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P. Reto. Saint Andrews Presbyterian College.

Learning and memory in University Press discount 5 mg hytrin visa, 1998:251–376 purchase 2 mg hytrin with mastercard. Plasma membrane transport- bridge University Press order hytrin 5 mg on-line, 1995. COYLE Until recently, the developmental aspects of psychiatry were grounds for linking behavioral pathology to specific devel- at best tenuously connected to the rapidly advancing neuro- opmental processes. To a significant Wassink and his colleagues review the very promising extent, this reflected the historical accident that child psy- and rapidly advancing area of the genetics of autism and chiatry evolved out of the child guidance movement, which related pervasive development disorders. From being mis- had a psychosocial orientation and was not associated with perceived as being caused by poor maternal care ('refrigera- medical schools. Nevertheless, the last decade has witnessed tor mother'), autism is now known to be highly heritable, a remarkable advancement in the appreciation of the neuro- resulting from the interaction of several genes. McDougle biologic underpinnings of behavioral disorders affecting reviews the evidence that psychotropic medications can at- tenuate specific subsets of symptoms and pathologic behav- children. For With increasing evidence of genetic risk factors for psy- too long, this area of the psychopharmacologic management chiatric disorders, the developmental features that transform of developmental disorders has rested on anecdotes and genetic risk to phenotype have become of particular interest hunches; but, increasingly now, these issues are being ad- to psychiatric research, especially with regard to prevention. Furthermore, family studies are disclosing the early the subject of criticism by those who oppose psychopharma- manifestations of serious psychiatric illness including affec- cology, recent research has elucidated the pathophysiology tive disorders, anxiety disorders, and schizophrenia in chil- of the disorder, thereby establishing face validity for the dren, raising the question of appropriate pharmacologic diagnosis. Faraone and Biederman provide a thorough re- treatments. To this end, the Food and Drug Administration view of the area with special emphasis on the genetics of (FDA) is now requiring the pharmaceutical industry to carry ADHD. In a related and often co-morbid clinical condi- out controlled studies of the efficacy of all drugs that might tion—learning disorders—much progress has been made be used in the treatment of children, and the National Insti- in understanding the neurobiologic mechanisms as well as tute of Mental Health (NIMH) has funded the Research characterizing effective interventions, as reviewed by Con- Units on Pediatric Psychopharmacology (RUPP) to provide ners and Schulte. The chapters in this section demonstrate the scientific Joshi and Towbin provide a lucid analysis of the causes of vigor and rigor that are transforming pediatric neuropsycho- psychosis and how to treat them. This is especially so for those disorders that an overview of the emerging area of behavioral phenotypes have traditionally been at the borderlands between psychia- of neurodevelopmental disorders. Careful analysis has dif- try and developmental pediatrics that now provide fertile ferentiated subtypes of developmental disorders in which 548 Neuropsychopharmacology: The Fifth Generation of Progress specific behaviors can be linked to specific genes or groups children are simply small adults, who should exhibit compa- of genes in the case of deletions or reduplications. Nevertheless, the advances in advances have important implication for the field of behav- pediatric neuropsychopharmacology raise important ques- ioral genetics. VIELAND JOSEPH PIVEN Autism is a behavioral syndrome that is generally associated included elaborate stereotyped behaviors (e. Epidemio- or environment)as an essential, pathognomonic compo- logic research over the past two decades has demonstrated nent. The severity of this component, however, has gradu- a significant role for hereditary factors in the etiology of ally been relaxed so that current criteria require the presence autism, stimulating an aggressive search for susceptibility of only milder behaviors in this domain. This chapter summarizes these efforts to elucidate Similarly, the concept of autism itself has been broadened the genetic basis of this severe neurodevelopmental disorder. The validity of these diagnostic distinctions, how- ritualistic and repetitive behaviors, deficits in communica- ever, is open to question. While the gene that causes Rett tion, and abnormal social interaction. These domains en- syndrome has recently been identified (1), and disintegrative compass a broad spectrum of behavioral and cognitive ab- disorder involves a clear loss of function that is likely to normalities such as speech delay, echolalia, decreased arise from a distinct mechanism, there is little evidence to spontaneous affection, reduced eye-to-eye gaze, motor ste- support the remaining PDDs being etiologically distinct. The onset of autism is variable, typically manifesting spectrum of related disorders demonstrate the complexity at age when the normal complements, such as speech and of the autism phenotype. The core symptom domains exist prosocial activity, to the disturbed behaviors are expected in varying combinations of severity across affected individu- to develop (usually by the age of 2). Symptoms change with als, and it is unclear whether these clinically defined do- development and generally continue throughout life. Less severe symp- first described in 1943, infantile autism was narrowly de- tomatology is represented as a distinct diagnostic entity, but fined, referring to a population of children with severe man- again whether this is genetically justified is not known. Kanner, for example, in his original descriptions of autism, Mental Retardation Thomas H. Wassink: Department of Psychiatry, University of Iowa Adding to the phenotypic complexity is the wide range of College of Medicine, Iowa City, Iowa. Sutcliffe: Program in Human Genetics, Department of Molecu- autism have normal or even exceptional IQs, 70% to 80% lar Physiology and Biophysics, Vanderbilt University Medical Center, Nash- ville, Tennessee. Vieland: Department of Biostatistics, University of Iowa with mental retardation (MR)are in the mildly affected College of Public Health, Iowa City, Iowa Joseph Piven: North Carolina Mental Retardation Research Center, Uni- range, the remainder have moderate to severe deficits, and versity of North Carolina, Chapel Hill, North Carolina. With the incorporation of less stringent Hyperserotonemia was the first biological abnormality to criteria into the Diagnostic and Statistical Manual of Mental be reported, found by some in up to one-fourth of autistic Disorders (DSM)and the International Classification of individuals (3).

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For patients with extrem e cation-exchange resins or dialysis buy hytrin 5mg with visa, as leukocytosis or throm bocytosis buy hytrin 1mg fast delivery, potassium levels should be m easured in plasm a sam ples attem pts at shifting potassium back into that have been prom ptly separated from the cellular com ponents since extrem e elevations in cells m ay not be successful generic hytrin 2 mg amex. N orm okalem ia can be m aintained in patients who consum e norm al quantities of potassium until GFR decreases to less than 10 m L/m in; however, dim inished GFR predisposes patients to hyperkalem ia from excessive exogenous or endogenous potassi- um loads. H idden sources of endogenous and exogenous potassium — and drugs that pre- dispose to hyperkalem ia— are listed. FIGURE 3-25 Approach to hyperkalemia: hyporeninemic hypoaldosteronism. Hyporeninemic hypoal- dosteronism accounts for the majority of cases of unexplained hyperkalemia in patients with reduced glomerular filtration rate (GFR) whose level of renal insufficiency is not what would be expected to cause hyperkalemia. Interstitial renal disease is a feature of most of the diseases listed. Although the transtubular potassium gradient should be low in both disorders, exogenous mineralocorticoid would normal- ize transtubular potassium gradient in hyporeninemic hypoaldosteronism. Secretion of potassium in the cortical collecting duct and outer medullary collecting duct accounts for the vast majority of potassium excreted in the urine. Potassium secretion in these segments is influenced mainly by aldosterone, plasma potassi- um concentrations, and the anion composition of the fluid in the lumen. Use of the TTKG assumes that negligible amounts of potassi- um are secreted or reabsorbed distal to these sites. The final urinary potassium concentration then depends on water reabsorption in the medullary collecting ducts, which results in a rise in the final urinary potassium concentration without addition of significant amounts of potassium to the urine. The TTKG is calculated as follows: TTKG = ([K+]urine/(U/P)osm )/[K+]plasm a The ratio of (U/P)osm allows for “correction” of the final urinary potassium concentration for the am ount of water reabsorbed in the medullary collecting duct. In effect, the TTKG is an index of the gradient of potassium achieved at potassium secretory sites, indepen- dent of urine flow rate. The urine must at least be iso-osmolal with respect to serum if the TTKG is to be meaningful. FIGURE 3-27 CAUSES FOR HYPERKALEMIA W ITH AN Clinical application of the transtubular potassium gradient (TTKG). INAPPROPRIATELY LOW TTKG THAT IS UNRESPONSIVE The TTKG in normal persons varies much but is genarally within TO MINERALOCORTICOID CHALLENGE the the range of 6 to 12. Hypokalemia from extrarenal causes results in renal potassium conservation and a TTKG less than 2. A higher value suggests renal potassium losses, as through hyperaldostero- Potassium-sparing diuretics Increased distal nephron potassium nism. The expected TTKG during hyperkalemia is greater than 10. Amiloride reabsorption An inappropriately low TTKG in a hyperkalemic patient suggests Pseudohypoaldosteronism type II hypoaldosteronism or a renal tubule defect. Administration of the Triamterene Urinary tract obstruction mineralocorticoid 9 -fludrocortisone (0. Circumstances are Tubular resistance to aldosterone listed in which the TTKG would not increase after mineralocorticoid Interstitial nephritis challenge, because of tubular resistance to aldosterone. Sickle cell disease Urinary tract obstruction Pseudohypoaldosteronism type I Drugs Trimethoprim Pentamidine Diseases of Potassium M etabolism 3. H eparin im pairs aldosterone synthesis by inhibiting the enzym e 18-hydroxylase. Despite its frequent use, heparin is rarely associated with overt hyperkalem ia; this suggests that other m echanism s (eg, reduced renal potassium secretion) m ust be present sim ultaneously for hyperkalem ia to m ani- fest itself. Both angiotensin-converting enzym e inhibitors and the angiotensin type 1 receptor blockers (AT1) receptor blockers interfere with adrenal aldosterone synthesis. FIGURE 3-29 Approach to hyperkalem ia: pseudohypoaldosteronism. The m echa- nism of decreased potassium excretion is caused either by failure to secrete potassium in the cortical collecting tubule or enhanced reabsorption of potassium in the m edullary or papillary collecting tubules. Decreased secretion of potassium in the cortical and m edullary collecting duct results from decreases in either apical sodium or potassium channel function or dim inished basolateral N a+-K+-ATPase activity. Alternatively, potassium m ay be secreted norm ally but hyperkalem ia can develop because potassium reab- sorption is enhanced in the intercalated cells of the m edullary col- lecting duct (see Fig. The transtubule potassium gradient (TTKG) in both situations is inappropriately low and fails to nor- m alize in response to m ineralocorticoid replacem ent. This rare autosom ally transm itted disease is characterized by neonatal dehydration, failure to thrive, hyponatrem ia, hyper- kalem ia, and m etabolic acidosis. Kidney and adrenal function are norm al, and patients do not respond to exogenous m ineralocorti- coids. Genetic m utations responsible for PH A I occur in the and subunits of the am iloride-sensitive sodium channel of the collecting tubule. Fram eshift or prem ature stop codon m utations in the cyto- plasm ic am ino term inal or extracellular loop of either subunit dis- rupt the integrity of the sodium channel and result in loss of chan- nel activity. Failure to reabsorb sodium results in volum e depletion and activation of the renin-aldosterone axis. Furtherm ore, since sodium reabsorption is indirectly coupled to potassium and hydro- gen ion secretion, hyperkalem ia and m etabolic acidosis ensue.

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Characterization of mechanical Arch Pharmacol 1995;352:565–575 hytrin 1mg on-line. Opposite modulation of nists in normal and -opioid receptor knockout mice discount 2mg hytrin otc. Brain Res opiate withdrawal behaviors on microinfusion of a protein kinase 1999;821:480–486 buy 5 mg hytrin with amex. Ainhibitor versus activator into the locus coeruleus or periaque- 65. Terwilliger RZ, Beitner-Johnson D, Sevarino KA, et al. Disruption of the - mediating the chronic actions of morphine and cocaine on neu- opioid receptor gene in mice enhances sensitivity to chemical ronal function. Involvement -agonist U-50,488H and attenuates morphine withdrawal. KOR-1: evidence for multiple kappa analgesic mechanisms. Quantitative autoradiogra- calmodulin-dependent protein kinase and protein kinase C. Can phy of mu, delta, and kappa1 opioid receptors in kappa-opioid J Neurosci 1995;15:2396–2406. Drugs of abuse and striatal gene expres- kinase C, but not of protein kinase A, blocks the development sion. Pain responses, anxiety mu-opioid receptor agonist in the mouse. Eur J Pharmacol 1995; and aggression in mice deficient in pre-proenkephalin. Region-specific up- ment in homologous desensitization of delta-opioid coupled to regulation of opioid receptor binding in enkephalin knockout Gi1-phospholipase C activation in Xenopus oocytes. Morphine activates opioid response and dysregulation of hearing ability in mice lacking the receptors without causing their rapid internalization. Targeted disruption nalization: opiate drugs have differential effects on a conserved of the orphanin FQ/nociceptin gene increases stress susceptibility endocytic mechanism in vitro and in the mammalian brain. Nociceptin/orphanin FQ regu- opioid receptor signaling and endocytosis: implications for lates neuroendocrine function of the limbic-hypothalamic-pitui- the biology of opiate tolerance and addiction. Enhanced mor- potentiation and memory in mice lacking nociceptin receptors. Morphine activated opioid recep- rat of brain sites sensitive to the direct application of morphine: tors elude desensitization by beta-arrestin. Proc Natl Acad Sci U observation of differential effect within the periaqueductal gray. Antagonism of stimulation- behavior, and sexual function in opioid receptor-deficient mice. Neurotransmitters in noci- phine-induced analgesia, reward effect and withdrawal symptoms ceptive modulatory circuitries. Annu RevNeurosci 1991;14: in mice lacking the -opioid receptor gene. Descending antinociceptive mechanisms in the brain- 61. J Physiol Paris of morphine-immunosuppression in mice lacking the -opioid 1996;20:15–25. Quantitative audioradio- expression in the rat CNS: anatomical and functional implica- graphic mapping of mu-, delta-, and kappa-opioid receptors in tions. Cellular mechanisms for anti- opioid receptor is maintained in mice lacking the -receptor. J analgesic action of agonists of the -opioid receptor. Jessel T, Iversen L, Opiate analgesics inhibit substance P release 92. Localization of or- from the rat trigeminal nucleus. Intrathecal morphine inhibits tral nervous system of the rat. J Comp Neurol 1999;406: substance P release from mammalian spinal cord in vivo. Spinal opioid analge- of intrathecally administered nociceptin, an opioid-receptor like sia: how critical is the role substance P signaling? Formalin pain is expressed in decere- tin: potent antinociceptive effect of orphanin FQ/nociceptin in brate rats but is not attenuated by morphine. Naloxone-sensitive or- phanin FQ-induced analgesia in mice.

This of interaction between loci all remain unknown order hytrin 2mg. The contri- rate is considerably higher than the rates of schizophrenia bution of individual genes to the familiality of a disorder or schizotypal personality disorder likely to develop in first- can be expressed in terms of (s (i purchase hytrin 1 mg with amex. The false-positives were largely the patible with the existence of a single locus having a value consequence of a combination of multiple testing and the of (s greater than 3 discount 1mg hytrin free shipping. Unless extreme epistasis (interaction use of statistical methodology and significance levels derived between loci) exists, models with two or three loci having from work on single-gene disorders. It should be Despite the failure to identify regions of unambiguous emphasized that these calculations are based on the assump- linkage in multiply affected families, modest evidence for tion that the effects of genes are distributed equally across several regions has been reported in more than one data set. It is quite possible that genes of larger Areas implicated for which supportive data have also been effect are operating in a subset of patients—for example, obtained from international collaborative studies include those from families with a high density of illness. A number of other promising evidence that genetic factors increase the risk for schizophre- areas of putative linkage are also currently under investiga- nia. However, although it is possible to state that, as a group, tion by international consortia. However, in each general population, it is not currently possible to translate case, both negative and positive findings have been ob- this figure to the level of risk for a particular sibling in a tained, and in only two cases, those of chromosomes particular family. Another These positive findings contrast with those from a large important point is that risk to related individuals does not systematic search for linkage in which a sample of 196 af- directly equate with genetic risk because some relatives carry fected sibling pairs, drawn typically from small nuclear fami- one or more susceptibility alleles for schizophrenia but re- lies rather than extended pedigrees, was used (101). In other words, the results of simulation studies suggest that the power of this accumulation of susceptibility alleles, environmental risk study is greater than 0. This study yielded evidence at the level of the definition of Lander and Kruglyak (102) of 'suggestive' linkage to chromosomes 4p, 18p, and Xcen. However, none MOLECULAR GENETICS: LINKAGE STUDIES of the findings approached a genome-wide significance of 0. This was done in the hope that such families, in the search for genes for complex traits (103–106). First, or at least a proportion of them, were segregating genes of no finding is replicated in all data sets. Second, levels of sufficiently large effect that they could be detected unequiv- statistical significance are unconvincing and estimated effect ocally in this way. This approach has been successful in sizes are usually modest. Third, chromosomal regions of other complex disorders—Alzheimer disease, for example, interest are typically broad [often 20 to 30 centimorgan in which mutations in three genes, APP, PS1, and PS2, are (cM)]. In such At the present time, therefore, the linkage literature sup- cases, the disease is of unusually early onset and is transmit- ports the predictions made by Risch (79); it is highly un- ted through multiplex pedigrees in an autosomal dominant likely that a commonly occurring locus of effect size [(s] fashion (80–82). Studies of such large families also initially gions suggest that rarer alleles of larger effect may be segre- produced positive findings in schizophrenia (83), but unfor- gating in some large, multiply affected families. The reasons for this Linkage methods in sample sizes that are realistically have become clear as data from systematic genome scans achievable can detect smaller genetic effects than those in have accumulated; highly penetrant mutations causing the studies to date. For example, it is possible to detect schizophrenia are at best extremely rare and quite possibly alleles with values of (s of 1. However, the purpose of experiment is to reject that priority should now be given to collecting such samples a null hypothesis, and in the face of uncertainty, the burden with a robust clinical methodology that is comparable across of proof remains with the proponents of a particular candi- all interested research groups. Overall, the results in this extensive literature CANDIDATE GENE ASSOCIATION STUDIES are disappointing, but it should be noted that the sample sizes in many of the older studies would now generally be Once genes of smaller effect than (s 1. For this reason, many research- represent functional variants and that few genes have been ers have tried to take advantage of the potential of candidate systematically screened even for common functional var- gene association studies to identify such loci (109,110). However, more promising reports of candidate gene though a potentially powerful means of identifying genes associations have recently appeared, three of which are con- of small effect, association studies are not without their sidered here. First, for a complex and poorly understood disor- der such as schizophrenia, the choice of candidate genes Serotonin 5-HT2A-Receptor Gene is limited largely by the imagination and resources of the researcher. This places a stringent burden of statistical proof Many novel antipsychotic drugs affect the serotoninergic on positive results because of low prior probability and mul- system. The first genetic evidence that serotoninergic recep- tiple testing (111). Second, case–control association studies tors may play a role in schizophrenia came from a Japanese have the potential to generate false-positives because of pop- group reporting an association between a T-to-C polymor- ulation stratification. This problem can be addressed by phism at nucleotide 102 in the 5-HT2A-receptor gene in a using family-based association methods (112), but because small sample (114). A large European consortium compris- of stigma, adult age at onset, and the disruptive effects of ing seven centers and involving 571 patients and 639 con- mental illness on family relationships, family-based samples trols then replicated this finding (115), which was further may be unrepresentative in addition to limited in size. Con- replicated with use of a family-based design (116). Although sequently, family-based studies may introduce more spu- many other studies followed with mixed results, a recent rious results than do case–control studies (113). It would metaanalysis of all available data from more than 3,000 seem unwise, therefore, to discard the case–control study subjects supports the original finding (p. A third problem common to all molecular genetic (117).

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