Peter A. Blume, DPM, FACFAS
- Clinical Assistant Professor of Surgery, Anesthesia, and
- Yale School of Medicine
- Director of North American Center for Limb Preservation
- New Haven, Connecticut
Hormone insulin is produced in bulk quantities by using this technology and used in treatment of insulin-dependent diabetics impotence jelqing tadalis sx 20 mg cheap. Other important proteins produced using this technology are growth hormones erectile dysfunction pills sold at gnc buy cheap tadalis sx 20 mg line, interferon etc erectile dysfunction when young order tadalis sx online pills. Proteins used for vaccination and for the development of diagnostic tests are obtained by this technology erectile dysfunction treatment massachusetts buy tadalis sx 20mg line. Expression of antigen gene (s) in the muscle cells or epidermal cells leads to production of antigen molecules erectile dysfunction causes and treatment buy tadalis sx 20 mg cheap. Stimulation of B cells by lymphokines produced by T-helper cells leads to production of anti-bodies erectile dysfunction statistics us buy tadalis sx 20 mg with amex. Some of the B cells serve as reservoir of antigen and produce memory cells that gives protection against further infections. Bio sensors Many naturally occurring biological macromolecules have tendency to recognize each other and react to form new molecule or complex or hybrid. For example, an enzyme recognizes its substrate among many molecules and reacts to form product. A biosensor is designed by combining this property of biomolecules with chemistry and electronics. Biosensors are used to detect genes, mutations, insects, microorganisms, toxins or pollutants etc. A portable biosensor that measures blood glucose instantly is used by diabetics in several parts of the world. In near future, an individual may find out what is wrong in his health at home by using appropriate portable bio sensor. Like wise he may be able to check quality of air, food or water he consumes with the help of biosensors. Gene therapy Some inherited diseases due to deficiency of a particular gene or gene product are fatal and generally proper treatment is not available. Gene therapy is the use of genes to correct genetic disease or use of genes as therapeutic agents. Eventhough, the gene therapy was initially developed for the treatment of inherited diseases, now it is used in treatment of cancer, neurological diseases and infectious diseases. Cancer gene therapy involves introduction of tumor cells containing genes for cytokines into patient. An alternative cancer gene therapy involves introduction of tumor suppressor gene into patient. Steps involved in production of transgenic goat that produces human gene product in milk are given below. They are used as bioreactors for the production of antigens (vaccines) and antibodies. Edible vaccines Edible vaccines are edible plant parts containing antigens of infectious agents. For production of edible vaccine, a plant whose products are consumed as such (raw) and stable to cooking condition is selected. Feeding of edible part containing antigen elicits immune response by stimulating mucosal immune system. Antibodies are produced in the body at mucosal surfaces of gut and respiratory tract. Coli infections is available in the form of infant food in some parts of the World for vaccination of children. Potatoes containing vaccines against cholera, diarrhoea and tobacco containing vaccine against hepatitis B are at different stages of development in several countries. Gene targeting is used to establish function of gene or gene product like enzyme or hormone etc. In pharmaceutical industry, gene targeting is used to over express proteins of therapeutic value in milch animals. In 1998, isolation of human-stem cells by using two different approaches is published. Further, they can be maintained as undifferentiated cells in culture and are able to reproduce themselves throughout life span of organisms. Generally developmental potential of a stem cell is restricted to differentiate cell of the tissue in which it is present. Applications Stem cells have many potential uses in medicine and molecular biology. For example, neural stem cells are used for gene therapy of tumor growth suppression. Mono-clonal antibodies are antibodies produced by one cell line (clone) and they are directed against one specific antigen. Lymphocytes in the body are polyclonal (multiple cell lines) and they can produce many types of antibodies (polyclonal) against antigens. Separation of single cell line that produce only one antibody from the mixture of polyclonal cells is a hard task. Hybridoma technology involves preparation of hybridoma (hybrid) cells to produce monoclonal antibodies. Hybridomas A simple method of producing single cell line of polyclonal cells involves fusion of two cell populations. During this period, antibodies producing cells are formed in sufficient amounts in the spleen. Myeloma cells are used for funsion because lymphocytes obtained after immunization are incapable of continous growth in culture. Therefore, fusion of lymphocytes with myeloma cells leads to immortalization (infinite life span) of cells. Finally mono-clonal cells are obtained and cultured to produce mono-clonal antibodies. In cancer therapy, mono-clonal antibodies are made to carry a toxin, which can kill cancer cells after binding to cancer cells. Inter strand hydrogen bonding between complementary sequences favours duplex formation. This probe hybridizes with the gene of interest thus leading to its identification. Hence, fluoroscent 482 Medical Biochemistry signal at the site of hybridization reveals presence of gene of interest. It is mainly used to identify chromosomes, regions of chromosomes and of course individual genes. Western blot It is also similar to southern blot in many ways except in the nature of probe used. In this blotting technique, radiolabelled (polyclonal) or (monoclonal) is used as probe. Protein mixture containing desired protein is subjected to elctrophoresis to separate proteins. For example, diagnostic chips are prepared to detect mutant alleles in cystic fibrosis and beta globin genes. It involves introduction of deletions/insertions or substitutions at will followed by analysis of their fitness. Their enzymes have remarkable properties like stable to extreme temperature (heat). Then polymorphisms are detected by presence or absence of bands after hybridization. For example, HbS: In HbS gene there is loss of one restriction site for restriction enzyme due to mutation where as normal HbA gene has two cleavage sites. It is defined as application of information technology and science for organisation management, mining and use of life sciences. Main application areas of bioinformatics are genomics, proteomics, pharmacogenomics, chemiinformatics etc. One of the earliest application are a of bioinformatics is in drug design process. Bioinformatics revolutionized traditional approach of drug discovery from target discovery and screening to discovery and development of therapeutic agents whose role in prevention of cure of a disease is well validated. Following steps of bioinformatics based method of designing drug that is an enzyme inhibitor. Following are steps of drug designing process, which involves genome sequence knowledge. Mechanism of hair graying: Incomplete melanocyte stem cell maintenance in the Niche. Several types of cancers affecting major organs like lung, brain, kidney, colon, breast, oesophagus and stomach have been identified. Rate of incidence of cancer of particular organ in particular population depends on several factors like age, sex, dietary habits, environment, geographical location, genetic make up, culture, physical exercise etc. For example in India oral cancer is common in betal nut chewing regions and in reverse smokers. Colon cancer is common in advanced countries and lung cancer is common in smokers. Rate of incidence of cancer of particular organ varies from developed countries to developing countries. Lung and colorectal cancers are high in developed countries while stomach and cervical cancer are more in developing countries. Further in India pharyngeal cancers are high in Western India where as stomach cancers are more common in Southern India. It is estimated that by 2020 ten million persons would die of cancer every year World wide. Like wise new tumour marker based on nuclear structural changes may be used in cancer diagnosis. Extensive research carried out for the last two decades on various types of cancer led to development of proper treatment for at least some types of cancers. In developing countries it is spreading faster due to prevalent socioeconomic conditions. If the growth of cell is not controlled they continue to proliferate which leads to malignancy. Cancer of a particular organ or tissue develops when the cells of that organ have lost growth control. Cancer cells are carried to other parts of the body by circulation where they develop further. Nomenclature and classification of Cancers Generally cancers are named according to the organ affected. However they are classified based on the three embryonic germ layers from which tissue or organ is derived. Carcinomas Are the cancer of cells or organs derived from either ectoderm or endoderm. Generally cancers of bone, cartilage, connective tissue, muscle etc are called as sarcomas. The product of oncogenes disturbs the normal cell growth control mechanism leading to cancer. Usually products of oncogenes are protein kinases that phosphorylate tyrosine residues of proteins. When normal cells are cultured with oncogenic viruses, the normal cells are transformed into cancer (tumour) cells. Activation of protooncogene to oncogene By several ways activation of protooncogene to oncogene can occur. Amplification of oncogenes results in the formation of products of these genes by several folds. Mechanism of action of oncogenes or Mechanism of carcinogenesis the product of oncogene converts normal cell to cancer cell by several ways. As a result cellular metabolism is altered and normal cell is transformed into cancer cell. Some oncogene products are polypeptide growth factors that affect cell cycle and mitosis. The E7 protein releases transcription factor which activates genes engaged in cell cycle progression. The E6 protein binds P53 and abolishes its tumour suppressive and Trans activational properties. Thus E6 and E7 are able to immortalize cells independently and both genes cooperate effectively in immortalization of cells. Metabolism of carcinogen Metabolism of carcinogen after entering the body is mainly directed towards producing metabolites which can be excreted. Components of nuclear matrix play a role in organization of chromosomes and nuclear components. Oncogenes induce tumor-specific nuclear changes and these in turn changes gene regulation. Structural changes in tumour cells lead to changes in nucleoli and perinuclear compartment. These changes can be used as potential tumour markers and targets for anti-cancer drugs. Treatment of cancer Several types of treatments are available for cancer management. Chemotherapy Compounds that block replication of cells and anti metabolites that block nucleotide biosynthesis are used as anticancer agents or in chemotherapy of cancer. It is converted into nucleotide in vivo and incorporated into nucleic acids and interferes with replication. It blocks nucleic acid biosynthesis (replication) by inhibiting glutamine dependent metabolic reactions. Methotrexate, azaserine and acivicin are anti metabolites used in cancer treatment. They are called as anti metabolites because they block nucleic acid synthesis by anatgonizing metabolic role of glutamine.
Atlantic salmon possesses two clusters of type I interferon receptor genes on different chromosomes erectile dysfunction hypertension drugs order tadalis sx uk, which allows for a larger repertoire of interferon receptors than in zebrafish and mammals erectile dysfunction at 18 discount tadalis sx 20 mg on-line. Mutant U5A cells are complemented by an interferon-alpha beta receptor subunit generated by alternative processing of a new member of a cytokine receptor gene cluster popular erectile dysfunction drugs order 20mg tadalis sx visa. Multiple regions within the promoter of the murine Ifnar-2 gene confer basal and inducible expression erectile dysfunction doctor new jersey proven tadalis sx 20 mg. Structural linkage between ligand discrimination and receptor activation by type I interferons erectile dysfunction fact sheet purchase tadalis sx overnight. Hydrophobic cluster analysis reveals duplication in the external structure of human alpha-interferon receptor and homology with gammainterferon receptor external domain erectile dysfunction foods to eat discount 20 mg tadalis sx free shipping. An interferon-induced mouse protein involved in the mechanism of resistance to influenza viruses Its purification to homogeneity and characterization by polyclonal antibodies. Susceptibility of Xenopus laevis tadpoles to infection by the ranavirus Frog-Virus 3 correlates with a reduced and delayed innate immune response in comparison with adult frogs. No enhanced influenza virus resistance of murine and avian cells expressing cloned duck Mx protein. Native antiviral specificity of chicken Mx protein depends on amino acid variation at position 631. Association of Mx1 Asn631 variant alleles with reductions in morbidity, early mortality, viral shedding, and cytokine responses in chickens infected with a highly pathogenic avian influenza virus. Asparagine 631 variants of the chicken Mx protein do not inhibit influenza virus replication in primary chicken embryo fibroblasts or in vitro surrogate assays. Susceptibility of different chicken lines to H7N1 highly pathogenic avian influenza virus and the role of Mx gene polymorphism coding amino acid position 631. Mx is dispensable for interferon-mediated resistance of chicken cells against influenza A virus. Immune responses elicited in rainbow trout through the administration of infectious pancreatic necrosis viruslike particles. Antigen dose and humoral immune response correspond with protection for inactivated infectious pancreatic necrosis virus vaccines in Atlantic salmon (Salmo salar L). Inhibition of infectious pancreatic necrosis virus replication by atlantic salmon Mx1 protein. Enhanced grass carp reovirus resistance of Mxtransgenic rare minnow (Gobiocypris rarus). Protective roles of grass carp Ctenopharyngodon idella Mx isoforms against grass carp reovirus. Survey of transcript expression in rainbow trout leukocytes reveals a major contribution of interferonresponsive genes in the early response to a rhabdovirus infection. Rock bream (Oplegnathus fasciatus) viperin is a virusresponsive protein that modulates innate immunity and promotes resistance against megalocytivirus infection. Viperin protein expression inhibits the late stage of respiratory syncytial virus morphogenesis. Equine viperin restricts equine infectious anemia virus replication by inhibiting the production and/or release of viral gag, env, and receptor via distortion of the endoplasmic reticulum. Viperin regulates cellular lipid metabolism during human cytomegalovirus infection. Rothenburg S, Deigendesch N, Dittmar K, Koch-Nolte F, Haag F, Lowenhaupt K, et al. The cloning and characterization of a maternally expressed novel zinc finger nuclear phosphoprotein (xnf7) in Xenopus laevis. Molecular cloning and characterization of bloodthirsty from Atlantic cod (Gadus morhua). Chapter 8 Lectins as Innate Immune Recognition Factors: Structural, Functional, and Evolutionary Aspects Gerardo R. Consequently, the identification and structural/functional characterization of the other recognition factors, such as lectins, toll and toll-like receptors, and other "nonself" recognition and effector mechanisms that in invertebrates may be responsible for defense against infectious disease, has generated substantial interest. Additionally, the early realization that many of these factors/mechanisms have been conserved along the vertebrate lineages leading to the mammals has expanded the interest on these studies even further. Therefore, attention has focused on the potential germline-encoded diversity of the lectin repertoires, including allelic variation; the presence of multiple carbohydrate the Evolution of the Immune System. Among the lectin families that mediate innate immune recognition in both invertebrate and vertebrate species, the C- and F-type lectins, rhamnose-binding lectins, pentraxins, and galectins (formerly S-type lectins) have been characterized in considerable detail. Lectins as Innate Immune Recognition Factors Chapter 8 207 For example, among the lectin families present in both invertebrate and vertebrate species, it has been concluded that galectins have been highly conserved through evolution,12,28 whereas the F- and C-type lectins, which are largely heterogeneous from the structural standpoint, are considered as evolutionary diversified lectin families. Most galectins are soluble proteins, although a few exceptions have transmembrane domains. Detail of the binding cleft, indicating the amino-acid residues that interact with the disaccharide. The identification of galectin-like proteins in the fungus Coprinopsis cinerea and in the sponge Geodia cydonium, and a protein sharing the galectin fold in the protozoan parasite Toxoplasma gondii revealed the early emergence and structural conservation of galectins in eukaryotic evolution. Based on the structure of their binding sites, they are likely to differ in their fine specificity and recognize distinct ligands. A phylogenetic analysis indicated that MjGal clustered with galectins from invertebrates and a hemichordate, and was clearly distinct from the vertebrate galectins. This remarkable structural conservation of the biologically active carbohydrate-binding domains in the evolution of the mollusk taxa supports the key roles of galectins in essential biological functions related to Я-galactoside recognition. In addition, any galectin subtype may exhibit multiple isoforms in a single individual. Later studies revealed their roles in neoplastic transformation and progression, and metastasis (reviewed in Vasta and Ahmed12). From the functional standpoint, galectins can function as opsonins,56 inhibit viral adhesion to the host cell,90 or directly kill bacteria. By also binding to the shrimp hemocyte surface, MjGal functions as an opsonin for microbial pathogens, promoting their phagocytosis and clearance from circulation. The F-type lectin family is the most recent to be identified, and it is characterized by a unique structural fold and a canonical sequence motif in the F-type sugar-binding domain. The interaction of the disulfide bond (Cys82Cys83) with the C1C2 bond of the L-fucose is indicated with a circle. A van der Waals contact is established between a unique disulfide bridge, formed by contiguous cysteines (Cys78 and Cys79) and the bond between ring atoms C1 and C2 of the monosaccharide, and the C6, which docks loosely in a hydrophobic pocket, stacking against the aromatic rings of two residues His16 and Phe,44 together with the Leu24 and Tyr91 residues. F-lectins specifically recognize selected oligosaccharides via interactions with amino-acid residues, located in what is known as an "extended binding site. Variability of critical residues in the binding pocket and surrounding loops in the multiple isoforms, as expressed in the Japanese eel,101,102,104 suggests that alternative interactions with terminal and subterminal sugar-units may expand the range of diverse oligosaccharides recognized by the lectin isoform repertoire. However, the F-type lectin sequence motif appears to be absent from protozoa, fungi, nematodes, ascidians, and higher vertebrates such as reptiles, birds, and mammals. These tandem arrays may yield mosaic proteins by including pentraxin (Xenopus laevis) or C-type domains (D. The F-type sequence motif is also present in lophotrochozoan (ie, mollusks and planaria) and ecdysozoan protostomes (ie, horseshoe crabs and insects), invertebrate deuterostomes (ie, echinoderm), elasmobranchs (ie, skate), lobe- and ray-finned teleost fish, and amphibians (ie, X. This observation begs the question of whether this lectin family is uniquely restricted to invertebrates and cold-blooded vertebrates, and had been subsequently lost, as such, above the level of the amphibians. The absence of the F-type lectin sequence motif in protozoa, fungi, nematodes, ascidians, and higher vertebrates suggests that it may have been selectively lost, even in relatively closely related lineages. Even the multiple duplicate tandem homologs present within modern teleost orders appear to be the product of independent duplications. This would take place by crosslinking "nonself" carbohydrate ligands and "self" carbohydrate ligands, such as sugar structures, displayed by microbial pathogens and glycans on the surface of phagocytic cells from the host. The immune-recognition functions of F-type lectins that we have identified in teleost fish are not always shared by those F-lectins expressed in other taxa. For example, the sperm "bindins" from the Japanese oyster (Crassostrea gigas), recently identified as F-type lectins, are polymorphic gamete-recognition proteins stored in the acrosomal rings that bind sperm to egg during fertilization. However, only one or two polymorphic molecular species housing between one and five tandemly arrayed F-lectin domains are translated in each individual male oyster. However, allantoicase is the first reported analog to exhibit intrinsic enzyme activity. Furthermore, in recent years evidence has accumulated to support the notion that selected members of both families have been coopted to carry out other functions that, in several cases, are not dependent on their carbohydrate-binding sites, a property that is key to their definition as lectins, and appears to have been lost in the evolutionary process. With regard to their roles in immune recognition, recent studies have firmly established that both F-type lectins and galectins can recognize self and nonself glycans. The recent availability of genomic databases for numerous animal species has enabled greater insight into the structural complexity and functional diversity, and of lectin repertoires in invertebrates, protochordates, and ectothermic vertebrates. The identification in these taxa of members of the lectin families typical of mammals such as galectins, has resulted in the discovery of novel structural features, most likely revealing functional adaptations along the lineages leading to the higher vertebrate taxa. Further, the identification of novel lectin families such as the F-type lectins, underscores the fact that more research in nonmammalian model organisms will provide new information on all of the structural, functional, and evolutionary aspects of lectin repertoires that may not be as obvious in mouse or man. For example, structural analysis of the eel multiple isoforms as mechanisms that generate substantial diversity in oligosaccharide binding, provide the structural basis for a tantalizing novel mechanism for generating diversity for nonself recognition in innate immunity, that resembles those operative through adaptive immunity in higher vertebrates. Similarly, analysis of the genetic mechanisms that are operative in the diversification of the bindin transcripts in the Pacific oyster,113 has contributed conceptually transformative evidence for the processes through which lectins can generate structural (and possibly, functional) diversity. The ongoing genome, transcriptome, and proteome projects on additional model organisms representative of nonmammalian taxa will reveal not only the extent of their full lectin repertoires, but, coupled to the structural analysis of selected components, has the potential to uncover novel structural features, on which a rigorous experimental assessment of their biological roles may be supported. In turn, these studies will provide greater insight into the evolutionary history of the various lectin families, from prokaryotes to the mammals. Structural and functional diversity of lectin repertoires in invertebrates, protochordates and ectothermic vertebrates. Ancient evolutionary origin of diversified variable regions demonstrated by crystal structures of an immune-type receptor in amphioxus. Galectins in teleost fish: zebrafish (Danio rerio) as a model species to address their biological roles in development and innate immunity. Hydrophobicity: an ancient damage-associated molecular pattern that initiates innate immune responses. Structural and functional aspects of complement activation by mannose-binding protein. Proteolytic activities of two types of mannose-binding lectin-associated serine protease. Structure of S-lectin, a developmentally regulated vertebrate beta-galactosidebinding protein. Soluble beta-galactosyl-binding lectin (galectin) from toad ovary: crystallographic studies of two protein-sugar complexes. New alternatively spliced form of galectin-3, a member of the beta-galactosidebinding animal lectin family, contains a predicted transmembrane-spanning domain and a leucine zipper motif. Export of galectin-3 from nuclei of digitonin-permeabilized mouse 3T3 fibroblasts. Galectins: matricellular glycan-binding proteins linking cell adhesion, migration, and survival. Expanding the universe of cytokines and pattern recognition receptors: galectins and glycans in innate immunity. Galectin-3 induces death of Candida species expressing specific beta-1,2linked mannans. Specific recognition of leishmania major poly-beta-galactosyl epitopes by galectin-9: possible implication of galectin-9 in interaction between L. A novel galectin-like domain from Toxoplasma gondii micronemal protein 1 assists the folding, assembly, and transport of a cell adhesion complex. The Geodia cydonium galectin exhibits prototype and chimera-type characteristics and a unique sequence polymorphism within its carbohydrate recognition domain. Structural, functional, and evolutionary aspects of galectins in aquatic mollusks: from a sweet tooth to the Trojan horse. A family of variable immunoglobulin and lectin domain containing molecules in the snail Biomphalaria glabrata. The family of metazoan metal-independent beta-galactoside-binding lectins: structure, function and molecular evolution. A galectin of unique domain organization from hemocytes of the Eastern oyster (Crassostrea virginica) is a receptor for the protistan parasite Perkinsus marinus. Molecular and functional characterization of a tandem-repeat galectin from the freshwater snail Biomphalaria glabrata, intermediate host of the human blood fluke Schistosoma mansoni. A galectin from the kuruma shrimp (Marsupenaeus japonicus) functions as an opsonin and promotes bacterial clearance from hemolymph. X-ray crystal structure of the human galectin-3 carbohydrate recognition domain at 2 1-A resolution. Galectin-1 from bovine spleen: biochemical characterization, carbohydrate specificity and tissue-specific isoform profiles. Novel carbohydrate specificity of the 16-kDa galectin from Caenorhabditis elegans: binding to blood group precursor oligosaccharides (type 1, type 2, Talpha, and Tbeta) and gangliosides. Characterization of the Xenopus galectin family three structurally different types as in mammals and regulated expression during embryogenesis. The S-type lectin from calf heart tissue binds selectively to the carbohydrate chains of laminin. Characterization of quail intestinal mucin as a ligand for endogenous quail lectin. The involvement of galectin-1 in skeletal muscle determination, differentiation and regeneration. Galectin-3 is expressed in the notochord, developing bones, and skin of the postimplantation mouse embryo. Biochemical and molecular characterization of galectins from zebrafish (Danio rerio): notochord-specific expression of a prototype galectin during early embryogenesis. Differential roles of galectin-1 and galectin-3 in regulating leukocyte viability and cytokine secretion. An emerging role for galectins in tuning the immune response: lessons from experimental models of inflammatory disease, autoimmunity and cancer.
The two types of spin have different energy levels an high energy spin level and low energy spin level (Figure 28 erectile dysfunction research purchase discount tadalis sx line. When a magnetic field and electromagnetic radiation is applied to such nuclei they absorb electro magnetic radiation of specific frequency and resonate or assume other high energy spin state top erectile dysfunction doctor purchase line tadalis sx. Conversely resonance can be achieved by fixing electromagnetic radiation and varying magnetic field strength impotence synonym cheap 20 mg tadalis sx. The differences in resonance frequency are expressed as chemical shifts (symbol) with respect to reference material added in the sample erectile dysfunction at the age of 28 buy discount tadalis sx on-line. The resonance of a inorganic phosphate (Pi) is shown as absorption band or peak in Figure 28 impotence your 20s buy tadalis sx 20 mg fast delivery. It is used to follow metabolic changes as they occur in living animals under various conditions erectile dysfunction statistics worldwide order tadalis sx. It is used in tumour grading, early detection of anaplastic transformation and monitoring treatment methods. Imaging is mainly based on detection of resonance signal from proton (1H) of water. It is used for anatomical localization and characterization of neoplastic (cancerous) lesions. Tuberculomas account for 20-40% of intracranial space occupying mass lesions in developing countries. The total lesion volume reflects overall disease burden and thus useful in quantifying the lesion. Since deoxyhaemoglobin is paramagnetic substance in the presence of external magnetic field it alters magnetic field in its vicinity. This in turn affects magnetic resonance behaviour of water protons within the surrounding blood vessels which manifest as changes in image intensity. An increase in neuronal activation by stimulus or task lead to an increase in arterial blood with proportionate decrease in venous deoxyhaemoglobin in capillaries. Some of the radio isotopes emit positrons (anti electrons) which combines with electrons to produce rays. The images of -ray emitting regions of organ of interest are obtained by using scanner. The half lifes of these positron emitting radio isotopes ranges from 2-100 minutes. Since carbon, nitrogen and oxygen are constituents of large number of biomolecules and drugs these compounds are labelled with 11C, 13N and 15O and used in positron emission tomography. Insights into muscle diseases gained by phosphorus magnetic resonance spectroscopy. In vivo magnetic resonance spectroscopy and its application to neuro psychiatric disorder. In the body cells of different organs communicate with each other through specific chemical substances which may be referred as biochemical messengers. Hormones produced in the body by various glands are involved in regulation of blood glucose (Chapter 9), calcium and phosphorus (chapter 23) and water, electrolyte levels (Chapter 26). Anti inflammatory, immuno suppressive and anticancer activities of glucocorticoids involves inhibition of target genes. Thyroid function tests are widely used in diagnosis of thyroid diseases which are most prevalent endocrine disorders in India. Different types of memory formation involves structural and functional changes in synapse. Understanding of cellular and molecular mechanism of memory lead to development of new therapeutic agents for dementia patients and improvement of memory function. Loss of dopamine making cells which occurs in Parkinsonism is treated by administering (a) Dopamine precursor L-dopa (b) Dopamine receptor agonist like bromocriptine (c) Embryonic stem cells. Alteration in taste is common disorder associated with several types of illness and use of drugs. Hence knowledge of molecular mechanisms involved in taste signal transduction is useful in development of drugs for treatment of taste disorders. Hormones arc involved in development and maintenance of secondary sex characteristics, menstrual cycle and pregnancy. Over production and diminished synthesis of hormones leads to pathological conditions. For example over production of thyroxine causes thyrotoxicosis and decreased synthesis leads to goitre. Progesterone agonists are used as contraceptives and estrogen antagonists are used as anticancer agents. Several toxins like cholera, pertusis, stimulants like caffeine and theophylline work by affecting second messenger levels by which hormone action is mediated. Lithium used in treatment of manaic depression also work by altering second messenger levels in brain. Botulinus toxin produced by clostridium botulinum which causes food poisoning syndrome botulism work by inhibiting release of neurotransmitter at neuromuscular junction. Chemical nature of biochemical messengers Biochemical messengers differ in their chemical nature. They may be proteins (polypeptides), peptides, amino acids, amino acid derivatives, steroids, fattyacid derivatives and gas. Classification of biochemical messengers Based on their ability to communicate over a distance they are classified into endocrine hormones, local mediators and neurotransmitters. Usually tissues that produce this type of biochemical messengers are called as endocrine glands. The tissues which produce this type of biochemical messengers may be called as paracrine glands. Neurotransmitters: They act between nerves (cells) and nerve and muscle at which they are formed. Some common biochemical messengers, their chemical nature, origin, effects (actions) are given in Table 29. Name Hormones Insulin Glucagon Cholecystokinin Parathyroid hormone Calcitonin Thyroxine Catecholamines Pancreas Pancreas Intestine Parathyroid Thyroid Thyroid Adenal medulla Protein Protein Protein Protein Protein Amino acid derivative Amino acid derivatives Promotes glycogenesis and lipid synthesis Promotes glycogenolysis and gluconeogenesis Promotes secretion of enzymes by pancreas Stimulates Ca2+ absorption in intestine and kidney. Usually translation of chemical message into biochemical effect involves two or three steps as given below. Binding of hormone to receptor on membrane of target cells or intracellular receptor initiates conversion of signal or message. The remaining steps of conversion process varies from one chemical messenger to other. The second messengers produces final biochemical effect of hormone by inducing changes in enzyme activities etc. They are peripheral membrane proteins present on cytoplasmic side of various cells. When hormone combines with receptor on membrane it causes conformational change in the receptor. Vibrio cholerae microorganism which causes cholera acts by irreversible activation of Gproteins of intestinal mucosal cells. Usually mutation in ras gene converts ras gene to ras oncogene which leads to cancer development. This largest single super family of receptors include over 2000 receptors which responds to varieties of molecules. They have an extracellular N-domain, seven trans membrane domains which form transmembrane core and an intracellular Cdomain. They act as key players in several physiological process such as cellular metabolism, cell growth and differentiation, cell secretion, neurotransmission, inflammation, immunity, taste and odor perception. E xtra cellu lar Tra nsm em b ran e core In tra cellu lar N -d om a in (a) C -d om a in N L S -1 A /B N -te rm in us C C e ntral po rtion (b) D N L S -2 E /F C -Term inu s. In response to ligand binding the cytoplasmic portion undergoes conformational change and interact with G-proteins. The signal transduction across membrane involves dimer formation of two receptors in the membrane. The production of these intracellular second messengers is dependent on G-proteins and calcium influx as mentioned in chapter 23. Tumor promoters are substances that promote tumors and as such they may not be carcinogenic. The active protein kinase C catalyzes phosphorylation of some intracellular proteins. Lithium used to treat manic depressive mental illness work by blocking production of inositol phospholipids in brain. Hormonal signalling through tyrosine phosphorylation Insulin effects on target cells involves phosophorylation of tyrosine residues of intracellular protein substrates. The two -subunits are located on extracellular side and are involved in insulin binding. The cytoplasmic domain of -subunit possess intrinsic tyrosine kinase activity and an autophosphorylation site. When insulin binds to receptor, tyrosine kinase activity of -subunit of receptor is stimulated. These active kinases and phosphatases regulates activities of enzymes of various metabolic pathways by phosphorylation and dephosphorylation (Figure 29. The effect of these hormones on target cells is mainly increased expression of certain genes as mentioned in chapter 19. All members of super family share three characteristic structural or functional domains. A typical glucocorticoid steroid receptor contain six regions or domains A, B, C, D, E and F. The variable N-terminal domain (A/B region) is involved in activation of genes and interacts with transcription machinery or transcription factors. The less conserved C-terminal domain (D/ E/F region) is known as hormone binding domain which binds to hormone. Transport of Glucocorticoids across membrane Lipophilic nature of glucocorticoids allows transport of glucocorticoids across cell membrane by simple diffusion. Then it inhibits transcription of target genes stimulated by transcription factor. Glucocorticoids are essential for normal physiology and survival of mammals including man. Glucocorticoids arc involved in the regulation of carbohydrate metabolism, lipid metabolism, protein metabolism, oxidative metabolism, electrolyte balance, reproduction, growth, apoptosis, immuno suppression, anti inflammatory action, anti tumor activities etc. Anti inflammatory, immuno suppressive and antitumor activity of glucocorticoids are achieved by inhibition of target genes. Mechanism of thyroid hormone action Thyroid hormone regulates many physiological and developmental processes. Thyroid hormone transport across membrane Although T3 and T4 forms of thyroid hormones are lipophilic in nature, the polar amino acid side chain retards their passage across cell membrane. Recent research indicates a saturable transport mechanism for thyroid hormone movement across membrane. Since these transporters are important for the delivery of thyroid hormones to cell interior the transport of thyroid hormones across plasma membrane is one of the important step for the control of cellular thyroid hormone signalling and action. Thyroid hormone nuclear receptors In side the cell thyroid hormone binds to the thyroid hormone nuclear receptors. Thyroid hormones nuclear receptors belong to super family of nuclear receptors which consist of several domains. Thyroid hormone nuclear receptors are transcription factors with ligand regulated activity. In the absence of T3 unliganded receptor (apo-receptor) recruit corepressors and repress expression of target genes. Under physiological conditions conversion of apo-receptors to holo receptor act as molecular switch. Non-genomic actions of thyroid hormone A number of thyroid hormone effects occur rapidly and unaffected by inhibitors of transcription and translation. They are observed in various cell types, brown adipose tissue, heart and pituitary. The non genomic actions are localized to cytosol, plasma membrane and cell organelles. Thyroid disorders Thyroid disorders are the most common among all the endocrine diseases in India. The Biochemical Communications 679 estimated disease burden in the country due to these disorders is approximately 42 million. Endemic goiter and thyrotoxicosis are widely prevalent disorders of thyroid in India. Thyroid goiter is found in the entire country where as thyrotoxicosis is seen in north Indian states. Thyroid function Tests Since thyroid disorders are common among endocrine disorders in this country, several tests are used to assess the level of functioning of thyroid gland. If hypothyroidism is due to defective hypothalamus or pituitary gland then the level of all three hormones i. Radioactive iodine uptake test Since iodine is required for the synthesis of thyroid hormones thyroid gland take up iodine 680 Medical Biochemistry and concentrates it in the cells. It involves intravenous administration of fixed dose of radioactive iodine 131I to the patient. In contrast hypodense areas in the scan due to defective uptake of iodine are seen in cancer of thyroid gland. Regulation of hormone action So far I explained mechanisms by which hormonal message is translated into biochemical effect or biological response in target cells. Now we shall examine when and how endocrine gland receives signal to secrete or stop production of hormones. Usually release or secretion or inhibition of hormones by endocrine glands is under control of higher centres in brain. Depending on needs of organism or individual a particular hormone is produced or inhibited and this signal is delivered to target gland through chemical substances known as releasing factors or release inhibiting factors and trophic hormones.
It has also been suggested a potential treatment for heart disease by preventing low-density lipoprotein oxidation best erectile dysfunction pills review tadalis sx 20 mg line. It reduced hyperalgesia in a chronic muscle pain fibromyalgia model presumably by affecting the opioid and Myrcene is common in highly aromatic plants such as sweet basil erectile dysfunction medications causing buy discount tadalis sx 20mg, bay leaves erectile dysfunction chicago cheapest tadalis sx, lemongrass erectile dysfunction treatment shots order tadalis sx 20 mg with amex, wild thyme erectile dysfunction psychological treatment best tadalis sx 20mg, parsley erectile dysfunction doctors san antonio purchase tadalis sx once a day, tropical fruits such as mango, and hops. It has potent anti-inflammatory, analgesic, and anxiolytic properties694,695 and is used extensively in the cosmetics industry. The analgesic effects of myrcene were antagonized by naloxone suggesting an opioid-mediated mechanism. It is found in herbs and spices such as hops, clove, basil, sage, ginger, spearmint, and ginseng as well as some fruits and vegetables. It has strong anti-inflammatory properties comparable to dexamethasone systemically, topically, and in allergic airway inflammation,667669,732,733 as well as anti-nociceptive and analgesic properties. Humulene was shown to increase the rate 1154 Headache July/August 2018 Headache Currents Carophyllene has anti-fungal828 properties including onychomycosis comparable to sulconazole and ciclopiroxolamine,834 insecticidal,835 and anti-ischemic and anti-platelet aggregation properties. It has analgesic and anti-insomnia properties as well as bronchodilator and anti-septic effects. It promotes bone growth and repair,855 and has insecticidal and repellent qualities. It is used as a food additive for flavoring and infused into topical creams and perfumes for fragrance. Camphene has antioxidant and analgesic effects861 even when used topically,843 antifungal action,862 lowers cholesterol and triglycerides,863 and acts as an antioxidant in inflammatory lung disease. Sabinene is found in various plants including marjoram, holm oak, juniper, Norway spruce, black pepper, nutmeg, and is a major component of carrot seed oil. It has benefits in digestion, antioxidant, inflammation, arthritis, soothing skin conditions,707,864,865 and is anti-bacterial and anti-fungal. It also has skin penetration enhancing effects,796 airway smooth muscle relaxation in asthma,797 vasorelaxation and blood pressure reduction effects,798 and anxiolytic and sedative effects. It has anti-inflammatory,706 antifungal,799 antiviral,728 and antibacterial800 benefits. Valencene is found in Valencia oranges, grapefruit, tangerines, and other citrus fruits. It has anti-inflammatory effects,801 insecticidal benefits,802 and is a tick repellent. Its properties are anti-nociceptive,804 anti-inflammatory,805 antioxidant in inflammatory lung disease,806 skin penetration enhancing effects,807 antibacterial,808810 antifungal,811,812 and antiparasitic. It has anti-inflammatory effects in the skin,814 as well as anti-nociceptive and neuroprotective benefit. It has anti-insomnia and sedative properties,825 anti-leishmanial activity,826 anti-parasitic effects against Babesia parasites,827 antifungal effects828 against Microsporum gypseum,829 anti-malarial effects,748,830 and enhanced sensitization of Staphylococcus aureus and Escherichia coli to multiple antibiotic therapies. It is an analgesic used topically for inflammatory pain such as sprains, joint and muscle pains, and is antipruritic. Its properties include anti-inflammatory and gastroprotective,911 antidepressant and antianxiety,912 and antioxidant and anticonvulsant properties. It has analgesic and anti-inflammatory properties including opioid system involvement, 914,915 antibacterial,916 antifungal,917 and is protective against acute lung injury. It has antioxidant,754,919 antibacterial and antifungal,920 muscle relaxation including gastrointestinal,921 and sleep benefits. It has shown promotion of wound healing, anti-cancer, anti-inflammatory, analgesic, and antioxidant benefits. According to the Natural Health Research Institute, it has been proven to improve memory and cognitive learning. Geranyl acetate is found in citronella, sassafras, roses, lemongrass, geranium, coriander, and carrot. It is used in inflammation-related disorders including sprains, rheumatism, muscle pains, and is antipruritic because of its local anti-inflammatory, anesthetic and analgesic properties. These compounds normally act as antioxidants in plants and protect against oxidative stress. The health and medicinal benefits of many fruits, vegetables, whole grains, and other plant foods are the result of synergy between the various nutrients and bioactive compounds within the food rather than a single compound. To illustrate, in a rat model of neuropathic pain (thermal hyperalgesia), a controlled cannabis sativa extract containing multiple cannabinoids in a defined ratio along with other noncannabinoid compounds such as terpenes and flavonoids provided better and total relief of neuropathic pain compared to pure cannabinoids alone. Cannabis sativa strains are commonly described as energetic, uplifting, creative, euphoric, spacey, cerebrally focused effects, and better for day use. Cannabis indica strains are described as relaxing, calming, sedative, having full body effects such as "body buzz," and better for night use. These different subjective effects are most likely due to varying ratios of major cannabinoids, minor cannabinoids, terpenes and probably additional phytochemicals. Some strains were more dominant in terpinolene or -pinene, while others were dominant in -myrcene. In a recent study evaluating cannabis use patterns among medicinal cannabis patients who were treating for migraine and headache, hybrid strains were the most preferred. Cannabis should be thought of as a broad category of medicines comprised of many different strains varying in their targets, responses, and side effects. This is synonymous to the broad category of antidepressants, comprised of many different medication classes varying in their neurotransmitter targets, responses and side effects. There is growing evidence for therapeutic benefits of cannabis/cannabinoids in many diseases and symptoms, especially in the treatment of chronic pain with extension to migraine and headache, as well as a potential weapon in battling the opioid epidemic. More data are needed to determine what the most effective therapeutic ratios of cannabinoids, terpenes, flavonoids, and other compounds may be for these pain syndromes, as well as for other diseases and symptoms. These data will ultimately unveil optimal reproducible strain combinations to be bred for maximum predictable therapeutic efficacies. Many of the individual cannabinoids, terpenes, and flavonoids, have strong anti-inflammatory and analgesic properties that work individually and synergistically to provide the well-described analgesic benefits of cannabis/cannabinoids. The National Academies of Sciences, Engineering, and Medicine now state that the use of cannabis for the treatment · · 1157 Headache July/August 2018 Headache Currents 11. Hemp for headache: an in-depth historical and scientific review of cannabis in migraine treatment. Anandamide is able to inhibit trigeminal neurons using an in vivo model of trigeminovascular-mediated nociception. An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity. Pharmacological management of chronic neuropathic pain: revised consensus statement from the Canadian Pain Society. Committee of the Health Effects of Marijuana: An Evidence Review and Research Agenda. The prevalence and incidence of medicinal cannabis on prescription in the Netherlands. This benefit may extend to migraine and headache based on overlapping neurobiological mechanisms of pain and early research, although prospective studies are necessary. The well-documented opioid-sparing effect of cannabis/ cannabinoids in conjunction with opioid use leads to lower opioid dose requirements, allowing for easier detoxification and weaning, and a potential tool against the opioid epidemic. Cannabis science is a rapidly growing new medical sector and industry involving sophisticated crossbreeding of specific strains for standardized compositions of cannabinoids, terpenes, and other phytochemicals, to target individualized diseases and/or symptoms including migraine and headache. Global, regional, and national burden of neurological disorders during 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. An introduction to the endocannabinoid system: from the early to the latest concepts. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Multiple mechanistically distinct modes of endocannabinoid mobilization at central amygdala glutamatergic synapses. Cannabinoid-induced immune suppression and modulation of antigen-presenting cells. The Michigan Department of Licensing and Regulatory Affairs, Bureau of Medical Marihuana Regulation. Cannabinergic pain medicine: a concise clinical primer and survey of randomized-controlled trial results. Endocannabinoid influence in drug reinforcement, dependence and addiction-related behaviors. The endocannabinoid system as a key mediator during liver diseases: new insights and therapeutic openings. Nicolodi M, Sandoval V, Terrine A, Therapeutic use of cannabinoids - Dose Finding, Effects, and Pilot Data of Effects in Chronic Migraine and Cluster Headache. Nabilone for the treatment of medication overuse headache: results of a preliminary double-blind, active-controlled, randomized trial. A randomized, placebo-controlled, crossover trial of cannabis cigarettes in neuropathic pain. Smoked cannabis for spasticity in multiple sclerosis: a randomized, placebo-controlled trial. Dose-dependent effects of smoked cannabis on capsaicin-induced pain and hyperalgesia in healthy volunteers. Systematic review: Efficacy and safety of medical marijuana in selected neurologic disorders: Report of the Guideline Development Subcommittee of the American Academy of Neurology. Results of a standardized survey on the medical use of cannabis products in the German-speaking area. Remarks on the value of Indian hemp in the treatment of a certain type of headache. An analysis of applicants presenting to a medical marijuana specialty practice in California. Cannabinoids block release of serotonin from platelets induced by plasma from migraine patients. Effects of medical marijuana on migraine headache frequency in an adult population. On the physical and medicinal qualities of Indian hemp (Cannabis indica); with observations on the best mode of administration, and cases illustrative of its powers. A multicenter dose-escalation study of the analgesic and adverse effects of an oral cannabis extract (Cannador) for postoperative pain management. Efficacy of dronabinol as an adjuvant treatment for chronic pain patients on opioid therapy. Effect of the synthetic cannabinoid dronabinol on central pain in patients with multiple sclerosissecondary publication. Low dose treatment with the synthetic cannabinoid Nabilone significantly reduces spasticity-related pain: a double-blind placebo-controlled cross-over trial. Benefits of an add-on treatment with the synthetic cannabinomimetic nabilone on patients with chronic paina randomized controlled trial. An enriched-enrolment, randomized withdrawal, flexible-dose, double-blind, placebo-controlled, parallel assignment efficacy study of nabilone as adjuvant in the treatment of diabetic peripheral neuropathic pain. The pharmacokinetics, efficacy, safety, and ease of use of a novel portable metered-dose cannabis inhaler in patients with chronic neuropathic pain: a phase 1a study. Cannabis use in patients with fibromyalgia: effect on symptoms relief and health-related quality of life. Sativex successfully treats neuropathic pain characterised by allodynia: a randomised, double-blind, placebo-controlled clinical trial. Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis. Preliminary assessment of the efficacy, tolerability and safety of a cannabis-based medicine (Sativex) in the treatment of pain caused by rheumatoid arthritis. Oromucosal delta9-tetrahydrocannabinol/cannabidiol for neuropathic pain associated with multiple sclerosis: an uncontrolled, open-label, 2-year extension trial. Longterm use of a cannabis-based medicine in the treatment of spasticity and other symptoms in multiple sclerosis. Nabiximols for opioid-treated cancer patients with poorly-controlled chronic pain: a randomized, placebo-controlled, graded-dose trial. A preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms. Efficacy of two cannabis based medicinal extracts for relief of central neuropathic pain from brachial plexus avulsion: results of a randomised controlled trial. The effectiveness of cannabinoids in the management of chronic nonmalignant neuropathic pain: a systematic review. Medical cannabis access, use, and substitution for prescription opioids and other substances: A survey of authorized medical cannabis patients. Substituting cannabis for prescription drugs, alcohol and other substances among medical cannabis patients: the impact of contextual factors. Cellular mechanisms underlying the interaction between cannabinoid and opioid system. Antinociceptive activity of intrathecally administered cannabinoids alone, and in combination with morphine, in mice. The role of endogenous opioids in enhancing the antinociception produced by the combination of delta 9-tetrahydrocannabinol and morphine in the spinal cord. The enhancement of morphine antinociception in mice by delta9-tetrahydrocannabinol. Enhancement of transdermal fentanyl and buprenorphine antinociception by transdermal delta9-tetrahydrocannabinol. Enhancement mu opioid antinociception by oral delta9-tetrahydrocannabinol: dose-response analysis and receptor identification. Antinociceptive synergy between delta(9)-tetrahydrocannabinol and opioids after oral administration. Nabilone as an adjunctive to gabapentin for multiple sclerosis-induced neuropathic pain: a randomized controlled trial. Delta-9tetrahydrocannabinol shows antispastic and analgesic effects in a single case double-blind trial.
Prior advances in related areas of medicine have resulted from a close dialogue between researchers working in clinical and basic areas erectile dysfunction uncircumcised buy discount tadalis sx online. It is essential to stimulate such dialogue in research on the biological aspects of mental illness other uses for erectile dysfunction drugs buy tadalis sx from india. In particular impotence guidelines buy tadalis sx 20 mg with amex, research should be pursued that studies components of psychological processes across developmental periods using comparable methodologies in humans and other species erectile dysfunction after radiation treatment prostate cancer buy tadalis sx 20 mg low price. This research might begin by examining relatively well-understood phenomena what age does erectile dysfunction usually start order 20mg tadalis sx otc, such as attention regulation impotence quitting smoking buy tadalis sx mastercard, socialization, and the expression of fear or nurturing behaviors. Third, developmental perspectives on many chronic mental disorders emphasize the need for research on prevention. A few controlled prevention studies have begun to target such risk factors, but as knowledge of risk factors and their amenability to intervention increase, controlled prevention trials should also increase. In another set of studies, some of the proposed new psychiatric assessment tools described earlier in this chapter might be embedded within research designs where there is knowledge of the genetics. This could provide knowledge on other potential risk markers to be targeted in future prevention trials. Although prior studies established the familial nature of many mental syndromes, integrating diverse measures into future studies may elucidate mechanisms through which risk, protection, and diagnoses are transmitted from parents to children. Fourth, developmental perspectives have also heightened interest in procedures for making diagnoses among preschoolers. Studies are needed to evaluate procedures for applying current criteria sets to this population, for evaluating the properties of these criteria sets, and for considering alternative procedures or potential alternative criteria for use in this population. In closing, understanding of psychopathology has advanced enormously during the past two decades. Moreover, the fields related to developmental psychopathology have witnessed particularly marked advances. This chapter reviews the nature of advances in relevant developmental science, and it outlines a set of central questions that follow from such advances. Res Dev Disabil 17:4157, 1996 American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th Edition. Nat Genet 23:185188, 1999 Angold A: Assessment in child and adolescent psychopathology, in the New Oxford Textbook of Psychiatry. Arch Gen Psychiatry 57(10):979986, 2000 Avenevoli S, Stolar M, Li J, et al: Comorbidity of depression in children and adolescents: models and evidence from a prospective high-risk family study. Biol Psychiatry 49(12):10711081, 2001 Berkson J: Limitations of the application of fourfold table analysis to hospital data. Child Dev 45:15, 1974 Bronfenbrenner U: Toward an experimental ecology of human development. J Child Psychol Psychiatry 6:871889, 1990 Canino G, Lewis-Fernandez B: Methodological challenges in cross-cultural mental health research. Arch Gen Psychiatry 53:10331039, 1996 Cicchetti D: the emergence of developmental psychopathology. J Am Acad Child Adolesc Psychiatry 30:989993, 1991 Cohen P, Cohen J, Kasen S, et al: An epidemiological study of disorders in late childhood and adolescence, I: Age- and gender-specific prevalence. New York, Guilford, 1993, pp 225235 Erlenmeyer-Kimling L: Neurobehavioral deficits in offspring of schizophrenic parents: liability indicators and predictors of illness. J Am Acad Child Adolesc Psychiatry 32(2):419423, 1993 Garber J: Classification of childhood psychopathology: a developmental perspective. Child Dev 55:3048, 1984 Gersten M: the contribution of temperament to behavior in natural contexts. Child Dev 58:601622, 1987 Gould E, Tanapat P, Rydel T, et al: Regulation of hippocampal neurogenesis in adulthood. Am J Psychiatry 156(9):13221327, 1999 Ialongo N, Edelsohn G, Werthamer-Larsson L, et al: the course of aggression in first-grade children with and without comorbid anxious symptoms. Phobia, generalized anxiety disorder, panic disorder, bulimia, major depression, and alcoholism. Curr Opin Neurobiol 9:203208, 1999 Kolb B, Forgie M, Gibb R, et al: Age, experience, and the changing brain. Am J Psychiatry 157:15841591, 2000 Lewis-Fernandez R, Kleinman A: Culture, personality, and psychopathology. J Clin Child Psychol 28:322332, 1999 Maier W, Lichtermann D, Minges J, et al: Continuity and discontinuity of affective disorders and schizophrenia: results of a controlled family study. Arch Gen Psychiatry 50:871883, 1993 Maier W, Lichtermann D, Minges J: the relationship between alcoholism and unipolar depression-a controlled family study. Am J Psychiatry 155:479485, 1998 Neeleman J, Wessely S, Wadsworth M: Predictors of suicide, accidental death, and premature natural death in a general-population birth cohort. Neurosci Res 38:437446, 2000 Nolen-Hoeksema S: An interactive model for the emergence of gender differences in depression in adolescence. Am J Public Health 78(10):13151321, 1988 Paus T, Zijdenbos A, Worsley K, et al: Structural maturation of neural pathways in children and adolescents: in vivo study. J Am Acad Child Adolesc Psychiatry 40(6):685695, 2001 Pickens R, Svikis D, McGue M, et al: Heterogeneity in the inheritance of alcoholism: a study of male and female twins. Am J Psychiatry 156:133 135, 1999 Power C, Hertzman C, Matthews S, et al: Social differences in health: life-cycle effects between ages 23 and 33 in the 1958 British birth cohort. Proceedings of the Royal Society of Medicine 59:382387, 1966 Rutter M, Graham P: the reliability and validity of the psychiatric assessment of the child, I: interview with the child. Dev Psychopathol 12:265296, 2000 Shaffer D, Richters J (eds): Assessment in Child and Adolescent Psychopathology. Nature 410(6826):372376, 2001 Silberg J, Pickles A, Rutter M, et al: the influence of genetic factors and life stress on depression among adolescent girls. Arch Gen Psychiatry 54:801808, 1997 Simonoff E, Pickles A, Meyer J, et al: Genetic and environmental influences on subtypes of conduct disorder behavior in boys. Child Dev 55:1729, 1984 Steffenburg S, Gillberg C, Steffenburg U: Psychiatric disorders in children and adolescents with mental retardation and active epilepsy. Psychol Med 26(5):963973, 1996 Tiihonen J, Isohanni M, Rasanen P, et al: Specific major mental disorders and criminality: a 26-year prospective study of the 1966 northern Finland birth cohort. Nature 400:766768, 1999 Zero to Three: Diagnostic Classification, 03: Diagnostic Classification of Mental Health and Developmental Disorders of Infancy and Early Childhood. In this chapter we review both the current status and problems in each of these areas and offer suggestions for a possible research agenda that might provide the empirical base to allow a solution to the problems and gaps that have been identified. Maladaptive personality traits can have a significant impact on other mental disorders and on physical disorders, and might themselves result in clinically significant impairments to social or occupational functioning or personal distress (Livesley 2001; Millon et al. For example, one of the more well-validated personality disorders is the antisocial or psychopathic personality disorder (Stoff et al. Persons who have a personality disturbance that meets the various diagnostic criterion sets for this personality disorder have been shown to be at significant risk for unemployment, impoverishment, injury, violent death, substance and alcohol abuse, incarceration, recidivism (parole violation), and significant relationship instability (Hart and Hare 1997; L. This section focuses on two related issues around which confusion and lack of clarity exists: one is how best to describe and conceptualize the maladaptive personality patterns themselves; the other is the nature of the relationship between maladaptive personality patterns/traits/disorders and Axis I disorders. However, a variety of studies using diverse methodologies have raised compelling concerns regarding the validity of this assumption of distinct diagnostic categories (Clark et al. There does not appear to be a qualitative distinction between normal personality functioning and personality disorder, nor does there appear to be a qualitative distinction among the individual personality disorders. They reported that "the personality disorders led the list of diagnostic categories with which respondents were dissatisfied" (Maser et al. The personality disorders were considered to be problematic by 56% of the respondents. The second most frequently cited category were the mood disorders, cited by only 28%. Much of this dissatisfaction could be secondary to the inadequacies, limitations, and problems generated by the categorical model of classification. Researchers have been unable to identify a qualitative distinction between normal personality functioning and personality disorder. No explanation, rationale, or justification has been provided for any of the other diagnostic thresholds, and the justification for the thresholds for the borderline and schizotypal diagnoses may no longer apply (Widiger 2001). For example, much of the symptomatology of borderline personality disorder can be understood as extreme variants of the angry hostility, vulnerability, anxiousness, depressiveness, and impulsivity included within the broad domain of neuroticism (identified by others as negative affectivity or emotional instability) that is evident within the general population (Clarkin et al. Similarly, much of the symptomatology of antisocial personality disorder appears to be extreme variants of low conscientiousness (rashness, negligence, hedonism, immorality, undependability, and irresponsibility) and high antagonism (manipulativeness, deceptiveness, exploitativeness, aggressiveness, callousness, and ruthlessness) that have long been evident within the general population (Miller et al. Livesley and colleagues (1998) compared the phenotypic and genetic structure of a comprehensive set of personality disorder symptoms in samples of 656 personality disorder patients, 939 general community participants, and 686 twin pairs. Principal components analysis yielded four broad dimensions (emotional dysregulation, dissocial behavior, inhibitedness, and compulsivity) that were replicated across all three samples. The researchers concluded that "the stable structure of traits across clinical and nonclinical samples is consistent with dimensional representations of personality disorders" (Livesley et al. Research has also failed to support the existence of qualitatively distinct boundaries among the personality disorder diagnostic categories. In fact, research has consistently indicated the presence of excessive diagnostic co-occurrence (Bornstein 1998; Lilienfeld et al. They reported that administration of one of the interviews resulted in the diagnosis of 290 personality disorders in the 100 patients; administration of the other interview resulted in 249 diagnoses. Fewer than 15% of the patients had a personality disturbance that met the criteria for just one personality disorder. These findings were consistent with previously published comorbidity studies (Widiger et al. They conducted independent principal-axes confirmatory factor analyses for alternative dimensional models on 12 correlation matrices provided in the nine studies. The personality disorder matrices were rotated to a least-squares fit to the target matrices generated by the alternative dimensional models. Highly significant congruence coefficients were obtained for all 12 correlation matrices for two of the dimensional models. The apparent imposition of arbitrary categorical distinctions on what might instead be dimensions of personality functioning appear to have contributed to a number of diagnostic quandaries, frustrations, and dilemmas for the practicing clinician, including the presence of overly heterogeneous diagnostic categories, inadequate coverage of clinically significant maladaptive personality traits, problematic differential diagnoses, and confusing multiple diagnoses (Clark et al. These monothetic criteria sets would presumably identify relatively homogeneous groups of persons. However, it quickly became evident that the reality did not match the assumption of diagnostic homogeneity. The vast majority of persons with personality disorders do Personality Disorders and Relational Disorders 129 not match prototypical cases. The polythetic format is more consistent with clinical reality but it also results in substantial diagnostic heterogeneity (Clarkin et al. There is considerable variability among patients with the same personality disorder diagnosis, which contributes to inconsistent clinical description and research findings. In some instances, patients can even have the same personality disorder diagnosis but have none of the same diagnostic criteria. Nevertheless, the broader polythetic diagnostic criteria sets have still failed to result in an adequate coverage of clinical cases. Clinicians also fail to recognize the entire array of personality disorder symptoms that are typically present in their patients. Sixty-five percent of the clinicians provided only one diagnosis, 28% provided two, and none provided all four. The reason that clinicians provide only one personality disorder diagnosis per patient is unclear. One possibility is the failure to conduct systematic or comprehensive assessments; another possibility is that the presence of multiple personality disorder diagnoses is confusing and inconsistent with clinical theory. Patients have just one personality (excluding those with a dissociative disorder); it is inconsistent with most clinical theory to suggest that a person has two, three, or even five qualitatively distinct personality disorders, each with its own particular etiology and pathology (Lilienfeld et al. It might be more consistent with clinical theory to indicate that a patient has one personality disorder, characterized by the presence of a variety of maladaptive personality traits (Widiger and Costa 1994). The presence of alternative dimensional models of personality disorder is itself an indication of the theoretical, scientific, and clinical interest Personality Disorders and Relational Disorders 131 in the development of this alternative method for diagnosis and classification. The viability of a dimensional model of personality disorder is becoming increasingly recognized by theorists and researchers (Oldham and Skodol 2000; Widiger 1992), and one expected response would be the development of alternative models. Some of the proposed models have been developed largely on the basis of theoretical reasoning informed by research. The models can also be differentiated with respect to whether they are confined largely to personality disorder symptomatology. The generation of alternative dimensional models may continue until an authoritative or governing body imposes or compels a uniform classification of general personality functioning. No comparable authority or control is present in the classification and assessment of general personality functioning. It is apparent from simply scanning the constructs presented in Table 41 that there should be substantial convergence among these alternative dimensional models. The domains of functioning that they cover overlap substantially, and the ways in which these models cover these domains are in some cases quite comparable. An important and fundamental question is the extent to which alternative dimensional models of general personality functioning would or could adequately represent the personality disorder psychopathology diagnosed by the existing diagnostic categories. If dimensional models of personality disorder were to replace the existing diagnostic categories, it would be important to indicate that the symptomatology and traits covered by the existing categories would still be covered by the dimensional model. Nevertheless, compelling criticisms of the decision to downgrade the passive-aggressive personality disorder diagnosis to the appendix have been raised (Wetzler and Morey 1999), proposals for a depressive personality disorder diagnosis have been offered (Huprich 1998; Phillips et al. An important question for future research is how best to obtain a scientifically based decision for what constitutes a necessary or adequate coverage of maladaptive personality functioning. With respect to the alternative dimensional models, future research should address the question of which model best provides the fundamental biobehavioral dimensions that constitute temperament and personality. The existing dimensional models do offer theoretical and empirical arguments for what are proposed by these models to be the fundamental biobehavioral dimensions of personality functioning (Benjamin 1993; Clark et al. An important scientific and clinical question is which model best accounts for the behavioral, neurobiological, genetic, and epidemiologic data. The decision of which dimensional model is to be used in clinical practice should be informed by scientific research that compares the alternatives with respect to clinical utility and predictive validity, as well as other forms of construct validity, rather than leaving any such future decisions to subjective or arbitrary decisions that are only weakly guided by empirical data.
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