acidic internal pH which may be essential for sodium accumulation stage 1 hiv infection timeline generic zovirax 800 mg with visa. Evidence that cathepsin L-like proteinase is stored as a latent hiv infection rates in the world buy generic zovirax, acid-activable proenzyme hiv infection rates by state purchase zovirax with visa. Release of ovoperoxidase from sea urchin eggs hardens the fertilization membrane with tyrosine crosslinks hiv infection rate ukraine generic zovirax 200 mg without a prescription. This preliminary survey now enables us to better understand the influence of genome dynamics and evolution on reproduction and development in this basal deuterostome antiviral herpes zovirax 200 mg on-line. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10. Characterization of yolk platelets isolated from developing embryos of Arbacia punctulata. Molecular cloning of the first metazoan beta-1,3 glucanase from eggs of the sea urchin Strongylocentrotus purpuratus. Hierarchies of protein cross-linking in the extracellular matrix: involvement of an egg surface transglutaminase in early stages of fertilization envelope assembly. Transferrin in the developing ovarian follicle: evidence for de-novo expression by granulosa cells. The major yolk protein in sea urchins is a transferrin-like, iron binding protein. Molecular characterisation of ovarian cathepsin D in the rainbow trout, Oncorhynchus mykiss. Molecular cloning, characterization, and expression in brain and gonad of Dmrt5 of zebrafish. Proteolytic cleavage of the cell surface protein p160 is required for detachment of the fertilization envelope in the sea urchin. Hardening of the sea urchin fertilization envelope by peroxidase-catalyzed phenolic coupling of tyrosines. The major yolk glycoprotein precursor in echinoids is secreted by coelomocytes into the coelomic plasma. Identification and characterization of proteases involved in specific proteolysis of vitellogenin and yolk proteins in salmonids. Gene families encoding transcription factors expressed in early development of Strongylocentrotus purpuratus. Mice null for Frizzled4 (Fzd4-/-) are infertile and exhibit impaired corpora lutea formation and function. Growth differentiation factor 9 and bone morphogenetic protein 15 are essential for ovarian follicular development in sheep. Analysis of changes in a yolk glycoprotein complex in the developing sea urchin embryo. Molecular characterization of putative yolk processing enzymes and their expression during oogenesis and embryogenesis in rainbow trout (Oncorhynchus mykiss). Sea urchin ovoperoxidase: oocyte-specific member of a heme-dependent peroxidase superfamily that functions in the block to polyspermy. Developmentally regulated proteolytic processing of a yolk glycoprotein complex in embryos of the sea urchin, Strongylocentrotus purpuratus. Positional cloning and characterization of Mei1, a vertebrate-specific gene required for normal meiotic chromosome synapsis in mice. Proteolysis of the major yolk glycoproteins is regulated by acidification of the yolk platelets in sea urchin embryos. Intercellular communication in the mammalian ovary: Oocytes carry the conversation. Expression patterns of four different regulatory genes that function during sea urchin development. Ultrastructure of the proteoliaisin-ovoperoxidase complex and its spatial organization within the Strongylocentrotus purpuratus fertilization envelope. Centriole behavior during meiosis in oocytes of the sea urchin Hemicentrotus pulcherrimus. Acidification of yolk granules in Blattella germanica eggs coincide with proteolytic processing of vitellin. Specific proteolysis regulates fusion between endocytic compartments in Xenopus oocytes. A glycoprotein in the accessory cells of the echinoid ovary and its role in vitellogenesis. Growth differentiation factor 9 regulates expression of the bone morphogenetic protein antagonist gremlin. A protein identical to the yolk protein is stored in the testis in male red sea urchin, Pseudocentrotus depressus. Nutritive phagocyte incubation chambers provide a structural and nutritive microenvironment for germ cells of Strongylocentrotus droebachiensis, the green sea urchin. Potential role in development of the major cysteine protease in larvae of the brine shrimp Artemia franciscana. Assembly of the sea urchin fertilization membrane: isolation of proteoliaisin, a calcium-dependent ovoperoxidase binding protein. Functions of mammalian Smad genes as revealed by targeted gene disruption in mice. A molecular analysis of hyalin-A substrate for cell adhesion in the hyaline layer of the sea urchin embryo. Developmentally regulated and non-sex-specific expression of autosomal dmrt genes in embryos of the Medaka fish (Oryzias latipes). Major components of a sea urchin block to polyspermy are structurally and functionally conserved. Rendezvin: an essential gene encoding independent, differentially secreted egg proteins that organize the fertilization envelope proteome after self-association. The oxidative burst at fertilization is dependent upon activation of the dual oxidase Udx1. Synergistic roles of bone morphogenetic protein 15 and growth differentiation factor 9 in ovarian function. Molecular cloning and functional characterization of chicken cathepsin D, a key enzyme for yolk formation. Selective resorption in nutritive phagocytes of the sea urchin Anthocidaris crassispina. An ultrastructural study of phagocytosis and shrinkage in nutritive phagocytes of the sea urchin Anthocidaris crassispina. A functional genomic and proteomic perspective of sea urchin calcium signaling and egg activation. Vitellogenin receptors: oocyte-specific members of the low-density lipoprotein receptor supergene family. Structure of a major yolk glycoprotein and its processing pathway by limited proteolysis are conserved in echinoids. Involvement of the lysosomal system in yolk protein deposit and degradation during vitellogenesis and embryonic development in trout. Comparative biology of calcium signaling during fertilization and egg activation in animals. Nobox is a homeobox-encoding gene preferentially expressed in primordial and growing oocytes. Mouse embryos lacking Smad1 signals display defects in extra-embryonic tissues and germ cell formation. Cloning, deduced protein sequence, expression during the life cycle, gene localization and upregulation on bacterial infection. Sequence analysis and neuronal expression of fasciclin I in grasshopper and Drosophila. Movement of a new gene (gene 7) into the region from an unlinked chromosomal location. All types of rearrangements are observed, including small inversions, deletions, duplications, and long-distance movements to new chromosomal locations. In a comparison of orthologous adh regions of rice, sorghum, and maize, for instance, four genes were inserted into the adh region in the ancestral lineage that gave rise to sorghum. One of these was a two-gene insertion that occurred prior to the divergence of maize and sorghum ancestors. The other two were insertions of a single gene from unlinked chromosomal locations into adjacent positions after the divergence of maize and sorghum lineages (Ilic et al. We also do not know the origins of specific events that caused small inversions, gene deletions, or gene duplications in plants, but unequal recombination is a candidate. For a single-gene inversion found near the barley Vrn1 homologue, Ramakrishna and coworkers observed two highly degenerate flanking transposable elements of the same family in inverted orientation (Ramakrishna et al. Intrastrand unequal recombination between these elements would have led to just such an inversion. Similarly, unequal recombination between flanking direct repeats or directly repeated gene family members can give rise to the frequent gene duplications and deletions found for all genes, but especially in tandem gene families. Figure 2 provides a summary of the events that can alter gene order and content in specific small regions of a plant genome. Now that we know that local genome rearrangement is an aggressive and ongoing process in plants, it becomes clear that we need to know much more about it. What are the precise mechanisms that dominate genome rearrangement in any given genome context Are there periodicities in the generation of rearrangements, and might these be caused by particular environmental inputs For all of these questions, are there lineage-specific differences in the answers Last, and perhaps most important, what effects do these local rearrangements have on gene and genome function This same lack of sensitivity to chromosomal environment has been observed for the majority of other plant genes, indicating that chromosomal rearrangement has surprisingly little influence upon gene expression. Much of this resistance to position effect in plants is probably epigenetic, as shown by the sudden transcriptional alterations that can occur after epigenetic balance is disturbed (Kashkush et al. Moreover, so many rearrangements occur that it seems likely that even a low frequency of biological significance to individual events will eventually be swamped by rare events that affect gene function. A prime example of this is the insertion of a transposable element into a promoter region, thereby providing the raw material for the evolution of new regulatory properties (reviewed in Wessler et al. In summary, local genomic rearrangement is a continuous and highly active process in seed plant genomes. However, we need much more information to determine the relative frequencies of different classes of rearrangement, whether they differ between plant lineages, and the biological outcomes of these rearrangements. The youth of these elements is misleading, however, because their ubiquity and the great divergence of active elements indicate that their origin only slightly postdates the origin of eukaryotes. Future studies will need to determine whether differences in genome size in any particular lineage are caused by an unusually low or high rate of transposable element amplification or by differences in the mechanisms of transposable element removal. Similarly, Kirik and colleagues (2000) have shown that double-strand breaks are more commonly resolved with insertions and less commonly with deletions in tobacco, a plant with a relatively large genome, than in Arabidopsis. Lynch and Conery (2003), working with a large sample of prokaryotes and eukaryotes, showed clearly that genome size is negatively correlated with the parameter Ne, which is the product of the effective population size and the mutation rate per nucleotide. Because the range of mutation rates is rather narrow, variation in this parameter generally reflects variation in population size. Vinogradov (2003) found a similar result in angiosperms, by comparing genome size in rare angiosperms with that of more common species. There was no correlation, however, with life history, a result also found for species of Hordeum (Poaceae; Jakob et al. In some clades of Hordeum, annual species had smaller genomes than perennials, whereas the relationship was reversed in other clades. This inference of fluctuation is expected in part because they used both parsimony and squared-change parsimony to estimate ancestral states. Both methods assume that increasing and decreasing values are equally likely, the latter giving the equivalent of a Bayesian reconstruction that assumes a Brownian motion model of evolution of the character (Maddison, 1991) and that Brownian motion is ``infinitely jiggly' (Felsenstein, 2004, p. For example, Bennetzen and Kellogg (1997) reconstructed ancestral genome sizes under both the Brownian motion model and a model in which genomes could only get bigger. Not surprisingly, the reconstructions were sensitive to the underlying model of character state change. Sampling is more comprehensive than in our previous study (Bennetzen and Kellogg, 1997) but remains heavily biased toward subfamily Pooideae (all taxa derived from the common ancestor of Nardus and Aegilops). We retrieved 1C values for all diploid grasses and outgroups from Cyperaceae and Juncaceae from the Angiosperm C-values Database (Bennett and Leitch, 2003). Lygeum spartum (2n 40) and Deschampsia antarctica (2n 26) are listed as diploids but almost certainly are polyploid based on their chromosome numbers; they were therefore excluded. For monophyletic genera with more than one species, we calculated the average 1C value. If, however, more than one chromosome base number was present, we calculated the average value for each base number separately. This assumes that each chromosomal group within a genus is monophyletic, which is in fact unlikely. However, phylogenetic trees are not available for many of the individual genera in the tree. Averaging chromosome numbers within a genus therefore seemed a reasonable compromise between illustrating variation vs. Because Festuca is paraphyletic and contains Lolium, we used an average value for Lolium, but then treated each clade of Festuca separately following the molecular cladogram presented by Catalan et al.

It is expected that all institution inventories and ordering procedures will be conducive to acceptable inventory practices antiviral drug for herpes discount zovirax uk. This may be prompted by consistent failure of the institution staff to appropriately initiate or complete all elements of the non-formulary request does hiv infection impairs humoral immunity buy zovirax 200mg online, particularly the required supporting documentation hiv infection of the mouth cheap 800 mg zovirax with amex. An allowance is given to dispense/administer a non-formulary medication for four days while waiting for nonformulary approval antiviral spices cheap zovirax amex. This provision is not a substitute for adequate follow up antiviral questions purchase genuine zovirax, monitoring hiv infection probability buy zovirax 200mg line, and initiation of non-formulary medications for patients maintained within the facility for chronic ongoing conditions. Epinepherine Auto-injector (Epipen): Epipen may be issued to inmates with known anaphylaxis utilizing the procedure outlined below. The inmate will present the Epipen at pill line every day to insure the seal is intact and that no manipulation has occurred. Medical Center Only A restriction placed on some medication requiring that the use of this drug only be within a Federal Medical Center. There are some medications that are designated as directly observed therapy only for certain indications (see details). Page 7 of 46 Placebos - Statement on Use Placebos will not be utilized within the Federal Bureau of Prisons. This responsibility is deferred to the local level due to the varying missions of our institutions. The pharmacy and therapeutics committee at each institution shall determine which additional medication(s) items are restricted to directly observed therapy. Health care professionals may also place specific patient orders on directly observed therapy. Page 10 of 46 Non-Formulary Clinical Criteria/Justification Requirements, Algorithms, and Treatments Acitretin (Soriatane) 1. Evidence (with specific examples) of inability to function in the correctional environment. Contingent to formulation compatibility, stimulant medications will be crushed prior to administration. Drug induced extrapyramidal reactions not responsive to trihexyphenidyl or benztropine. Antiepileptic Medications: ethosuximide (Zarontin), felbamate (Felbatol), zonisamide (Zonegran) Approval of any non-formulary antiepileptic medications will be considered on an individual basis. Please be aware that many of the antiepileptic agents have potentially life- threatening side effects under certain conditions, or in some individuals. Antifungals - Oral for onychomycosis: itraconazole (Sporanox), ketoconazole (Nizoral), griseofulvin, fluconazole (Diflucan), terbinafine (Lamisil) 1. Onychomycosis requests meeting criteria will be approved for terbinafine (Lamisil) 250 mg daily for 6 to 12 weeks for fingernails or toenails respectively. Patients taking antipsychotic medication with extrapyramidal symptoms not responsive to benztropine and trihexyphenidyl (diphenhydramine and hydroxyzine only). Chronic idiopathic urticaria (consider other formulary H2 blockers such as doxepin). Ascorbic Acid (Vitamin C) Concomitant administration with an imidazole antifungal agent to improve bioavailability by increasing stomach acidity. Patients should have a recent glycosylated hemoglobin (hemoglobin A1C or HbA1C) less than 8. The wound must have an adequate blood supply measured by Oscillometry (at least 2 units), transcutaneous oxygen pressure (TcpO2 >30 mm Hg) or bleeding with debridement. Control of severe agitation in psychiatric patients When lack of sleep causes an exacerbation of psychiatric illness Part of a prolonged taper schedule Detoxification for substance abuse Failure of standard modalities for seizure disorders (4th line therapy) Long-term use for terminally ill patients for palliative care. Nausea and Vomiting in Oncology Treatment Patients (Lorazepam only) Brimonidine 0. Request for its non-formulary use requires completion of the "Donepezil Non- formulary Use Criteria Algorithm" form. Page 15 of 46 Clonazepam long-term use - See Benzodiazepines Clonidine (Catapres) 1. Dose taper over 2 to 4 days for arriving inmates taking greater than 1 mg per day. These effects generally appear within two to three hours after the first missed dose. This potential may be exacerbated after administration of higher doses or continued concurrent therapy with a beta-blocker. If a patient is taking clonidine concurrently with a beta-blocker, it is best to gradually withdraw the beta blocker, then withdraw the clonidine over two to four days. Cyclobenzaprine (Flexeril) - See Muscle Relaxants Cyclosporine ophthalmic emulsion 0. Failed appropriate duration of carboxymethylcellulose (Celluvisc) containing ocular lubricants via approved non-formulary request. Patient does not have exclusion criteria: Uncontrolled hypertension or risk for thrombosis. Trials on multiple formulary statins to be considered before determining a patient "intolerant" to all statins and/or when considering highest tolerable statin dose. Chemotherapy primary prophylaxis for patient older than 65, poor performance status, combined chemoradiotherapy, poor nutritional status, advanced cancer, or other serious comorbidities. All of the following must be true for patient to be eligible for filgrastim treatment of hepatitis C treatmentrelated neutropenia: a. Fluticasone Oral inhaler (Flovent) Must fail two other inhaled corticosteroids with demonstrated compliance. Approved for neuropathic pain after failure of duloxetine, plus at least one other medication from the tricyclic antidepressant or antiepileptic categories. All new and renewal prescriptions require consultation with an appropriate specialist based on the disease state being treated (for example, dermatologist, gastroenterologist, or rheumatologist). Recurrent episodes of symptomatic hypoglycemia despite multiple attempts with various insulin dosing regimens. Unable to achieve glycemic control targets with the use of regular insulin, despite multiple attempts with various insulin dosing regimens. Ability to eat a meal immediately (within 15 minutes) after injecting rapid- acting insulin. Patient will be prescribed other concurrent analgesic therapies effective for neuropathic pain. Documentation of culture and sensitivity data must be submitted with non- formulary request. Approval for baclofen may be considered for intractable pain from neurological conditions, such as trigeminal neuralgia, that has been unresponsive to formulary agents. When naloxone nasal is prescribed, appropriate education on the risks and symptoms of opioid overdose and the use of naloxone must be provided to the inmate and documented in the medical record. Non-Formulary Drug requests for TamiFlu will be processed and expedited through Central Office. Partial onset seizures - well documented intolerance or insufficient response to at least two other agents. Request for its non-formulary use requires completion of the "Nutritional Supplements Worksheet". Failed maximum tolerated dose of metformin or documented contraindication to metformin. These agents may also be considered as a bridging option before resorting to surgery. Mini-Mental State Score: (Other objective measures may be utilized, such as Dementia Rating Scale, however, the same test should be used at each interval to document response to treatment). Comments: Dates: (Date): Recommendations by Institution Chief Psychiatrist or Clinical Director: +++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Approved: Disapproved: Inmate Name: Institution: Medical Director Medical Director Date: Date: Reg. Patients with severe pain must receive an appropriate evaluation to rule out causes that require urgent intervention rather than just pain management. Yes Indigent Dispense 15 days per month (no refills) only if medically appropriate. All institutions should provide a local in- service for their providers regarding the appropriate management for these situations. All patients should be scheduled for follow up with their primary care provider within several days following an episode of severe asymptomatic hypertension. May increase dose of furosemide to 40 mg if patient has documented renal insufficiency. Cardiac problems - history of heart attacks, abnormal heart rhythms, congestive heart failure, or currently having chest pain. Hepatitis C infection - currently being treated with interferon/ribavirin, with or without protease inhibitors* 12. Medications with withdrawal potential - chronic benzodiazepines, barbiturates, chronic narcotics, etc. Page 41 of 46 Guidance on Therapeutic Substitution on Intake Introduction this document provides guidance to local Pharmacy and Therapeutics (P&T) meetings that choose to adopt a process of therapeutic substitution by pharmacists for intake orders. When properly established, a therapeutic substitution program may reduce costs, prevent unnecessary non-formulary requests, increase workplace efficiency, enhance medication access, and improve inventory management. Documentation of this approval must be included in the institutional P&T minutes which are sent to Central Office. Requests for additions to the approved list may be submitted for consideration to the National P&T Meeting via the P&T mailbox. As previously noted, these substitutions must be approved by the local P&T before they are used. Process the following process will be adhered to by the pharmacist when performing therapeutic substitution of an intake medication order: 1. All notes will discontinue the non-formulary drug order and add a drug order for the equivalent drug and strength found in the below equivalency tables. Local P&T meetings should periodically review substitution procedures for quality assurance. Fluticasone Furoate Beclomethasone Budesonide Ciclesonide Flunisolide Mometasone *Formulary agent in bold. Reactions were run in triplicate, and repeated in at least 2 separate experiments. Results and discussion Transcription factors the oocyte synthesizes several unique organelles and gene products that enable it to achieve the developmental transitions. Tissues tested include ovary (red), testis (blue) and gut (gold), as well as isolated oocytes of various stages (dashed black) and eggs (standard, not shown). Transcription factors that are enriched in more than one tissue are highlighted in the merged color. Enrichment of a transcription factor in a particular tissue was determined by a 2-fold threshold comparing levels across all samples tested. Number of molecules of each transcript per egg is also shown (see above websites). Transcription factors expressed during oogenesis may be expected to have different, but overlapping, profiles compared to embryos and/or other adult tissues. We focused on factors that have putative binding sites within several oocyte gene promoters identified bioinformatically (data not shown), and factors that are in very low abundance or are completely absent in embryos (HowardAshby et al. We tested the expression of these factors in oocytes, ovary, testis, and gut from Stronglyocentrotus purpuratus. We have not found any transcription factors exclusive to one tissue, although several of the factors are remarkably enriched in the gonads. This class of factors was emphasized, since promoters of oocyte-specific genes. The remaining Fox factors are expressed in a sex-specific manner: foxO, foxJ1, and foxM are enriched in the testis, whereas foxQ2, foxN1/4, and foxX are enriched in oocytes and ovary. Of these, smad1, dsx, pitx3, atonal, and lm04, are also expressed later in embryogenesis vanbeneden. The obox genes are preferentially expressed in the gonads, but their role in gonadal development is not known. For example, unlike mammalian oocytes that share intimate cytoplasmic continuity with their surrounding follicle cells, the sea urchin oocyte develops within nutrientrich chambers established by specialized somatic epithelial cells called nutritive phagocytes (Walker et al. A clear, ultrastructural distinction is present between the germ and somatic cells within this chamber, and oocytes instead form pseudopodia that contact the nutritive phagocytes, suggesting that a true intercellular communication mechanism functions during oogenesis (Walker et al. Oocytes grow and differentiate in response to signals from the environment and from ovarian somatic cells (reviewed in Eppig, 2001; Walker et al. The Wnt signaling pathway has been implicated in mammalian ovarian development, oogenesis, and early development (Hsieh et al. Wnt4 is required for gonadal differentiation and maintenance of the female germ line in mice; animals null for Wnt4 have masculinized gonads (Jeays-Ward et al. In addition, mice null for frizzled-4, one of the Wnt signaling receptors, are infertile (Hsieh et al.

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If the therapy is effective jiangmin antivirus guard 800mg zovirax overnight delivery, the attacks become less frequent and milder in intensity hiv infection after 1 year symptoms purchase zovirax 800mg with amex. If the response is good hiv infection rates kenya cheap zovirax 200 mg amex, the medication may be tapered gradually after 9-12 months hiv infection rates among youth cheap zovirax 400 mg online. Amitriptyline in the low dose of 5-10 mg at bedtime daily is especially useful in patients who have concomitant depression hiv infection stories gay buy zovirax now. Propranolol antiviral young living oils order zovirax 800mg with amex, a beta adrenergic blocker (Chapter 18), is considered the drug of choice in patients with attacks related to stress. Oral diuretics are sometimes helpful in such cases as they counter fluid retention. Angiotensinogen, synthesised by the liver, is converted by the circulating renin from the kidney into angiotensin I, a decapeptide. Local renin-angiotensin system in the tissues exists independently of the renal-hepatic based system. It increases the peripheral resistance, prevents renal sodium excretion and modulates cardiovascular morphological structure. The direct action of angiotensin on some tissues stimulates the formation of counterregulatory substances, including vasodilating prostaglandins and nitric oxide. On the other hand, the target organs may release substances such as catecholamines, endothelin and growth factors, which may amplify the effects of angiotensin. Kinins the kinins are vasoactive polypetides released from an alpha2 globulin fraction of the plasma, termed as kininogens, by the action of enzymes termed kallikreins. The kallikreins (Kallikreas, the Greek name for pancreas) are highly specific proteases, and exist in two forms: (a) plasma kallikreins, and (b) tissue kallikreins. When this system binds to a receptor complex on the endothelial cell membrane, it gets activated to kallikrein. Tissue prekallikrein is present in epithelial or secretory cells of salivary glands, pancreas, prostate, distal nephron and human neutrophils. The activation sequence of this tissue form is not well delineated but the active tissue kallikrein acts locally near the site of its origin. Various factors such as tissue damage, infection, inflammation and allergic reactions can generate tissue kinins. In addition to kallikreins, various other serine proteases like trypsin and certain snake venoms are capable of generating kinins. They may also modulate migration of leucocytes and tissue cells that take part in the inflammatory process. In the absence of inflammation, most of the actions of the kinin are mediated through B2 receptors which are constitutive. Kinins have been incriminated in the processes of inflammatory and allergic reactions (asthma), shock, disseminated intravascular coagulation and inflammatory bowel disease. Pharmacological actions: Vessels and heart: the kinins have about 10 times the vasodilator activity as histamine. The kinins also have direct positive chronotropic and inotropic actions on the myocardium and in moderate doses, release adrenaline from the adrenal medulla. The kinins are rapidly inactivated by the plasma and erythrocyte aminopeptidases and carboxypeptidases. A high molecular weight polypeptide aprotinin, extracted from the parotid glands and lymph nodes of cattle, also present in mast cells, inhibits and inactivates kallikrein, trypsin and other proteolytic enzymes. It has been used in the treatment of acute pancreatitis, to prevent blood loss during open heart surgery and in the treatment of hemorrhage due to , hyperplasminemia (Chapter 33). They are the most potent bronchoconstrictors known and are involved in the pathogenesis of asthma. This was confirmed by von Euler (1935) who demonstrated a substance present in the extracts of human seminal fluid, which caused contraction of the isolated intestinal and uterine muscle, and vasodilatation. This substance was named as prostaglandin because of its probable origin from the prostate. They are ubiquitous both in animals and (together with the precursor oil) in various plants. Nature of the substituents in the side chain determines the type (A, B, C, D, E, F) of the eicosanoid. It has been suggested that certain constituents of onions, apples and spices such as turmeric and red peppers (red chilly) may enhance the anti-inflammatory effect of omega-3 fatty acids. Various synthetic derivatives available, however, overcome some of these limitations. Therapeutic uses of prostaglandins: (1) As abortifacients and cervical ripeners (Chapter 44). The effector phases of both natural and acquired immunity are in large part mediated by protein hormones called cytokines, which are released from a variety of cell types in response to a number of stimuli (induced secretion). These cytokines activate, modulate and control various aspects of body defence and repair. T cells produce several cytokines that serve primarily to regulate the growth, differentiation and activation of various lymphocyte populations (constitutive secretion). They activate and regulate inflammatory cells such as monocytes, neutrophils and eosinophils. Like other polypeptide hormones, the cytokines act by binding to specific receptors on the surface of target cells. Such target cells may be (1) the same cells that secrete the cytokine (autocrine action); (2) nearby cells (paracrine action); or (3) distant cells as in the case of classical hormones (endocrine action). General properties of cytokines: Cytokines are low molecular weight proteins secreted mainly by white blood cells and other cells, and are responsible for cell to cell communication. Failure of termination of their induced secretion can lead to chronic inflammatory disorders. Thus, even if small number of cells are involved in the beginning, this cascade induction leads to amplification of the biological effects and involves a larger cellular network. It is also possible that cytokines may enhance or suppress the production of other cytokines. Cytokines can also be classified into four groups according to their functions (Table 25. Both can induce the burst in neutrophils and monocytes and the associated production of free radicals, myeloperoxide and hydrogen peroxide, that play an important role in killing the invading organisms. These actions are useful in generating the inflammatory responses which help to counter the microbial infections. Although over 200 cytokines have been detected and shown to be involved in physiological functions, only a few have been shown to be clinically relevant. It is released during mast cell degranulation and is implicated in pathophysiological states including allergic inflammation, anaphylactic shock and bronchial asthma. It is also formed by eosinophils, macrophages, neutrophils, vascular endothelium and the renal medullary cells. It activates most inflammatory cells and is believed to be responsible for mobilisation of eosinophils, neutrophils and/or platelets in lungs after exposure to the allergen. Given by aerosol inhalation, it causes dose dependent broncho-constriction and inflammation of airways. Further, it also induces non-specific bronchial hyper-responsiveness in non- asthmatic subjects. A substance called Ginkgolides isolated from the extract of the tree Ginkgo biloba has been used in China for the treatment of asthma and other disorders. Its possible use in the treatment of bronchial asthma and other allergic disorders is under investigation. These are carried by afferent fibres in the vagus and sympathetic nerves to the brain stem nucleus solitarius which is connected to the respiration-related neurons in the central cough generator (cough centre), which initiates the act of coughing. C fibre receptors are chemoreceptors, highly sensitive to bradykinin, capsaicin and H ions (pH). The respiratory mucosa contains cells bearing cilia which transport the locally produced mucus towards the throat, from where it can be either coughed out or swallowed to keep the respiratory tract clean (mucociliary clearance). This mucociliary clearance can be defective or even absent in persons with immotile, dysfunctional or congenitally absent cilia. This leads to retention of secretions in the respiratory tract and recurrent respiratory infections including sinusitis and bronchiectasis. In turn, respiratory infection impairs the mucociliary clearance further, with worsening of the infection. The act of coughing involves an initial deep inspiration followed by forced expiration against a temporarily closed glottis. When the glottis opens suddenly the pulmonary air is forced, through the trachea almost at the speed of sound, throwing out the respiratory tract secretions as expectoration. The cough reflex has a tremendous reserve capacity and most coughs are greatly in excess of that required to expel particulate material. Furthermore, the strong expiration leads to a stronger succeeding inspiration and thus produces a vicious cycle in the form of a fit of coughing. Cough may be: Productive, associated with a large amount of sputum; or Non-productive, dry and usually useless. Environmental pollutants may cause cough by irritating the lungs, trachea or bronchi. Cough due to the inhalation of allergens such as dust, chemicals and pollen is commonly observed in asthmatics. The commonest cause of transient cough is common cold, and is due to postnasal drip that stimulates receptors in the upper respiratory tract. A similar mechanism probably operates in case of chronic persistent cough observed in persons with allergic rhinitis, chronic sinusitis and obstruction due to enlarged adenoids. Enlarged, infected tonsils, an abnormally elongated uvula or nasal polyps can also cause chronic persistent cough. Other important causes of cough are: Upper respiratory tract infections, which may be self-limiting or persistent. Thus, wax impacted in the ear, inflammation or eczema or even irritation of the drum by hair can cause dry cough. Only when cough serves no useful purpose and causes insomnia, or interferes with daily work, symptomatic treatment is indicated. In case of productive cough, the patient should be encouraged to cough voluntarily in appropriate posture from time to time. In cases of bronchiectasis or lung abscess, postural drainage aided by percussion of the chest is useful. Since inflamed trachea or bronchi are irritated by cold or dry air, a warm room with humid atmosphere is beneficial. Many patients with cough feel comfortable after a cup of warm tea or even warm water; and simple steam inhalation with or without tincture benzoin, menthol or eucalyptus oil effectively liquifies tenacious respiratory tract secretions (Hydroponic therapy). Cough can be: (1) Acute self limiting (less than 3 weeks); (2) Subacute (3-8 weeks) or (3) Chronic (more than 8 weeks). Acute cough such as during and after common cold is usually due to upper respiratory viral infection. Non-viral causes include environmental pollution, asthma, cough-variant asthma and occupational exposure. From therapeutic point of view, chronic cough with normal chest X-ray can be either: (a) Glucocorticoid responsive, due to eosinophilic disorders as in asthma, eosinophilic bronchitis and allergic rhinitis; or (b) Inhaled glucocorticoid resistant. Barking cough, stridor and chest wall withdrawal are characteristic of croup, common in children. Drugs used in the symptomatic treatment of cough classification: I Pharyngeal demulcents and local sialogogues. A mucoactive drug is defined as an agent with the capability of modifying mucus production, secretion, its nature and composition, or its interactions with the mucociliary epithelium. Mucoactive drugs include: (i) Expectorants: which induce cough or increase the volume of secretions. Pharyngeal Demulcents Demulcents are useful in cough due to irritation of the pharyngeal mucosa above the larynx. They act by increasing the flow of saliva, the best natural demulcent which produces a protective and soothing effect. Salivary secretion can be increased by such simple methods as using a few lemon drops, candy sugar, glycerrhiza or drops of lemon juice in a syrupy base. Costly preparations like lozenges and troches containing multiple ingredients such as menthol and antiseptics are usually unnecessary and wasteful. Expectorants are the drugs which increase the production of demulcent respiratory tract fluid that covers and protects the irritated mucosa. These drugs are useful in the treatment of useless cough due to irritation of the respiratory mucosa below the larynx and respiratory conditions in which the secretion is thick and viscid, needing liquefaction. Expectorants can stimulate the output of respiratory tract fluid either directly or reflexly (reflex expectorants). Direct stimulants: Volatile oils like oil of eucalyptus, anise and lemon, administered orally or inhaled with steam, increase the respiratory secretions probably by a direct action. Alcohol and cedar wood oil (active ingredient terpene hydrochloride), added to steam inhalation, have a similar effect. Large doses of creosote and guaiacol have also been shown to possess this action in animals; and glyceryl guaiacolate forms an important ingredient of many commercial cough mixtures. Reflex expectorants: these drugs act by stimulating the gastric reflex which helps to increase the respiratory secretions. Obviously they produce mild irritation of the gastric, mucosa and may produce nausea. Thus, emetic drugs in subemetic doses increase bronchial secretion producing a less tenacious sputum, easier to expectorate. Tincture ipecacuanha 1 ml may increase the respiratory tract fluid and lower the viscosity of the sputum. Saline expectorants: Ammonium carbonate, once, used as a saline expectorant, causes anorexia and nausea. It is generally advocated in productive cough associated with chronic bronchitis, asthma and emphysema. Potassium iodide can cause symptoms of iodism, characterised by nasal catarrh, conjunctival swelling, edema of eyelids, lacrimation, edema of the larynx, headache and various types of skin rashes.

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Significantly hiv infection no antibodies discount zovirax online amex, sirolimus is not nephrotoxic hiv infection levels buy zovirax 800mg with visa, but it can suppress bone marrow hiv infection mayo clinic buy generic zovirax 800 mg online, mainly causing thrombocytopenia antiviral drug list zovirax 200 mg sale. Dose: Initially loading dose 1 mg/m2 daily antiviral cold sore cream purchase zovirax visa, followed by titrated lower doses for maintenance antiviral botanicals cheap 200 mg zovirax with amex. The most important application of azathioprine is prevention of renal and other graft rejection, but it is less effective than cyclosporine; generally combined with it or used in patients developing cyclosporine toxicity. It may be an alternative to long-term steroids in some other autoimmune diseases as well. It has been used as a first line drug in many autoimmune diseases like rapidly progressing rheumatoid arthritis (see p. It has been particularly utilized in bone marrow transplantation in which a short course with high dose is generally given. In rheumatoid arthritis, it is rarely used, only when systemic manifestations are marked. Low doses are occasionally employed for maintenance therapy in pemphigus, systemic lupus erythematosus and idiopathic thrombocytopenic purpura. Chlorambucil It has relatively weak immunosuppressant action which is sometimes utilized in autoimmune diseases and transplant maintenance regimens. The shortlived rapid lymphopenic effect of steroids is due to sequestration of lymphocytes in tissues. The corticosteroids are widely employed as companion drug to cyclosporine or other immunosuppressants in various organ transplants. They are used in practically all cases of severe autoimmune diseases, especially during exacerbation. Longterm complications are the greatest limitations of steroid use; and it is maintenance of remission for which other immunosuppressants often prove safer. They are important recent additions, mostly as supplementary/reserve drugs for severe and refractory cases of autoimmune diseases and graft versus host reaction. It is used mostly in combination with Mtx in rheumatoid arthritis patients who fail to respond adequately to the latter (see p. It is also approved for severe/refractory ankylosing spondylitis, polyarticular idiopathic juvenile arthritis and plaque psoriasis. Both daclizumab and basiliximab can cause anaphylactic reactions and promote opportunistic infection. Consequently, antigen recognition is interfered, and participation of T-cells in the immune response is prevented. Following antibody binding, the T-cell receptor is internalized and the T-cells get rapidly depleted from blood, partly by cytolysis and partly by their migration to non-lymphoid organs. Subsequent courses are not recommended, because the first course produces antibodies against mouse protein which neutralise it. It has also been used to depletecells from the donor bone marrow before transplantation. Occasionally aseptic meningitis, intragraft thrombosis, life-threatening pulmonary edema, seizures and a shock-like state are produced. It can also be used in induction regimens, but this has the potential to produce serum sickness or anaphylaxis. Many experts do not give cyclosporine preoperatively, and try to delay its induction as far as possible to avoid nephrotoxicity, particularly in renal transplantation. If no rejection develops, the doses are gradually reduced after 2 weeks and this phase merges imperceptably with maintenance phase. Nephrotoxicity is often the limiting factor with cyclosporine/tacrolimus, while long-term steroid therapy has its own problems. Two drug and one drug regimens are also used, but are associated with more episodes of acute rejection. After 1 year, cyclosporine is generally dropped, but its continuation is associated with fewer acute rejections. If the maintenance regimen had not included cyclosporine, its addition can treat acute rejection, but can be damaging to the transplanted kidney. Anti-D immune globulin It is human IgG having a high titer of antibodies against Rh (D) antigen. It binds the Rho antigens and does not allow them to induce antibody formation in Rh negative individuals. Administered within 72 hours of delivery/ abortion, such treatment prevents Rh haemolytic disease in future offspring. In general 3 types of regimens are used depending upon the stage of transplantation. Two drug and single Chapter 64 Drugs Acting on Skin and Mucous Membranes A variety of drugs applied topically to the skin or mucous membranes produce therapeutic effects localized to the site of application. They act primarily by virtue of their physical/mechanical/ chemical/biological attributes and may be divided into several categories designated by the most prominent action. They are, in general, high molecular weight substances and are applied as thick colloidal/viscid solutions in water. Some, like gum acacia, gum tragacanth produce foam with water, reduce surface tension and act as suspending/emulsifying agents. Glycyrrhiza is a sweet tasting root (liquorice); used in cough lozenges to sooth the throat and as sweetening/flavouring agent in mixtures. It contains a glycoside glycyrrhizin which has steroid like salt retaining action when taken orally. Methylcellulose It is a synthetic cellulose derivative used as bulk purgative, in nose drops and contact lens solutions. They form an occlusive film over the skin, preventing evaporation, thus restoring elasticity of cracked and dry skin. Olive oil, arachis oil, sesame oil, cocoa butter, hard and soft paraffin, liquid paraffin, wool fat, bees wax and spermaceti are the commonly employed emollients. They are also used as vehicles for topically applied medicaments and as ointment bases. They are also called protectives because they afford physical protection to the skin or mucosa. Other protectives form a continuous, adherent and flexible occlusive coating on the skin. Magnesium/zinc stearate They have very smooth surface-prevent friction, and are not water wettable-can be used on exuding surfaces because they allow evaporation of water and do not form a crust. Talc It is native hydrous magnesium silicate, which spreads easily-used in talcum/face powders. Entering raw surfaces, it can form granulomas-should not be sprinkled on wound or used for surgical gloves. Propylene glycol is a clear, viscous liquid, miscible with water as well as some oils that is used in cosmetics and as occlusive dressing for ichthyosis, etc. Undiluted glycerine has dehydrating property- produces a warm sensation and irritates mucous membranes. Applied to dry skin and cracked lips (50% in water) it acts as emollient and is a popular vehicle for gum/throat paints. Used in calamine lotion along with zinc oxide and bentonite (native hydrated aluminium silicate) which have similar properties, as cosmetic, on sunburn, insect bite, urticaria and contact dermatitis. Starch It is used in dusting powders and for surgical gloves, but should not be used on exuding surfaces because it absorbs moisture, crusts on drying and encourages fermentation. Aloe vera gel It is a mucilaginous preparation from the fleshy leaves of Aloe vera plant with soothing and moisturising property, widely included in cosmetic and skin care products. Sucralfate (topical) this aluminium salt of sulfated sucrose used primarily as peptic ulcer protective (see p. Applied on burns, bedsores, diabetic/ radiation/aphthous ulcers, excoriated skin, sores, etc. Drugs are: Tannic acid and tannins Tannic acid is present in many plants but is generally obtained from nutgalls of oak. Sufficient systemic absorption often occurred to cause centrilobular necrosis of the liver. Feracrylum It is a water-soluble biodegradable polymer which forms gel-like complexes on coming in contact with blood. Applied to fresh abrasions, it stops oozing of blood and protects the wound by acting as a physical barrier. Dimethicone (Dimethyl polysiloxane, Simethicone) It is a silicone polymer-a viscous, amphiphilic liquid. It is pharmacologically inert, has water repellent and surface tension reducing properties (collapses froth). Denatured spirit rubbed on the skin prevents bedsores, but should not be applied on the sores once these have formed, as it is highly irritating to raw surfaces. They diffuse through the sweat ducts, reduce secretion from glands and partially block the ducts as well. Their antibacterial action prevents decomposition of sweat by bacteria, reducing body odour. Depending on their nature, concentration and sensitiveness of the site, they produce cooling sensation or warmth, pricking and tingling, hyperaesthesia or numbness and local vasodilatation. Irritants which cause local hyperemia with little sensory component are called Rubefacients. Stronger irritants which in addition increase capillary permeability and cause collection of fluid under the epidermis (forming raised vesicles) are termed Vesicants. Certain irritants also produce a remote effect which tends to relieve pain and inflammation in deeper organs-called Counter-irritants. Volatile oils (essential oils) are terpene hydrocarbons of plant origin having a characteristic odour. Camphor It is obtained from the bark of Cinnamomum camphora or produced synthetically. Taken internally- small doses produce a warm and comforting sensation in epigastrium; large doses are emetic. It is added to pain balms, throat paints, throat lozenges and inhalers for relief of nasal congestion. When ground seeds are soaked in water, myrosin hydrolyses sinigrin to release allyl isothiocyanate which is a strong irritant. It is a popular condiment in Indian cooking, and is included in some counterirritant preparations. After initial stimulation, capsaicin depletes afferent nerve endings of the transmitter substance P; may relieve post-herpetic neuralgia on local application. A spinal segment, receiving afferent impulses from the surface as well as from deeper organs, modulates them- preferentially conducting the former to the higher centers. When a counter-irritant is applied to the area of skin supplied by nerves from the same segment as the deeper organ from which pain impulses are coming, the cutaneous impulses obscure the deeper sensation. Irritation of afferent nerve endings produces arteriolar dilatation in the adjoining areas of skin by axon reflex (which mediates flare in triple response). Through segmental association of afferents, vasodilatation also occurs in the corresponding deeper organ. Increased blood supply helps to fight the cause of pain and inflammation in the deeper organ. Counterirritants are generally massaged to relieve headache, muscular pain (torticollis, backache, sprain), joint pain, pleural/peritoneal pain, colics, etc. It is a strong irritant, higher concentrations damage the epithelium and cause vesication-has been used to remove warts, etc. It is added to hair tonics-claimed to increase vascularity of scalp and promote hair growth. Methyl salicylate (oil of wintergreen) In contrast to other salicylates, it is not used internally (induces vomiting, gastritis and systemic toxicity). It is combined with other irritants in liniments and ointments for muscle and joint pain. These drugs are used on hyperkeratotic lesions like corns, warts, psoriasis, chronic dermatitis, ringworm, athletes foot, etc. Applied under polyethylene occlusive dressing, it causes maceration of skin and acts as a keratolytic, supplementing the action of salicylic acid. An escharotic, in addition, precipitates proteins that exude to form a scab-gets fibrosed to form a tough scar. They are used to remove moles, warts (including genital warts) condylomata, papillomas and on keratotic lesions.

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