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Investigation of Sinus Rhythm Management 2006;13(4):331-7 order on line cyklokapron. Control of heart rate versus rhythm in rheumatic atrial fibrillation: a randomized study discount cyklokapron 500 mg otc. Control of rate versus rhythm in rheumatic atrial fibrillation: a randomized study buy generic cyklokapron 500 mg. Pulmonary-vein isolation for atrial fibrillation in patients with heart failure discount cyklokapron 500mg without a prescription. Comparison of rate and rhythm control in hypertension patients with atrial fibrillation. A randomised, controlled study of rate versus rhythm control in patients with chronic atrial fibrillation and heart failure: (CAFE-II Study). Maintenance of sinus rhythm and survival in patients with heart failure and atrial fibrillation. Rhythm control versus rate control for atrial fibrillation and heart failure. Radiofrequency ablation for persistent atrial fibrillation in patients with advanced heart failure and severe left ventricular systolic dysfunction: a randomised controlled trial. Critical to this process are the osmoreceptors in the hypothalamus that control the secretion of antidiuretic hormone (ADH ) in response to changes in tonicity. In turn, ADH governs the excretion of water by its end-organ effect on the various segments of the renal collecting system. The unique anatomic and physiologic arrangement of the nephrons brings about either urinary concentration or dilution, depending on prevail- ing physiologic needs. In the first section of this chapter, the physiol- ogy of urine formation and water balance is described. The kidney plays a pivotal role in the maintenance of normal water homeostasis, as it conserves water in states of water deprivation, and excretes water in states of water excess. W hen water homeostasis is deranged, alterations in serum sodium ensue. The pathogenesis, causes, and management strategies are described in the second part of this chapter. W hen any of the components of the urinary concentration mecha- nism is disrupted, hypernatremia may ensue, which is universally characterized by a hyperosmolar state. In the third section of this chapter, the pathogenesis, causes, and clinical settings for hyperna- tremia and management strategies are described. In m ost steady-state situations, hum an water intake m atches water losses through all sources. W ater intake is determ ined by thirst (see Normal water intake (1. W ater intake is finely balanced by the need to m aintain physiologic serum osm o- lality between 285 to 290 m O sm /kg. Both water that is drunk and that is generated W ater of cellular through m etabolism are distributed in the metabolism extracellular and intracellular com part- (350–500 mL/d) m ents that are in constant equilibrium. Intracellular Extracellular Total body water Total body water equals approxim ately compartment compartment 42L (27 L) (15 L) (60% body weight 60% of total body weight in young m en, in a 70-kg man) about 50% in young wom en, and less in older persons. In a 70-kg m an, in tem perate conditions, total body water equals 42 L, 65% of which (22 L) is in the intracellular com partm ent and 35% (19 L) Fixed water excretion Variable water excretion in the extracellular com partm ent. Assum ing norm al glom erular filtration rate to be about 125 m L/m in, the total volum e of blood filtered by the kidney is Filtrate/d about 180 L/24 hr. H um an kidneys have two popula- tions of nephrons, superficial and juxtam edullary. This anatom ic arrangem ent has im por- tant bearing on the form ation of urine by the countercurrent m echanism. After two thirds of the filtered load (180 L/d) is isotoni- cally reabsorbed in the proxim al convoluted tubule, water is handled by three interrelated processes: 1) the delivery of fluid to the diluting segm ents; 2) the separation of solute and water (H 2O ) in the diluting segm ent; and 3) variable reabsorption of water in the collect- ing duct. These processes participate in the renal concentrating m echanism. D elivery of sodium chloride (N aCl) to the diluting segm ents of the nephron (thick ascending lim b of the loop of H enle and the distal convoluted tubule) is determ ined by glom erular filtration rate (GFR) and proxim al tubule function. G eneration of m edullary interstitial hypertonicity, is determ ined by norm al functioning of the thick ascending lim b of the loop of H enle, urea delivery from the m edullary col- lecting duct, and m edullary blood flow. Collecting duct perm eability is determ ined by the presence of antidiuretic horm one (ADH ) and norm al anatom y of the collecting system , leading to the form ation of a concentrated urine. GFR— glom erular H2O filtration rate; N aCl— sodium chloride; NaCl collecting duct H 2O — water. Determinants of delivery of H O NaCl H O 2 2 to distal parts of the nephron GFR NaCl Proximal tubular H2O and NaCl reabsorption H2O NaCl H2O Collecting duct impermeability depends on H2O Absence of ADH Absence of other antidiuretic substances FIGURE 1-4 Distal tubule M echanism of urine concentration: Urea overview of the passive m odel. Several m odels of urine concentration have been 2 put forth by investigators. The passive Cortex H2O m odel of urine concentration described by H2O Kokko and Rector is based on perm e- Na+ Na+ + + ability characteristics of different parts of K K 1 2Cl2– 2Cl2– the nephron to solute and water and on the Urea Outer medullary fact that the active transport is lim ited to NaCl + + Na Na collecting duct the thick ascending lim b. NaCl NaCl Urea concentration in the tubular fluid rises Urea 5 on account of low urea perm eability. Urea plays an im portant role in the Cortex generation of m edullary interstitial hypertonicity. A recycling m ech- anism operates to m inim ize urea loss. The urea that is reabsorbed Urea into the inner m edullary stripe from the term inal inner m edullary Urea collecting duct (step 3 in Fig. Som e of the urea enters the descending lim b of the loop of H enle and the thin ascending lim b of the loop of H enle. It is then carried Urea through to the thick ascending lim b of the loop of H enle, the distal Outer collecting tubule, and the collecting duct, before it reaches the stripe Outer inner m edullary collecting duct (pathway B). This process is facili- Urea medulla tated by the close anatom ic relationship that the hairpin loop of Inner stripe H enle and the vasa recta share. Urea Collecting duct Urea Urea Ascending vasa recta Pathway B Pathway A Urea Inner medulla FIGURE 1-6 1500 Changes in the volume and osmolality of 20 mL 0. The osmolality of the tubu- 1200 lar fluid undergoes several changes as it pass- es through different segments of the tubules. Tubular fluid undergoes marked reduction in 900 its volume in the proximal tubule; however, this occurs iso-osmotically with the glomeru- lar filtrate. In the loop of Henle, because of the aforementioned countercurrent mecha- 600 nism, the osmolality of the tubular fluid rises sharply but falls again to as low as 100 mOsm/kg as it reaches the thick ascend- 300 M aximal ADH ing limb and the distal convoluted tubule. In the absence of ADH, very Proximal tubule Loop of Henle Distal tubule Outer and little water is reabsorbed and dilute urine and cortical inner medullary results. On the other hand, in the presence collecting tubule collecting ducts of ADH, the collecting duct, and in some species, the distal convoluted tubule, become highly permeable to water, causing reabsorp- tion of water into the interstitium, resulting in concentrated urine. Antidiuretic horm one is Pineal responsible for augm enting the water perm eability of the cortical Baroreceptors Third ventricle and m edullary collecting tubules, thus prom oting water reabsorp- VP,NP tion via osm otic equilibration with the isotonic and hypertonic Supraoptic neuron interstitium , respecively. The horm one is form ed in the supraoptic Tanycyte and paraventricular nuclei, under the stim ulus of osm oreceptors SON and baroreceptors (see Fig. It is from the posterior pituitary that the antidi- Portal capillaries uretic horm one is released into the system ic circulation. Antidiuretic horm one (ADH ) is a cyclic hexapeptide (m ol. The biologically (164 AA) (Cleavage site) inactive m acrom olecule, pre-pro-vaso- pressin is cleaved into the sm aller, biologi- Signal peptide cally active protein. The protein of vaso- pressin is translated through a series of sig- nal transduction pathways and intracellular Pro-vasopressin AVP Gly Lys Arg Neurophysin II Arg Glycopeptide cleaving. Vasopressin, along with its bind- ing protein, neurophysin II, and the glyco- protein, are secreted in the form of neurose- cretory granules down the axons and stored Products of AVP NH2 + Neurophysin II + Glycopeptide in nerve term inals of the posterior lobe of pro-vasopressin the pituitary. ADH has a short half-life of about 15 to 20 m inutes and is rapidly m etabolized in the liver and kidneys. The m ultiple actions AQP-3 of vasopressin can be accounted for by its interaction with the V2 receptor found in the kidney. After stim ulation, vasopressin binds to the V2 receptor on the basolateral m em brane of the collecting Recycling vesicle duct cell. In ATP AQP-2 turn, cAM P activates a serine threonine kinase, protein kinase A AQP-2 (PKA). Cytoplasm ic vesicles carrying the water channel proteins m igrate through the cell in response to this phosphorylation PKA H O 2 process and fuse with the apical m em brane in response to increas- ing vasopressin binding, thus increasing water perm eability of the Gαs AQP-2 collecting duct cells.

He found the last years boring and the thought of going directly into practice did not appeal discount 500 mg cyklokapron overnight delivery. He was given a commission and was among the first Australian soldiers sent to Vietnam in 1967 cheap 500 mg cyklokapron amex. He spent much of his time in the field generic 500mg cyklokapron visa, exposed to the danger of land mines and enemy fire 500mg cyklokapron amex. Bill met Pho in a small village close to Nui Dat, the Australian task force base. In spite of his neediness, he was protective toward her. They talked of marriage, but there would be huge hurdles. Although psychologically afflicted by his war experience, he volunteered for a second tour so that they could be together, at least for small amounts of time. When he finished his second tour he came home, and Pho followed six months later. Many Australians thought Pho was Chinese or Japanese; when they learned she was Vietnamese, they behaved as if she was a communist and an enemy. Bill and Pho were delighted when the children came along, and they could form their own complete, if somewhat socially isolated family. Bill had built up his own surveying company, they were doing well financially, and Pho was able to get the next plane to Vietnam to visit her mother. The old lady would not leave her native land, so over the years the family went to visit her three times. Both had straight black hair and looked part Asian, but neither spoke of suffering significant racial prejudice. She went to university with the intention of joining the diplomatic service. He started taking drugs in high school and did not seek further education. It was an open secret that the couple made a fair living growing marihuana, drifting from one coastal town to the next, staying one step ahead of the law. Bill suffered posttraumatic stress disorder following the war. Along with most other Australian Vietnam War Veterans, Bill felt betrayed by his country. They had been sent to fight and risk their lives overseas, but on return, they were criticized rather than appreciated for carrying out their orders. Then, along with others, either out of guilt or wisdom, Bill got involved in rebuilding Vietnam. Gangs would go, taking tools and materials, and build a school or orphanage or anything else they could put up in about a month. The children had come home for a week and she had looked after them. She was sad, had lost her appetite and had difficulty sleeping. She did not expect to ever be happy again, or to eat or sleep well. She was in a foreign country and had lost the husband who had been her best friend, her financial supporter and only lover. But then, she realised that Bill was indeed dead, and thought she must have heard his ghost. Then she concluded that it must have been a dream, and she must have drifted off to sleep for a moment, without noticing. Next afternoon, she was sitting in the same chair, staring at the wall. She looked away, not knowing what to do, when she looked back, he was gone. Pho heard and saw nothing of Bill in the week the children were at home. One Saturday afternoon she went into their bedroom and he was having his afternoon nap on the bed. After a good long drink of looking at him she backed out of the room to let him sleep. When she went back half an hour later, sadly, he was gone. As she came slowly up the drive, he was standing on the lawn. Their eyes met and his look of concentration softened and he raised his eyebrows in recognition. She drove into the garage, when she came out, he was gone. Vietnamese culture is awash with various deities, but these experiences did not fit with anything she could accept. In the first few weeks she did not care if she was mad or not. The day before going to the doctor, she heard Bill speak to her again. She had gone to the stone mason to talk about a headstone and was undecided about black or red granite. It was something which once done could not easily be undone. As she sat in the car, after the drive home she heard him say, Pridmore S. Is there something you can do, to stop me getting worse? The doctor later recommended Pho spend some time with a psychotherapist to look at the other losses of her life. At one point she took a small amount of sedation to help her sleep. Her hallucinations ceased without antipsychotic or antidepressant medication. Pho eventually visited her daughter in Washington, which she enjoyed greatly, and on return, she started corresponding with an American Vietnam veteran. The hearing or seeing of a close, recently deceased friend or relative is not a mental disorder. Figures are not available, but this is a common experience. Usually these hallucinations become less frequent and cease over weeks or months. Perhaps they have a role in helping the individual adjust to the loss. Pho was raised in social, political and military turmoil. Although she had been an adult when she lost her parents, the circumstances were still damaging. She was powerless, she did not have reliable information regarding their fate; thus her grieving for them was disrupted and protracted. She migrated to a foreign land, peopled by another race, where she experienced prejudice. When her husband died she lost most of her human contact. While there is no clear evidence that persons with limited social supports experience more hallucinations during bereavement than those people with extensive social supports, such a finding would not be unexpected. The grieving process is also normal and should not be confused with a depressive disorder (major depressive disorder of dysthymia). A depressive disorder may, however, develop following bereavement, and should be considered when the suffering persists for months or progressively worsens rather than improves. References Allen P, Laroi F, McGuire P, Aleman Al The hallucinating brain: a review of structural and functional neuroimaging studies of hallucinations. Amad A, Cachia A, Gorwood P, Pins D, Delmaire C, Rolland B, Mondion M, Thomas P, Jardri R.

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O kuda K best cyklokapron 500 mg, H ayashi H order cyklokapron, Yokozeki KEA: M ode of nosocom ial H CV and in the staff caring for them purchase cyklokapron 500 mg with amex. N atov SN order cyklokapron 500 mg, Pereira BJG: H epatitis C infection in patients on dialysis. PCR analysis of hem odialysis tis C infection by polymerase chain reaction among hemodialysis ultrafiltrate and whole blood. M orales JM , Fernandez-Zatarain G, M unoz M A, et al. ASAIO Trans 1991, ture and outcom e allograft m em branous glom erulonephritis in renal 37:97–109. N atov SN , Pereira BJG: H epatitis C infection in patients on dialysis. LaQ uaglia M P, Tolkoff-Rubin N E, Dienstag JL, et al. Am J Kidney D is 1988, feron therapy on H CV infection of hem odialyzed patients. Kidney Int 1994, tions in renal transplant patients. M ahony JF: Long term results and com plications of transplantation: 110. C virus RN A in organ donors positive for hepatitis C antibody and in the recipients of their organs. Seney FD Jr, Burns DK, Silva FG: Acquired immunodeficiency syndrome Transplantation 1994, 54:832. Vitting KE, Gardenswartz M H , Zabetakis PM , et al. Cockfield SM , Prieksaitis JK: Infection with hepatitis C virus increas- 124. Renal Disease in Patients Infected with Hepatitis and Human Immunodeficiency Virus 7. Clinicopathologic Conference: Fever and acute renal failure in a infections. In Renal and Urologic Aspects of H IV failure due to acyclovir: case report and review of the literature. Valeri A, N eusy AJ: Acute and chronic renal disease in hospitalized 154. Rao TK, Friedman EA: Outcome of severe acute renal failure in patients 131. Rao TK, Friedm an EA: Renal syndrom es in the acquired im m unode- with acquired immunodeficiency syndrome. Am J Kidney Dis 1995, ficiency syndrom e (AIDS): lessons learned from analysis over 5 years. Bourgoignie J: Glom erulosclerosis associated with H IV infection. Bourgoignie JJ: Renal com plications of hum an im m unodeficiency Contem p Issues N ephrol 1996, 29:59–75. Cantor ES, Kim m el PL, Bosch JP: Effect of race on expression of tal glomerulosclerosis in the acquired immunodeficiency syndrome. N acquired im m unodeficiency syndrom e–associated nephropathy. Ann Intern M ed 1984, nephropathy: a detailed m orphologic and com parative study. Clin N ephrol 1984, and safety of cidofovir in patients with hum an im m unodeficiency 21:197–204. M azbar SA, Schoenfeld PY, H um phreys M H : Renal involvem ent in Chem other 1995, 39:882–886. Seidel EA, Koenig S, Polis M A: A dose escalation study to determ ine H ospital. H um phreys M H : H um an im m unodeficiency virus–associated 7:941–945. Rao TKS, Berns JS: Acute renal failure in patients with H IV infections. In m egalovirus retinitis in patients with AIDS: the H PM C peripheral N ephrology, vol 1. Tokyo: Springer-Verlag; cytom egalovirus retinitis trial. Rashed A, Azadeh B, Abu Rom eh SH : Acyclovir-induced acute tubu- occurrence in specific risk groups. N Engl J M ed 1989, sulfadiazine in patients with AIDS. Carbone LG, Bendixen B, Appel GB: Sulfadiazine-associated obstruc- 165. J Am Soc induced crystalluria in AIDS patients with toxoplasm a encephalitis. Cohen AH , N ast CC: H IV-associated nephropathy: a unique com - 143. Becker K, Jablonowski H , H aussinger D: Sulfadiazine-associated bined glom erular, tubular and interstitial lesion. M odern Pathol nephrotoxicity in patients with the acquired im m unodeficiency 1988, 1:87–97. Bourgoignie JJ, Pardo V: The nephropathology in hum an im m uno- 145. Tashim a KT, H orowitz JD, Rosen S: Indinavir nephropathy [letter]. Cohen AH : Renal pathology of H IV-associated nephropathy. Pardo V, Strauss J, Abitbol C: Renal disease in children with H IV 127:119–125. Com iter S, Glasser J, Al-Askari S: Ureteral obstruction in a patient 150:287–292. H um phreys M H : H um an im m unodeficiency virus–associated 149. Shuka RR, Kim m el PL, Jum ar A: M olecular biology of H IV-1 and of the genitourinary tract. J Am Soc Nephrol 1997, peritoneal dialysis and survival of H IV infected patients with end- 8:492A. Casanova S, M azzucco G, Barbiano di Belgiojoso G, et al. Kim m el PL, M ishkin GJ, Um ana W O : Captopril and renal survival in patients with hum an im m unodeficiency virus nephropathy. Korbet SM , Schwartz M M : H um an im m unodeficiency virus infection Kidney D is: 1996, 28:202–208. Kim m el PL, Phillips TM : Im m une-com plex glom erulonephritis associ- 182. W atterson M K, Detwiler RD, Bolin P Jr: Clinical response to pro- ated with H IV infection. Schectman JM , Kimmel PL: Remission of hepatitis B–associated mem- branous glomerulonephritis in human immunodeficiency virus infection. O uelette DR, Kelly JW , Anders JT: Serum angiotensin converting Am J Kidney Dis 1991, 17:716–718. Kusner DJ, Ellner JJ: Syphilis, a reversible cause of nephrotic syn- M ed 1992, 152:321–324. Rao TKS, Friedm an EA, M icastri AD: The types of renal disease in 205. Kim m el PL, Phillips TM , Farkas-Szallasi T, et al.

Moreover generic 500 mg cyklokapron with visa, behavioral lationships between the stress-related hormone cortisol or inhibition in childhood (based on retrospective self-reports) asymmetric frontal EEG activity and individual differences is highly associated with anxiety in adulthood (35) purchase generic cyklokapron canada. Thus purchase genuine cyklokapron on line, in 28 mother- of the physiologic correlates that have been observed in ex- infant pairs purchase cyklokapron 500mg without prescription, it was found that in both mothers and infants tremely inhibited children are elevated levels of the stress- freezing duration was significantly and positively correlated related hormone cortisol (36) and greater sympathetic with baseline (nonstressed) cortisol levels (38). In nonhuman primates, indi- are consistent with findings from human studies demon- vidual differences in defensive behaviors have been studied strating that extremely inhibited children have elevated lev- in an attempt to elucidate the neuroendocrine and neuro- els of salivary cortisol (36,37), and is also consistent with biological concomitants of extreme behavioral inhibition findings in rodents that corticosterone (the rodent analogue and to characterize a primate analogue of an anxiety-related of cortisol) is required for rat pups to develop the ability endophenotype. Marked individual differences among rhesus monkeys Extremely fearful monkeys (as identified by the HIP) have been noted with regard to the intensity of context- also exhibit characteristic EEG patterns. In adult humans, Chapter 62: Animal Models and Endophenotypes of Anxiety and Stress Disorders 887 asymmetric right frontal brain activity has been associated species. The examination of naturally occurring genetic with negative emotional responses (40). Our studies in rhe- variations with regard to stress reactivity may have impor- sus monkeys have demonstrated similarities in this measure tant implications for the elucidation of individual differ- between monkeys and humans (41). Thus, it has been found ences in sensitivity to stressful situations. One example of that dispositionally fearful monkeys have extreme right naturally occurring individual differences comes from the frontal brain activity, paralleling the pattern of extreme right study of different rodent strains with regard to their level of frontal activity in humans who suffer from anxiety-related stress-like behavioral responding to environmental stimuli. In addition, it was found that individual differ- Because of the important role of the CRH system in regulat- ences in asymmetric frontal activity in nonhuman primates ing defensive behaviors induced by stressful or threatening in the 4- to 8-Hz range are a stable characteristic of an situations, attention has been focused on identifying rat or animal (41,42). Furthermore, a significant positive correla- mouse strains that display differential stress reactivity and tion between relative right asymmetric frontal activity and different baseline levels of CRH gene expression. For exam- basal cortisol levels in 50 one-year-old animals was found. An extreme groups analysis re- fawn-hooded rats compared to either Sprague-Dawleys or vealed that extreme right compared to extreme left frontal Wistars (44,45). Fawn-hooded rats have also been reported animals had greater cortisol concentrations as well as in- to exhibit exaggerated behavioral responses to stress such as creased defensive responses, such as freezing and hostility. Strain differences, which right frontal animals continued to demonstrate elevated cor- essentially reflect differential genetic makeups, have also tisol levels at 3 years of age. These results are the first to link been found to influence the effects of acute environmental individual differences in asymmetric frontal activity with stressors on regulating CRH system gene expression. This finding is important be- the stress of whole-body restraint produces a much larger cause both factors have been independently associated with increase in CRH mRNA levels within the hypothalamus of fearful temperamental styles. Fisher rats than in Wistars or Sprague-Dawleys (46,47). It has recently been found that cerebrospinal fluid (CSF) Similarly, the spontaneously hypertensive and borderline levels of corticotropin-releasing hormone (CRH), a peptide hypertensive strains of rats have increased basal and stress- that mediates stress responses, are significantly elevated in induced levels of hypothalamic CRH mRNA compared to monkeys that display exaggerated defensive responses to the Wistar and Sprague-Dawley strains (48–50). As stated before, these extreme indi- In mice, it has been shown that the BALB/c strain is vidual differences in defensive behaviors are stable over time. Finally, when comparing avoidance of aversive areas in a light-dark transition test and monkeys with extreme right frontal activity (that display an open field (51,52). These mice also show high levels of exaggerated fearful responses) to those with extreme left neophobia (53). Recent genetic mapping studies in these frontal activity (that display low levels of fearful behaviors), strains have revealed that these behavioral differences may the right frontal group was found to consistently have in- be associated with differential levels of -aminobutyric acid creased CSFCRH levels over a period of 4 years (5). Thus, receptor A (GABA ) expression between the strains. For A it appears that extreme fearful behavioral responses in non- example, it has been found that BALB/c mice have signifi- human primates are associated with increased levels of stress cantly lower levels of benzodiazepine binding sites in the hormones such as cortisol and brain CRH, and also with amygdala compared to C57BL/6 mice (54). As described extreme right frontal brain activity versus left frontal brain below, alterations in the expression of GABAA receptors activity, a profile that has been found in humans suffering have been found to lead to increased anxiety-like behaviors from stress-related psychopathology (43). Taken together, in genetically modified mice (see CRH System Transgenic these findings suggest that in primates, a fearful endopheno- Mice). Studying dent strains, as a consequence of their distinct genetic make- species-specific defensive behaviors and their neuroendo- ups, display different baseline levels of gene expression crine and physiologic correlates offers a powerful approach within various systems that are known to regulate the for identifying animal correlates of anxiety. The study of various rodent strains may thus help to identify the neu- Rodents rogenetic differences that contribute to individual differ- Extreme individual differences in the expression of stress- ences in stress susceptibility, and thereby further character- related defensive behaviors have also been noted in rodent ize the interaction between genes and environmental 888 Neuropsychopharmacology: The Fifth Generation of Progress conditions in the etiology of anxiety. Although such infor- are produced as a result of separating infants from their mation is useful, it remains to be determined whether or mothers prior to weaning. The notion that perturbations not the specific genetic differences identified above actually in the early postnatal environment might have enduring underlie the different behavioral effects. It is probable that neuroendocrine, neurochemical, and behavioral effects was a number of genes in addition to those described above originally put forth several decades ago by Levine (58). It are differentially expressed across different rodent strains. Future studies in which behavioral phe- notypes are assessed after the application of novel gene tar- The classic studies by Harlow and colleagues (20,61,62) of geting techniques to selectively disrupt or restore gene func- the effects of maternal separation in primates found that in tion in these rodent strains will aid in clarifying these issues. During the first months of life, the MATERNAL DEPRIVATION: AN attachment between mother and infant is intense, and as a ENVIRONMENTAL MANIPULATION THAT consequence the infant remains in close proximity to its CAN LEAD TO FEARFUL ENDOPHENOTYPES mother (61,63). Long-term maternal separation can result IN PRIMATES AND RODENTS in profound alterations in stress-related behavioral responses in the separated offspring. Monkeys that have been sepa- Converging lines of evidence from a number of species point rated from their mothers for prolonged periods during this to the importance of the early postnatal period, and in par- time exhibit symptoms of enhanced defensive or fear-related ticular the bond between mother and infant, in the develop- behavioral responses into adulthood and appear socially ment of normal defensive behaviors and the putative emo- withdrawn, a phenomenon that has led to the suggestion tional states underlying these behaviors. It has been observed that the behavioral and neuroendocrine sequelae of maternal that children who were placed in nurseries that lacked ade- separation might provide a model for some of the dysfunc- quate social stimulation developed a syndrome of 'protest, tion that is observed in anxiety disorders and depression despair, and detachment' that may be analogous to an in- (64–68). Cortisol has been found to play the early development of mammals is the interaction be- an important role in mediating the development of defen- tween the infant and its mother. As described above, separa- sive responses (69); thus, factors that were expected to affect tion of an infant from its mother during this early develop- infant primate cortisol concentrations were examined. It mental phase represents a significant stressor that markedly was found that maternal cortisol levels were moderately cor- and negatively affects the subsequent emotional develop- related with those of their infants (38). In fact, disruption of normal also found that maternal parity was negatively correlated attachment behavior at critical developmental phases can, with infant cortisol levels such that the current infants of in a number of species, lead to marked and persistent distur- mothers that previously had more offspring were likely to bances in behaviors and brain systems that are thought to have lower cortisol levels. Although the precise mechanism for this interaction identifying an environmental manipulation that can be used remains to be determined, it is likely that mothers with to create animal models of increased stress-related function- little rearing experience would interact differently with their ing. Indeed, a large body of work in monkeys and rats indi- infants than mothers with more experience. Coplan and col- nursing and contacting the offspring is not affected, but leagues (70,71) found that CSFlevels of CRH are basally rather the quality of the interaction between mother and and chronically elevated in adult bonnet macaques whose pup is altered. In nonseparated pups, individual differences mothers were exposed for 3 months to an unpredictable in LG-ABN predict hypothalamic-pituitary-adrenal (HPA) variable foraging demand (VFD), in comparison to mothers axis responsivity in adulthood such that mothers that engage confronted with either a high but predictable or low but in high levels of LG-ABN have offspring that, as adults, predictable foraging demand. Infants reared by VFD-ex- show reduced HPA axis activation in response to stress and posed mothers have been found to subsequently display ab- have decreased levels of CRH mRNA in the paraventricular normal affiliative social behaviors in adulthood (72). Pups that are findings are consistent with the recent results from this lab born to mothers that naturally exhibit high levels of LG- that indicate that CSFCRH levels are elevated in disposi- ABN grow up into adults that display low-anxiety–like be- tionally fearful monkeys, and that this CRH elevation is a haviors (increased exploration of novel environments) and stable trait-like characteristic of fearful endophenotype (5). Taken Rats together, these findings indicate that increased nurturing These aforementioned findings in nonhuman primates sup- physical contact from the mother can lead to a toned-down port the notion that mother-infant interactions may be a stress-responsive system in the offspring. Maternal separation has also been found to have the opposite effect on stress-related functioning later to produce long-term changes in defensive behaviors into in life. Rat pups that are separated from the mother for 3 adulthood in rats. Using the maternal separation paradigm hours or longer (investigators have often used a 24-hour in rats, investigators have also been able to begin to elucidate separation) show in adulthood increased CRH system gene some of the alterations in gene expression that take place expression, exaggerated HPA axis responses to stress, and in response to this early life stressor. Other intense stressors such as direction of the long-term changes, as has been reviewed in an endotoxin insult during the perinatal stage are also able detail recently (73–75). Thus, brief periods of separation to produce marked elevations in basal CRH gene expression (3 to 15 minutes per bout, once a day, for roughly 2 weeks) and lead to an exaggerated stress-induced HPA axis response from the mother result in a profile indicative of diminished in adulthood (81). In an elegant series of studies by Plotsky and (perhaps through alterations in CRH system gene expres- Meaney (76), the long-term effects of these different types sion) for the remainder of its life (73–75). Maternally sepa- of maternal separation have been described, and the behav- rated rats also show alterations in other systems that are ioral and neuroendocrine mechanisms underlying these known to regulate stress-related behaviors and that are con- long-term effects have been characterized. It was initially sistent with an increased fearful endophenotype. For exam- found that rat pups that underwent very short periods of ple, maternal separation increases the release of norepineph- separation (termed 'handling') from their mothers had de- rine into the PVN of the hypothalamus in response to creased basal levels of hypothalamic CRH mRNA and me- restraint stress; stress-induced plasma adrenocorticotropic dian eminence CRH immunoreactivity as adults compared hormone (ACTH) levels were also elevated in maternally to undisturbed control rats. As adults, these 'handled' pups deprived rats (82). Early life stressors such as maternal sepa- also displayed significantly lower elevations of stress-in- ration may therefore play an important role in determining duced corticosterone levels and blunted CRH release from the eventual stress-related endophenotype that is exhibited the median eminence relative to controls. Moreover, the aforementioned studies pro- found that the mechanism underlying this reduction in vide an example of how the animal endophenotype ap- stress-related functioning in handled rat pups involves the proach can be applied to investigating molecular correlates type of maternal behavior that is displayed after the pups of anxiety-related conditions.

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