By J. Elber. Lutheran Theological Seminary at Gettysburg.

Therefore purchase dutas 0.5 mg on line, the tTA system has been called the Tet- off system purchase 0.5 mg dutas with visa, because in the presence of doxycycline buy 0.5mg dutas visa, transcription is pre- vented trusted 0.5mg dutas. In the Tet- on system order dutas 0.5mg with amex, the tetracycline-con- trolled activator has been mutated to reverse the action of doxycycline on the transactivator. By contrast with tTA, doxycycline binding to rtTA enables the complex to bind to tetO and activate gene transcription. In the absence of doxycycline, rtTA is unable to bind to tetO and cannot activatetranscription. Therefore,the rtTA system is also called the Tet-on system, because doxycycline acti- vates transcription of the regulated B gene. This is referred to as the tet-off sys- A line of mice was generated in which expression of a FosB tem—that is, when tetracycline is present, transcription is transgene was suppressed by continuous doxycycline treat- off. A tet-on system has also been developed, in which tetra- ment throughout development. Discontinuation of treat- cycline induces transcription of the gene of interest. It uti- ment in adult animals led to overexpression of the transgene lizes a reverse tetracycline transcriptional activator (rtTA), in the nucleus accumbens and to augmentation of the re- designed so that it would bind to tetO and activate tran- warding and locomotor stimulant properties of cocaine scription only in the presence of tetracycline-related com- (42). The utility of the tet-on system has also been demon- pounds (38). Doxycycline is most frequently used because strated. For example, a line of mice was developed to exam- it is a potent regulator in both the tet-off and tet-on systems ine the role of the Ca2 -activated protein phosphatase cal- (38), and can be easily supplied to mice through their water cineurin in synaptic plasticity. First, a tissue-specific promoter can be used to express Rather than generating regulatable gain of function mu- tTA or rtTA in a region or cell-type specific manner; then tants with the Tet system, regulatable loss of function mu- the gene of interest is inserted behind tetO and a minimal tants can also be generated by combining the Tet system promoter. This can be achieved by creating two separate with the Cre-lox system (43,44). In this arrangement, a cell- transgenic lines of mice and then cross-breeding to produce type–specific promoter drives rtTA expression and Cre is bigenic lines. In these lines, expression of the gene of interest linked to tetO and a minimal promoter. In the presence of may be induced by doxycycline (tet-on) or by the discontin- doxycycline, Cre is expressed in the cell type specified by uation of doxycycline treatment (tet-off). For example, the the promoter used to drive rtTA expression, and somatic 250 Neuropsychopharmacology: The Fifth Generation of Progress cell recombination excises floxed DNA fragments in those REFERENCES cells—achieving an inducible cell-type–specific knockout. Genetic transforma- This inducible knockout approach may be utilized to cir- tion of mouse embryos by microinjection of purified DNA. Proc cumvent concerns discussed above in the interpretation of Natl Acad Sci USA 1980;77:7380–7384. Integration and stable germ line trans- In these inducible knockout mice it must be remembered mission of genes injected into mouse pronuclei. Science 1981; 214:1244–1246 that although the excision of the floxed gene can be induced 3. Impairment of spatial relatively quickly, the appearance of any phenotype result- but not contextual memory in CaMKII mutant mice with a ing from the absence of the gene product will occur gradu- selective loss of hippocampal LTP in the range of the theta fre- ally, depending on the degradation rate of the relevant quency. CaMKII regulates the frequency-response function of hippocampal synapses for the limitation of strategies utilizing the Tet system relates to production of both LTD and LTP. OCD-Like behaviors of unwanted gene expression may occur during periods in caused by a neuropotentiating transgene targeted to cortical and which gene expression is expected to be turned off. Recent findings with tetracycline controlled tran- 7. Directing gene expression to cere- scriptional silencers indicate that it may be possible to mod- bellar granule cells using gamma-aminobutyric acid type A recep- ify the tet system to substantially reduce unwanted gene tor alpha6 subunit transgenes. In addition, workhas begun on alternative 9417–9421. One such system utilizes the insect hormone tein-coding regions of the adjacent beta 4 and alpha 3 acetylcho- line receptor genes direct neuron-specific expression in the central ecdysone as an induction signal. Conversion of normal behavior to shiverer by myelin basic protein antisense cDNA in transgenic mice. Impaired type II glucocorticoid- receptor function in mice bearing antisense RNA transgene. The development of transgenic and gene targeting technolo- 11.

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Renin ↑cAM P AT1 All secretion is also stim ulated when the concentration of sodium (N a) + and chloride (Cl) at the m acula densa (M D) decreases [12 buy 0.5 mg dutas otc,14] order 0.5 mg dutas otc. The – – + NO m ediators of this effect are less well characterized; however order 0.5mg dutas overnight delivery, som e ↑Ca ↑Ca studies suggest that the effect of N a and Cl in the lum en is m ore potent than is the baroreceptor m echanism generic dutas 0.5mg with mastercard. M any other fac- PGE2 – + PGI tors affect rates of renin release and contribute to the physiologic 2 M embrane depolarization regulation of renin best 0.5mg dutas. Renal nerves, by way of receptors coupled + + to adenylyl cyclase (AC), stim ulate renin release by increasing the M embrane production of cyclic adenosine m onophosphate (cAM P), which stretch reduces Ca release. Angiotensin II (AII) receptors (AT1 receptors) + inhibit renin release, as least in vitro. Prostaglandins E2 and I2 M D NaCl (PGE and PGI , respectively) strongly stim ulate renin release 2 2 Arterial through m echanism s that rem ain unclear. Atrial natriuretic peptide pressure (AN P) strongly inhibits renin secretion. Constitutive nitric oxide (N O ) synthase is expressed by m acula densa (M D) cells. N O appears to stim ulate renin secretion, an effect that m ay counteract inhibition of the renin gene by AII [17,18]. Aldosterone, the predom inant hum an m ineralocorticoid horm one, enters distal nephron cells through the plasm a m em - Cortisone brane and interacts with its receptor (the m ineralocorticoid receptor [M R], or Type I receptor). Interaction between aldosterone and this receptor initiates induction of new 11β HSD proteins that, by way of m echanism s that rem ain unclear, increase the num ber of sodium Cortisol Cortisol GR channels (EN aC) and sodium -potassium adenosine triphosphatase (N a-K ATPase) pum ps at the cell surface. This increases transepithelial N a (and potassium ) transport. Cortisol, ↑ ENaC the predom inant hum an glucocorticoid horm one, also enters cells through the plasm a Cortisone ↑ Na/K ATPase m em brane and interacts with its receptor (the glucocorticoid receptor [GR]). Cortisol, 11β HSD however, also interacts with m ineralocorticoid receptors; the affinity of cortisol and aldos- Cortisol terone for m ineralocorticoid receptors is approxim ately equal. In distal nephron cells, this M R interaction also stim ulates electrogenic N a transport. Cortisol norm ally circulates at concentrations 100 to 1000 tim es higher than the circulating concentration of aldosterone. Aldo Aldo In aldosterone-responsive tissues, such as the distal nephron, expression of the enzym e M R 11 -hydroxysteroid dehydrogenase (11 -H SD) perm its rapid m etabolism of cortisol so that only aldosterone can stim ulate N a transport in these cells. An inherited deficiency of the enzym e 11 -H SD (the syndrom e of apparent m ineralocorticoid excess, AM E), or inhi- Distal nephron cell bition of the enzym e by ingestion of licorice, leads to hypertension owing to chronic stim - ulation of distal N a transport by endogenous glucocorticoids. FIGURE 2-11 ↑ Preload Control of system ic hem odynam ics by the atrial natriuretic peptide (AN P) system. Increases in atrial stretch (PRELO AD) increase AN P + SLRRSSCFGGRLDRIGAQSGLGCNSFRY secretion by cardiac atria. The prim ary am ino acid sequence of AN P is shown in single letter code with its disulfide bond indicated Plasma ANP by the lines. The am ino acids highlighted in blue are conserved + – between AN P, brain natriuretic peptide, and C-type natriuretic pep- + – – tide. AN P has diverse functions that include but are not lim ited to Vagal afferent Capillary Renal NaCl Renin Arteriolar the following: stim ulating vagal afferent activity, increasing capillary activity permeability reabsoption secretion contraction perm eability, inhibiting renal sodium (N a) and water reabsorption, + inhibiting renin release, and inhibiting arteriolar contraction. These – + + + effects reduce sym pathetic nervous activity, reduce angiotensin II + Angiotensin II + + generation, reduce aldosterone secretion, reduce total peripheral Sympathetic Aldosterone + resistance, and shift fluid out of the vasculature into the intersti- efferent Fluid shift – tium. The net effect of these actions is to decrease cardiac output, activity into vascular volum e, and peripheral resistance, thereby returning pre- + interstitium Vascular load toward baseline. M any effects of AN P (indicated by solid volume Peripheral vascular arrows) are dim inished in patients with edem atous disorders (there Cardiac – + resistance is an apparent resistance to AN P). Effects indicated by dashed output arrows m ay not be dim inished in edem atous disorders; these effects ↓ Preload contribute to shifting fluid from vascular to extravascular tissue, + + + leading to edem a. This observation m ay help explain the association between elevated right-sided filling pressures and the tendency for Blood N a retention. Anim als with disruption of the particulate form of guanylyl Kidney cyclase (GC) m anifest increased m ean arterial pressure that is inde- Other somatic pendent of dietary intake of sodium chloride.

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This observation es in aldosterone during pregnancy discount 0.5 mg dutas with visa, 24-hour urinary sodium and suggests that other factors may regulate secretion to a greater degree potassium excretion rem ain in the norm al range generic dutas 0.5mg mastercard. Urinary aldosterone (From W ilson and coworkers; with perm ission order 0.5mg dutas with visa. W e determ ine whether changes in the RAS in pregnancy are prim ary quality 0.5 mg dutas, and the cause of the increase in plasm a vol- 80 20 um e discount 0.5mg dutas amex, or whether these changes are secondary to the vasodilation and changes in blood pressure. To do so, we adm inistered a single 75 15 * dose of captopril to norm otensive pregnant wom en in their first P <. W e then m easured m ean arterial pressure (M AP) P < 0. This observation suggests that the A B RAS plays a greater role in supporting blood pressure in pregnan- cy. B, Baseline PRA was higher in pregnant wom en com pared with those who were not pregnant, and pregnant wom en had a greater increase in renin after captopril com pared with those who were not pregnant. Som e wom en PREGNANCY AND RENAL DISEASE with intrinsic renal disease, particularly those with baseline azotemia and hypertension, suffer m ore rapid deterioration in renal function after gestation. In general, as kidney disease progresses and function Impact of pregnancy on renal disease Impact of renal disease on pregnancy deteriorates, the ability to sustain a healthy pregnancy decreases. The Hemodynamic changes → hyperfiltration Increased risk of preeclampsia presence of hypertension greatly increases the likelihood of renal deterioration. Although hyperfiltration (increased glom erular Increased proteinuria Increased incidence of prematurity, intrauterine growth retardation filtration rate) is a feature of norm al pregnancy, increased intra- Intercurrent pregnancy-related illness, eg, preeclampsia glom erular pressure is not a m ajor concern because the filtration Possibility of permanent loss fraction decreases. Possible factors related to the pregnancy-related of renal function deterioration in renal function include the gestational increase in proteinuria and intercurrent pregnancy-related illnesses, such as preeclam psia, that m ight cause irreversible loss of renal function. W om en with renal disease are at greater risk for com plications related to pregnancy such as preeclam psia, prem ature delivery, and intrauterine growth retardation. Diabetes M ellitus and Pregnancy FIGURE 10-7 RENAL DISEASE CAUSED Diabetes mellitus is a common disorder in pregnant women. Patients with overt nephropathy BY SYSTEM IC ILLNESS are likely to develop increased proteinuria and m ild but usually reversible deteriorations in renal function during pregnancy. H ypertension is com m on, and preeclam psia occurs in 35% of wom en. Pregnancies in women with evidence Pregnancy and SLE* Antiphospholipid antibody syndrome in pregnancy of nephritis are potentially hazardous, partic- ularly if active disease is present at the time Poor outcome is associated with the following: Increased fetal loss of conception or if the disease first develops Active disease at conception Arterial and venous thromboses during pregnancy. W hen hypertension and Disease first appearing during pregnancy Renal vasculitis, thrombotic microangiopathy azotemia are present at the time of concep- Hypertension, azotemia in the first trimester Preeclampsia tion the risk of complications increases, as it High titers of antiphospholipid antibodies or Treatment: heparin and aspirin? The lupus anticoagulant presence of high titers of antiphospholipid antibodies also is associated with poor preg- *Systemic lupus erythematosus (SLE) is unpredictable during pregnancy. The presence of anti- phospholipid antibodies or the lupus anti- coagulant is associated with increased fetal loss, particularly in the second trim ester; increased risk of arterial and venous throm - bosis; m anifestations of vasculitis such as throm botic m icroangiopathy; and an increased risk of preeclam psia. Treatm ent consists of anticoagulation with heparin and aspirin. Lupus Versus Preeclampsia FIGURE 10-9 LUPUS FLARE-UP VERSUS PREECLAM PSIA In the second or third trim ester of pregnancy a clinical flare-up of lupus m ay be difficult to distinguish from preeclam psia. Treatm ent of a lupus flare-up m ight involve increased im m unosuppression, SLE PE whereas the appropriate treatm ent of preeclam psia is delivery. Thus, it is im portant to accurately distinguish these entities. Erythrocyte casts and hypocom - Hypertension + + plem entem ia are m ore likely to be a m anifestation of lupus, whereas Erythrocyte casts + - abnorm al liver function test results are seen in preeclam psia and not Azotemia + + usually in lupus. Low C3, C4 + - Abnormal liver function test results - +/- Low platelet count + +/- Low leukocyte count + - C— complement; minus sign— absent; plus sign— present; PE— preeclampsia; SLE— systemic lupus erythematosus. O verall, the outcom e in pregnancy is favorable when the serum creatinine level is less than 1. Anatomic, congenital Glomerulonephritis Interstitial nephritis Polycystic kidney disease Advanced Renal Disease Caused by Polycystic Kidney Disease FIGURE 10-11 POLYCYSTIC KIDNEY DISEASE Although advanced renal disease caused by polycystic kidney disease (PKD) usually devel- AND PREGNANCY ops after childbearing, wom en with this condition m ay have hypertension or m ild azotem ia. Pregnancy is associated with an increased incidence of asym ptom atic bacteriuria and urinary infection that m ay be Increased incidence of urinary tract infection m ore severe in wom en with PKD. The presence of m aternal hypertension has been shown Maternal hypertension associated with poor outcome to be associated with adverse pregnancy outcom es.

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