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Arterial hypertension is the presenting clinical Clinical End-stage Death finding in about 20% of patients purchase urispas 200 mg otc. The differential diagnosis of acute abdom inal is detailed in Figure 9-22 purchase 200 mg urispas with amex. Gross hem aturia is m ost often due to bleeding into a cyst quality 200 mg urispas, and m ore rarely to stone discount urispas 200 mg with visa. Renal infection urispas 200mg overnight delivery, a frequent reason FIGURE 9-19 for hospital adm ission, can involve the upper collecting system , Autosom al-dom inant polycystic kidney disease (ADPKD): pheno- renal parenchym a or renal cyst. Diagnostic data are obtained by type PKD2 versus PKD1. Fam ilies with a PKD2 m utation have a ultrasonography, excretory urography and CT: use of CT in cyst m ilder phenotype than those with a PKD1 m utation. In this study infection is described in Figure 9-21. Frequently, stones are radiolu- com paring 306 PKD2 patients (from 32 fam ilies) with 288 PKD1 cent or faintly opaque, because of their uric acid content. The m ain patients (17 fam ilies), PKD2 patients were, for exam ple, less likely determ inants of progression of renal failure are the genetic form of to be hypertensive, to have a history of renal infection, to suffer a the disease (see Fig. H epatobiliary and intracranial m anifestations are detailed a consequence of the slower developm ent of clinical m anifestations, in Figures 9-23 to 9-26. Pancreatic and arachnoid cysts are m ost PKD2 patients were, on average, 26 years older at clinical presen- usually asym ptom atic. Spinal m eningeal diverticula can cause pos- tation, 14 years older when they started dialysis, and 5 years older tural headache. Early-onset ADPKD leading to renal failure in childhood has been reported only in the PKD1 variety. Exam ples of various cystic involvem ents of kidneys in stage of the disease, m aking the diagnosis m ay be m ore difficult (see ADPKD. Degree of involvem ent depends on age at presentation and Fig. A, W ith advanced disease as in this 54-year-old of ADPKD in PKD1 fam ilies). C, D, Contrast-enhanced CT is m ore wom an, renal parenchym a is alm ost com pletely replaced by innu- sensitive than ultrasonography in the detection of sm all cysts. B, presence of liver cysts helps to establish the diagnosis, as in this 38- M arked asymmetry in the number and size of cysts between the two year-old m an with PKD2 disease and m ild kidney involvem ent. Course of severe cyst infection in the right kidney of showed considerable enlargem ent of the infected cysts (arrows). This case illustrates the potential severity of cyst perform ed on adm ission showed several heterogeneous cysts in the infection and the contribution of sequential CT in the diagnosis right kidney (arrows). Infection did not respond to appropriate and m anagem ent of com plicated cysts. FIGURE 9-22 ADPKD: SPECIFIC CAUSES OF Autosomal-dominant polycystic kidney disease (ADPKD): specific ACUTE ABDOM INAL PAIN causes of acute abdominal pain. The most frequent cause of acute abdominal pain related to ADPKD is intracyst bleeding. Depending on the amount of bleeding, it may cause mild, transient fever. It may Cause Frequency Fever or may not cause gross hematuria. Cyst hemorrhage is responsible for most high-density cysts and cyst calcifications demonstrated by CT. Excretory urography or enhanced Cyst Bleeding ++++ Mild (<38°C, maximum 2 days) or none CT is needed mostly to locate obstructive, faintly opaque stones. Stone ++ W ith pyonephrosis Stones may be treated by percutaneous or extracorporal lithotripsy. Infection + High; prolonged with cyst involved Renal infection may involve the upper collecting system, Liver Cyst renal parenchyma, or cyst.

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The mRNA levels for extracellular dopamine when cocaine was added to heroin both dopamine D1 and D2 receptors was reduced after 1 in self-administration studies (66) cheap 200mg urispas visa. These findings may ex- day of withdrawal purchase urispas 200 mg overnight delivery, and both returned toward normal by plain order urispas 200 mg visa, in part order 200 mg urispas, the common co-dependency in humans of the third day after drug withdrawal discount urispas 200 mg. These findings may be both heroin and cocaine addictions. However, curiously in this neurons completely in discrete brain regions by use of a study, but not in other studies, reductions of mRNA levels neurotoxin, 6-hydroxydopamine, self-administration of for dynorphin and enkephalin genes were found during morphine proceeded normally as in unlesioned animals. In contrast, enhanced dynorphin However, in such animals, cocaine self-administration was mRNA levels have been found at least after acute single and eliminated. Further studies will be needed to determine the time instance, in one study using the technique of in vivo fast course of dynorphin mRNA level changes during morphine cyclic voltammetry, it was found that heroin caused a dose- exposure. Trujillo, Akil, and their colleagues showed that dependent increase in dopamine in the nucleus accumbens chronic injection or infusion of morphine caused increases during heroin self-administration, and co-administration of in levels of dynorphin peptides in the dorsal striatum (cau- a -agonist (U-50,488 H) with the heroin, or alternatively, date putamen) but not in the ventral striatum (nucleus ac- intracerebroventricular administration of dynorphin A, sig- cumbens) (73). Moreover, installation of the -synthetic compound or only a few (approximately 20%) nucleus accumbens neu- natural ligand dynorphin A alone decreased basal dopamine rons seem to exhibit an inhibitory response after heroin self- release, as had also been shown by Claye and others (68). Thus, the multiple -agonist morphine activates the mesolimbic-mesocortical changes in signal transduction observed and discussed ear- dopaminergic pathway and that -opioid-receptor activa- lier, including the effects of chronic morphine administra- 35 tion offsets, or counterregulates, that activation (67). In related studies, these investigators result from a direct opiate effect or an indirect effect by found, as have numerous others, that cocaine caused a strik- alteration of the dopaminergic system (40,42). Similar find- ing increase in extracellular dopamine concentrations in the ings were made by the group of Sim-Selley, Selley, Childers, nucleus accumbens, and, moreover, the combination of co- and colleagues after chronic heroin self-administration, with caine and heroin caused a synergistic elevation (66). Their the greatest decrease in -opioid-receptor–stimulated 35 finding that heroin alone failed to cause an increase in dopa- [ S]GTP S binding in the brainstem and the lowest altera- mine in the nucleus accumbens complemented several ear- tions in binding in the striatum and cortex (42). Because lier findings that heroin self-administration is not attenu- the changes of dopamine D1-receptor activation would act ated by administration of dopamine antagonists, as well as in one direction and dopamine D2-receptor activation even earlier studies showing that integrity of dopamine would act in the opposite direction on adenylyl cyclase activ- pathways in the nucleus accumbens is not essential for her- ity, the effects on these receptors could also influence the oin self-administration. These findings document further effects of -opioid-receptor activation, and the changes that the early hypothesis of the Kreek laboratory, and many oth- have been observed may result exclusively from the opioid ers, that the reinforcing properties of heroin are mediated effects acting at the -opioid receptors or also secondary primarily by dopamine-independent mechanisms and prob- indirect effects on dopamine receptors. This hypothesis has These and other findings suggest that opiates may act 1496 Neuropsychopharmacology: The Fifth Generation of Progress directly to alter dopaminergic systems both in the ventrome- that is, the neuroplasticity after chronic opiate administra- dial striatum, that is, the core and shell of the nucleus ac- tion that results in impairment of normal neural integrity. Clearly, there are abundant - regulatory events may alter neural growth, development, opioid receptors as well as -opioid receptors in those re- and synapse formation, signal transduction, and overall sys- gions (26,75–77). Work from the Kreek laboratory showed tem integrity (24,79). There have been no similar expression, as well as more direct effects of enhanced tran- findings with respect to increasing -opioid-receptor den- scription factors on dynorphin gene expression, may be sity after chronic opioid administration, however. It is not again important counterregulatory events, which also repre- really known to what extent reinforcement or reward result- sent examples of profound neuroplasticity of the brain. Such ing from heroin and morphine occurs because of activation findings have also been made during binge pattern cocaine directly in these areas, especially the nucleus accumbens and administration (80,81). Enhanced dynorphin peptides, in possibly also the amygdala, as contrasted to indirect effects turn, acting at -opioid receptors, may reduce dopaminergic on the ventral tegmental area. The effects on dopamine tone in many brain regions, including those involved in in each of these different locations and also the different reward and also locomotor activity, and they may also atten- mechanisms involved have not yet been fully elucidated uate opioid withdrawal in dependent animals or humans using a model of chronic, high-dose, intermittent but evenly (6,8,9–11,16). Again, these events must be considered to spaced opiate administration, mimicking the human pattern be a direct result of neuroplasticity and are counterregula- of heroin or morphine abuse and addiction, and also after tory, the attempt to attenuate, modulate, or even brake the withdrawal, as well as during reexposure after such opiate events caused by the rapid changes in dopaminergic tone administration. During chronic binge pattern cocaine ad- brought about especially by stimulants such as cocaine, but ministration, a pattern mimicking the human condition, also to a lesser extent also by opiates. Noble edly primarily the result of the effects of chronic opioid and Cox clearly defined a role of the dopaminergic system in administration. However, because there are also significant opioid-receptor desensitization in these brain regions during changes in dopaminergic tone with enhanced signaling chronic morphine administration (39). This is a rate-limiting enzyme in the biosyn- tion of the dopaminergic neurons, as stated earlier. They also found a reduction in mean D5-type dopaminergic receptors enhance adenylyl cyclase size of the ventral tegmental area dopaminergic neurons and activity, an effect similar to that occurring in the locus ceru- decreased axonal transport to the nucleus accumbens (24, leus after chronic, but not acute, morphine administration, 79). However, there were no changes in numbers of dopa- in most strains of rodents studied, and also in the nucleus minergic neurons and no changes in the size of nondopami- accumbens in some strains of some species. Within ventral tegmental area, infusion activation of the dopaminergic D2 receptors causes a reduc- of brain-derived neurotrophic factor prevented this mor- tion in adenylyl cyclase activity, such as observed during phine-induced reduction in size of dopaminergic neurons acute morphine administration in all brain regions of strains (79). Their group also found that chronic morphine admin- and species of rodents studied, as well as in all cell systems istration resulted in an increase of other components related studied, and an effect that continues to pertain in some to signal transduction, including the extracellular signal reg- specific regions of the brain and other parts of the body ulated kinases (ERKs), which are effectors for brain-derived during chronic opioid administration.

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The most commonly used SWB assessment tool is the “Happiness scale” purchase 200 mg urispas visa. Evidence suggests greater happiness is associated with being married buy 200mg urispas overnight delivery, religious generic urispas 200 mg online, extraverted and optimistic 200 mg urispas free shipping. Wealthier people are consistently found to be happier than poorer people trusted 200 mg urispas, but the effects are small (once basic needs have been obtained). Genetic factors have a significant impact on long-term SWB. This is unsurprising, as we know genetics strongly influences temperament and personality. Positive life experiences (in the early years in particular) help shape the phenotype by epigenetic processes. Other major influences include our ability to adapt and set goals. The ability to adapt is a boon when it comes to adjusting to a loss, but also a drawback, as when a new 4-weel drive makes us happy, but only briefly. Goals can be helpful, even if they are unachievable, as long as progress is being made toward them. From the writer: With respect to striving for “happiness”, I suggest two “quotes” for consideration: 1. Introduction to pathological mood elevation Low mood takes various forms. It is often difficult to be sure whether an individual who is looking and sounding unhappy is suffering a pathological mood disorder. In general, pathological mood elevation is less difficult to identify. There is an unusual amount of energy: the individual moves, smiles and talks more, and more rapidly than usual (along with other symptoms). While most of us have times when we lack energy, few of us times when we have excessive energy. Hypomanic symptoms may occur in both bipolar disorder and the elevated phase of cyclothymic disorder. As these are matters of degree and judgement, in a particular case, clinicians may disagree on the appropriate designation. The important issue it to identify when treatment is indicated, and to provide that treatment. Mood elevation often presents with euphoria, disinhibition and excessive friendliness. A middle aged woman was admitted to hospital with mania. While on the ward she used acrylic paint to adorn her jeans with word including Joy, Love, Peace, Kindness and Patients. Across the seat she painted “I love (indicated by a symbol of a heart) life”. These additions reflected her euphoria, but also her lack of inhibition and poor judgement. When she recovered she regretted ruining new and expensive clothing (which she had purchased during a manic buying spree). A manic female went to an occupational therapy session and made a card for her doctor, which stated she was ready to leave hospital. The construction (different coloured papers and pieces of bright cloth) tended to contradict her written message. Irritability often emerges later in an episode of mania (perhaps in response to clinicians obstructing patient wishes), but it may also manifest as an early feature. An unsolicited letter from a woman with mania to a male member of the hospital staff. This staff member was not involved in the care of the patient, and they had not been introduced. Thus, the endearments at the beginning and end of the letter indicate disinhibition. The patient reports being unable to sleep at night (a common manic symptom).

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The term transgenic was applied to mice expressing exogenous DNA that had been produced using this technique (2) purchase urispas 200mg with mastercard. With this method urispas 200 mg visa, the gene of interest is inserted into a random locus Laurence H purchase 200 mg urispas free shipping. The techniques required for intro- 242 Neuropsychopharmacology: The Fifth Generation of Progress ducing transgenes into the mouse genome have been highly rates of integration of transgenes than other known methods refined buy cheap urispas 200 mg on-line, permitting their widespread use buy urispas 200mg online. After microinjection, the embryos are ment of this technique, many thousands of lines of surgically transferred into the oviduct of pseudopregnant transgenic mice have been generated, and it has been the mice. Pseudopregnant females are generated by matings most widely utilized technique of genetic manipulation in with vasectomized males. The foster mothers give birth 19 Methods of Production of Transgenic to 21 days after oviduct transfer. For genotyping, DNA is Mice typically isolated from mouse tail biopsies and screened for Techniques for producing transgenic mice involve the mi- the presence of the transgene by Southern blotting or poly- croinjection of DNA constructs into fertilized mouse eggs merase chain reaction (PCR). DNA constructs used for the generation of of the mice that develop to term possess the transgene. In transgenic mice typically consist of a gene of interest located the majority of cases, integration of the transgene occurs 3′ to promoter sequences selected to produce a desired dis- during the one-cell stage, so that the transgene is present tribution of gene expression. The maximum length of the in every cell of the transgenic mouse. Integration usually DNA sequence that may be successfully incorporated into occurs at a single random chromosomal location, and, for the mouse genome is not known, and up to 70 kilobase reasons that are not fully understood, there are usually mul- (kb) DNA fragments have been successfully integrated. The tiple copies of the transgene inserted as head-to-tail conca- transgene is linearized and purified from prokaryotic vector tamers. Mice identified to possess the integrated transgene sequences. For optimal integration efficiency, about 1 to 2 are referred to as founders. The founders are typically used picoliter (pL) of DNA at a concentration of 1 to 2 ng/ L in a breeding strategy to produce animals that are homozy- (corresponding to a few hundred molecules of a 5-kb DNA gous for the transgene insertion. Although labor intensive, direct injec- Uses of Transgenic Mice tion of DNA into the pronucleus results in much higher Because transgenic mice often possess multiple copies of the transgene, this method can be used to produce animals with increased levels of expression of particular genes, i. In addition, it can be used to express altered forms of a gene product in the distri- bution of the endogenous gene. One example is a transgenic 2 line bearing a transgene composed of the Ca /calmodulin- dependent protein kinase subunit (CaMKII ) promoter driving expression of a mutant form of CaMKII that con- ferred Ca2 -independent activation. These mice exhibited an increased stimulation threshold for the induction of syn- aptic plasticity in the hippocampus, as well as deficits in spatial memory (3,4). Studies of these animals led to an enhanced understanding of the role of CaMKII in synaptic plasticity and spatial memory acquisition. In many cases, it is desirable to express a gene with an anatomic distribution that does not mirror its native expres- sion pattern in the mouse. Such ectopic expression of a gene may be achieved using a transgenic construct in which the gene of interest is preceded by promoter elements that direct expression in an anatomic distribution characteristic of an- other gene. An example of this approach is a transgenic line in which the D1 dopamine receptor promoter was used to FIGURE 19. A: drive expression of a cholera toxin subunit (which constitu- One-celled fertilized zygotes located in the oviduct ampullae of pregnant donor mice are surgically harvested. B: DNA encoding tively activates G ) in cells that express D1 dopamine recep-s the gene of interest is microinjected directly into the pronucleus tors (5). Studies of these animals revealed that chronic over- of the zygotes. C: Injected zygotes are surgically transferred into stimulation (by constitutively activated G ) of forebrain s the oviducts of pseudopregnant female mice. D: DNA from the progeny can be analyzed by Southern blot or polymerase chain neurons expressing D1 receptors results in an abnormal be- reaction (PCR) for the presence of the transgene. For most genes, the promoter elements necessary cause the likelihood of two founders possessing the same to reproduce the native patterns of expression are not well transgene integration site is minimal. A useful approach for identifying important pro- moter elements for genes of interest involves the generation of transgenic mice in which putative promoter sequences GENE TARGETING PROCEDURES are used to direct expression of reporter genes, whose expres- sion is readily determined in brain tissue. Comparisons may A mutational approach has proved to be invaluable to inves- then be made between the pattern of reporter gene expres- tigators examining the roles of gene products in complex sion and that of the gene of interest (6–8). Recently it has become possible to apply this ap- the expression of a particular gene product. The introduction of mutations that produce more thus decreasing production of the gene product of interest subtle alterations in gene function has also been achieved.

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