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By M. Norris. Shorter College. 2018.

Throughout most of as a whole was significantly impaired in comparison with the twentieth century discount 75 mcg synthroid with amex, studies of the neurocognition of normal controls order 100 mcg synthroid with mastercard, which suggests that the genetic structure schizophrenia focused rather narrowly on attempts to define that underlies impaired performance may also confer liabil- and characterize the deficits. To assess the suitability of cognitive outcome (50). Starting in the early 1990s, a large number function for use as a phenotype in genetic studies, Egan et of studies examined the associations between rather specific al. They hypothesized that the RR of cognitive dys- phrenia. This being said, individual studies were underpow- function would be moderate and that different subgroups ered with small sample sizes and were mainly atheoretic. A set of instruments measuring these constructs in- lap in either the neurocognitive or the functional outcome cluded IQ, set shifting and working memory, memory, measures. Nonetheless, some conclusions from this litera- speed, and fluency. RR was estimated by using cutoff scores ture can be drawn. The literature generally supports the conclusion that Patients performed markedly worse than controls on all tests neurocognitive deficits are related to functional outcome in except a measure of premorbid intelligence. The entire sib- schizophrenia (42,45), including skill acquisition in psycho- ling group showed impaired performance on the WCST, social rehabilitation programs, laboratory assessments of so- letter fluency, and Trails B. Siblings of patients with im- cial problem-solving ability or analogue measures of instru- paired performance also showed deficits on the CVLT, mental skills, and broader aspects of behavior in community Wechsler Memory Scale-Revised (WMS-R), and Trails A. When one standard deviation was used as the cutoff, the RR Indeed, using intrapair differences in twins concordant of siblings was elevated on the Trails B (RR, 3. In this design, the experience of illness, institutionalization, medication, psychotic symp- tomatology, and, of course, genome is shared. Although in one sense the design 'stacks the deck' because of its TABLE 48. Neurocognitive constructs and functional out- EXAMINED IN STUDIES OF FUNCTIONAL come. A heavy arrow OUTCOME indicates that at least four studies found a significant relationship between the neurocognitive construct and the outcome domain; Secondary memory Secondary (also called episodic or a thin arrow indicates that significant relationships were uncov- strategic) memory refers to the ered in two or three studies. Typically, this type of memory is assessed with a list of words or artificiality, it does illustrate the importance of neurocogni- passages of text. The amount of tion in predicting level of functioning. This is not to say that information in the words or symptoms do not have an impact on social and vocational passages exceeds the immediate memory span. What is impor- Working or Immediate memoryrefers to the ability tant to note is that cognitive impairment may also contrib- immediate memory to maintain a limited amount of ute in a unique manner to outcome. Immediate memory is considered to be a component of completing tasks, purposefully recalling old information, working memory. Most of the studies and generating novel plans or hypotheses may have an im- of neurocognition and functional pact on their capacity to perform a job efficiently, take part outcome have used passive tasks in social transactions, and make decisions. Despite this lack of consensus, studies on the relationships Attention/vigilance Sometimes called sustained attention, between neurocognition and functional outcome have fre- this ability involves maintaining a quently included assessments for one or more of the neuro- readiness to respond to a particular target stimulus and inhibiting cognitive constructs listed in Table 48. A tally of replications by them- signal (targets) from noise selves is not entirely useful because they do not indicate (nontargets), an ability known as sensitivity. It is typically measured how many times an association was sought, nor the strength with a CPT in which a series of of the relationships. Metaanalysis is more useful for examin- briefly presented stimuli ing the strengths of associations across studies. In Executive functioning/ Executive functioningrefers to volition, this type of analysis, the combined sample sizes are large card sorting planning, purposive action, and and the relationships between neurocognition and func- self-monitoring of behavior. The metaanalyses solving tests such as the WCST are demonstrate that these four neurocognitive constructs are frequently used to assess executive functioning. CPT, Continuous Performance Test; WCST, Wisconsin Card Sorting Most of the studies in this area have used rather specific Test. METAANALYSES: NEUROCOGNITIVE PREDICTION OF FUNCTIONAL OUTCOME Domain Total Sample Size Pooled Estimated ra Effect Size p Value Secondary verbal 727. Neurocognitive deficits and functional outcome in schizophre- nia: are we measuring the “right stuff”? Al- words, although negative symptoms covary to at least a though effect sizes for the individual constructs are mainly modest extent with neurocognition (17,104) and their rela- in the medium range, they can become quite large when tionship to function appears to be mediated through this global or composite measures of neurocognition are used overlap, in toto the results suggest that cognitive impair- instead of individual measures (48,104). Such composite ment, rather than symptoms, most strongly influences func- measures indicate that neurocognition can explain between tional outcome.

Because only a small portion of potassium is extracel- lular order synthroid 125 mcg free shipping, neuromuscular tissue excitability is markedly affected by small changes in extracellular potassium cheap synthroid 50mcg with visa. Thus, the body has developed elaborate regulatory mechanisms to maintain potassium homeostasis. Because dietary potassium intake is sporadic and it cannot be rapidly excreted renally, short-term potassium homeostasis occurs via trans- cellular potassium shifts. Ultimately, long-term maintenance of potassium balance depends on renal excretion of ingested potassium. The illustrations in this chapter review normal transcellular potassium homeostasis as well as mechanisms of renal potassium excretion. W ith an understanding of normal potassium balance, disorders of potassium metabolism can be grouped into those that are due to altered intake, altered excretion, and abnormal transcellular distribu- tion. The diagnostic algorithms that follow allow the reader to limit the potential causes of hyperkalemia and hypokalemia and to reach a diagnosis as efficiently as possible. Finally, clinical manifestations of disorders of potassium metabolism are reviewed, and treatment algo- rithms for hypokalemia and hyperkalemia are offered. Recently, the m olecular defects responsible for a variety of diseases associated with disordered potassium m etabolism have been discov- C H A P T ER ered [3–8]. The genet- rem ediable aldosteronism have recently been elucidated ic m utations responsible for hypokalem ia in the syndrom e of and are illustrated below. Overview of Potassium Physiology FIGURE 3-1 PHYSIOLOGY OF POTASSIUM BALANCE: External balance and distribution of potassium. The usual W estern DISTRIBUTION OF POTASSIUM diet contains approxim ately 100 m Eq of potassium per day. Under norm al circum stances, renal excretion accounts for approxim ately 90% of daily potassium elim ination, the rem ainder being excreted in stool and (a negligible am ount) in sweat. About 90% of total ECF 350 mEq (10%) ICF 3150 mEq (90%) body potassium is located in the intracellular fluid (ICF), the Plasma 15 mEq (0. Although the extracellular fluid (ECF) contains Interstitial fluid 35 mEq (1%) Liver 250 mEq (7%) about 10% of total body potassium , less than 1% is located in the Bone 300 mEq (8. Thus, disorders of potassium m etabolism can be classi- [K+] = 3. Stool 5–10mEq/d Stool 5–10mEq/d Sweat < 5 mEq/d Sweat < 5 mEq/d FIGURE 3-2 FACTORS CAUSING TRANSCELLULAR Factors that cause transcellular potassium shifts. POTASSIUM SHIFTS Factor Plasma K+ Acid-base status Metabolic acidosis Hyperchloremic acidosis ↑↑ Organic acidosis ↔ Respiratory acidosis ↑ Metabolic alkalosis ↓ Respiratory alkalosis ↓ Pancreatic hormones Insulin ↓↓ Glucagon ↑ Catecholamines -Adrenergic ↓ -Adrenergic ↑ Hyperosmolarity ↑ Aldosterone ↓, ↔ Exercise ↑ Diseases of Potassium M etabolism 3. Schematic representation of the cellular mechanisms by which insulin and -adrenergic stimulation promote potassium uptake by extrarenal tissues. Insulin binding to its receptor results in hyperpo- larization of cell membranes (1), which facilitates potassium uptake. After binding to its receptor, insulin also activates Na+-K+-ATPase pumps, resulting in cellular uptake of potassium (2). The second messenger that mediates this effect has not yet been identified. Catecholamines stimulate cellular potassium uptake via the 2 adren- ergic receptor ( 2R). The generation of cyclic adenosine monophos- phate (3 , 5 cAM P) activates Na+-K+-ATPase pumps (3), causing an influx of potassium in exchange for sodium. By inhibiting the degradation of cyclic AM P, theophylline potentiates catecholamine- stimulated potassium uptake, resulting in hypokalemia (4). M ore than half of filtered potassium is passively reabsorbed by the end of the proxim al convolted tubule (PCT). The m ajor site of active potassi- um reabsorption is the thick ascending lim b of the loop of H enle (TAL), so that, by the end of the distal convoluted tubule (DCT), only 10% to 15% of filtered potassium rem ains in the tubule lum en. Potassium is secreted m ainly by the principal cells of the cortical collecting duct (CCD) and outer m edullary collecting duct (O M CD). Potassium reabsorption occurs via the intercalated cells of the m edullary collecting duct (M CD). Urinary potassium repre- sents the difference between potassium secreted and potassium reabsorbed. During states of total body potassium depletion, potassium reabsorption is enhanced. Reabsorbed potassium initial- ly enters the m edullary interstitium , but then it is secreted into the pars recta (PR) and descending lim b of the loop of H enle (TDL). The physiologic role of m edullary potassium recycling m ay be to m inim ize potassium “backleak” out of the collecting tubule lum en or to enhance renal potassium secretion during states of excess total body potassium. The percentage of filtered potassium rem aining in the tubule lum en is indicated in the corresponding nephron segm ent. A, Principal cells of the cortical collecting duct: apical tion is closely coupled to proxim al sodium and water transport.

Collectively order 25 mcg synthroid overnight delivery, these that is designed to examine more specific cognitive and af- studies provide important clues regarding the types of acti- fective processing abnormalities synthroid 200mcg lowest price. This work holds promise vation paradigms that are most promising for use in patients in revealing additional targets for therapeutic intervention, with mood and anxiety disorders to probe the underlying both behavioral and pharmacologic. It also will be impor- circuitry of affect and cognition. Research in which activa- tant in helping to expose the heterogeneity of these disorders tion paradigms with neuroimaging are applied in patients and in offering more meaningful ways in which to parse with mood and anxiety disorders is reviewed in a subsequent various subtypes. Finally, by examining the impact of partic- section. The PFC is not a homogene- is most relevant to understanding mood and anxiety disor- ous zone of tissue; rather, it has been differentiated on the ders are first reviewed. The role of individual differences in basis of both cytoarchitectonic and functional considera- the functional activity of this circuitry is then considered. The three subdivisions of the primate PFC that have The next section reviews key approaches and findings of been consistently distinguished are the dorsolateral, ventro- activation paradigms that have been used in this area. In addition, chapter concludes with a summary and a discussion of fu- it appears that important functional differences exist be- ture trends in this rapidly developing area. The role of the PFC in cognitive control has recently been reviewed (1), so it is not extensively considered here Richard J. Davidson: Laboratory for Affective Neuroscience, University other than to underscore that a major function of the PFC of Wisconsin, Madison, Wisconsin. One of the principal roles tive and negative affective states shift the asymmetry in pre- of the PFC is to represent goal-relevant information, a key frontal brain electrical activity in lawful ways. For example, component of both complex thought and emotion. As many film-induced negative affect increases relative right-sided studies at the nonhuman primate level have now docu- prefrontal and anterior temporal activation (15), whereas mented, reward-related information plays a key role in mod- induced positive affect elicits an opposite pattern of asym- ulating the activity of PFC neurons. This general pattern has been replicated and ventromedial zones of the PFC is associated with the by others using similar measures (16,17). In positron emis- identity and size of expected rewards (2). This component sion tomography (PET) and functional magnetic resonance of PFC activity is likely governed by a dopaminergic input imaging (fMRI) studies, with considerably better spatial res- from the ventral tegmental area of the midbrain (see ref. Our notion of the role of the PFC in pre-goal though many important methodologic details must be con- attainment positive affect is based on this corpus of research, sidered in interpreting the findings (see ref. The most important of these is considered in a later section. The case for the differential importance of left and right In addition, a body of evidence supports the conclusion PFC sectors in emotional processing was first made system- that individual differences in baseline levels of asymmetric atically in a series of studies of patients with unilateral corti- activation in these brain regions are lawfully related to varia- cal damage (5–7). Each of these studies compared the mood tions in dispositional affective style (18). Bechara and colleagues (19) have reported that fairly gross and likely included more than one sector of the patients with bilateral lesions of the ventromedial PFC have PFC and often other brain regions as well. The general difficulty anticipating future positive or negative conse- interpretation that has been placed on these studies is that quences, although immediately available rewards and pun- depressive symptoms are increased following left-sided ante- ishments do influence their behavior. Such patients show rior PFC damage because this brain territory participates in decreased levels of electrodermal activity in anticipation of certain forms of positive affect, particularly pre-goal attain- a risky choice in comparison with controls, whereas controls ment positive affect; damage leads to deficits in the capacity exhibit such autonomic change before they explicitly know to generate this form of positive affect, a hallmark feature that a choice is risky (20–22). It should be noted that not all studies The findings from the lesion method when effects of support this conclusion. In a recent metaanalysis of lesion small unilateral lesions are examined and from neuroimag- studies, Carson et al. Davidson (10) has previously reviewed many of disorders converge on the conclusion that increases in right- these studies and has addressed a number of critical meth- sided activation in various sectors of the PFC are associated odologic and conceptual concerns in this literature. Less evidence is available for most important of these issues is that according to the dia- the domain of positive affect, in part because positive affect thesis stress model of anterior activation asymmetry pro- is much harder to elicit in the laboratory and because of posed by Davidson and colleagues (11–13), individual dif- the negativity bias (23,24). This latter phenomenon refers ferences in anterior activation asymmetry, whether lesion- to the general tendency of organisms to react more strongly induced or functional, represent a diathesis. As such, they to negative than to positive stimuli, perhaps as a conse- alter the probability that specific forms of emotional reac- quence of evolutionary pressures to avoid harm. The find- tions will occur in response to the requisite environmental ings of Bechara et al. In the absence of such a challenge, the pattern PFC lesions on the anticipation of future positive and nega- of asymmetric activation will simply reflect a propensity but tive affective consequences are based on studies of patients will not necessarily culminate in differences in mood or with bilateral lesions. In a recent study of mood sequelae in patients to examine patients with unilateral ventromedial lesions to with unilateral lesions with the largest sample size to date ascertain whether valence-dependent asymmetric effects are (n 193), Morris et al. It is likely that larger lesions intrude on other role played by various sectors of the PFC in emotion are brain territories and mask the relation between left PFC lacking, although a growing corpus of work illustrates the damage and depression. Many consistent with the findings derived from the lesion studies.

Thus order synthroid 125mcg with visa, self-reported tional activity can involve either cerebral blood flow(CBF) decreases in stimulant use may be important as a treatment or metabolic activity using fluorodeoxyglucose (FDG) order 50 mcg synthroid fast delivery. The outcome even when the goal may be abstinence initiation. In this study, selegiline reduced the available for intervention. Relapse that the cocaine-induced changes in metabolic activity were as defined by recurrent use or dependence after 'sustained blocked by the administration of selegiline (29). This surro- abstinence' first requires a definition of sustained absti- gate marker provided an interesting correlate of the attenua- nence, particularly among the binge users of stimulants. Because similar studies of subjective of the Diagnostic and Statistical Manual of Mental Disorders, effects alone have not had corresponding predictive validity fourth edition (DSM-IV) for stimulant dependence, the pe- for outpatient efficacy, these neuroimaging measures may riods of nonuse can manifest reasonable psychosocial func- have promise as a more rapid screening tool for medications. Simple definitions of sustained absti- roimaging focuses on the CBF defects that have been ob- nence can just be defined by a period of cocaine- or amphet- served in cocaine abusers and on the neuropsychological amine-free urines that lasts three, four, or perhaps ten times deficits that persist even during sustained abstinence (6,15, longer than the typical inter-binge interval. As reviewed below, these CBF defects may be respon- vestigations, an important prognostic stratification is evolv- sive to pharmacotherapy. The therapeutic implication is ing based on sustained abstinence; patients who are absti- that by resolving these CBF defects, cognitive functioning nent during the 2 to 5 weeks before entering a medication might improve, and the response to cognitive behavioral trial have better treatment outcomes than those who con- therapies also might be enhanced. Longer- term relapse prevention has also been an area where psycho- therapy may synergize with pharmacotherapy (32). For Outpatient Randomized Clinical Trials example, sustained abstinence with desipramine treatment Outpatient clinical trials remain the standard approach to for cocaine dependence was enhanced by relapse-prevention assessing efficacy of a medication. Although many principles cognitive behavioral therapy when examined at 6 and 12 of conducting randomized placebo-controlled clinical trials month follow-up. Relapse was significantly higher after at- in psychopharmacology apply to these studies, some specific taining abstinence with the medication alone than with both considerations are relevant to outcome measures that are not medication and the behavioral therapy. Urine toxicology is a most informative outcome that can be analyzed with both quantitative and qualitative approaches. The urines are typically obtained SPECIFIC MEDICATIONS three times per week for maximum sensitivity to repeated stimulant use based on the duration that detectable metabo- A large number of medications have been used for a variety lite levels remain after use. Analyses are most frequently of cocaine-related effects, including treatment of cocaine done with cutoff scores of 300 ng/mL, for example, with withdrawal or cocaine craving, and initiation and mainte- the cocaine metabolite benzoylecgonine, with any level nance of abstinence. Although many of these medications above this being considered an indication of cocaine use have appeared to be promising in open trials, randomized, within the last 3 days. More complex analyses have been placebo-controlled clinical trials have not shown any medi- proposed using quantitative levels either directly with gas cations to have substantial efficacy for cocaine dependence. This semiquantitation been hampered by large dropout rates. Diagnostic criteria Chapter 102: Pathophysiology and Treatment of Cocaine Dependence 1465 have varied across clinical trials (some studies enroll patients duction in both opioid and cocaine abuse with desipramine meeting diagnostic criteria for cocaine dependence or for (36). A recent report of desipramine in depressed cocaine cocaine abuse, and others do not specify patient diagnosis). Thus, these tricyclic anti- these patients tend to be more available for follow-up be- depressants do not have well-demonstrated utility even in cause of their need to report to a clinic daily for methadone the depressed cocaine abusers, who can be a substantial treatment, it is likely that they are different from patients subgroup comprising up to 40% of those presenting for with primary cocaine use disorders. Outcome clinical trials with fluoxetine have been conducted in pa- variables differ among clinical trials, making it difficult to tients with cocaine use disorders. Studies that utilized controlled, cocaine administration study examined the in- self-reports without confirmation by urine toxicology screen teraction of cocaine with fluoxetine at 0, 20, 40, or 60 mg may not be reflective of cocaine use by study participants. Fluoxetine has been utilized in outpatient clinical Antidepressants trials in both methadone-maintained, cocaine-dependent Desipramine, a tricyclic antidepressant agent, was one of patients and in patients with primary cocaine use disorders. It is one of the most extensively studied phar- dent patients found that fluoxetine at 45 mg daily signifi- macotherapies for cocaine dependence to date (4). The cantly reduced self-reported use and quantitative urine ben- initial study of desipramine suggested its efficacy based on zoylecgonine concentrations during 9 weeks of treatment self-report primarily, and two subsequent studies in metha- (39). More recently, fluoxetine has not reduced cocaine pos- done-maintained samples based on urine toxicology found itive urines more than placebo in either methadone-main- no difference from placebo (33–35). A large clinical trial tained or primary cocaine abusers (40). The consensus of examined the efficacy of desipramine and psychotherapy, these studies is that fluoxetine may not have a clinical role alone and in combination, as a treatment for ambulatory among unselected cocaine abusers, and side effects have lim- cocaine abusers (32). In this 12-week, double-blind, pla- ited its use in several studies. Al- vention plus placebo, and clinical management plus pla- though a pilot study suggested efficacy, a large multicenter cebo. The mean dose of desipramine was 200 mg daily and study in methadone-maintained patients showed little bene- was adjusted by a nonblinded psychiatrist in response to fit in cocaine dependence (41). All groups showed significant improvement in Dopaminergic Agents (DA) treatment retention and a reduction in cocaine use at 12 weeks, but there were no significant main effects for psycho- The most widely accepted explanation of cocaine-induced therapy, pharmacotherapy, or the combination.