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By E. Gancka. Hanover College.

As in gating order clomid 25 mg line, two this way clomid 100mg with amex, the antisaccade deficit meets the second criterion fundamental paradigms have been utilized: eye tracking buy clomid 100 mg mastercard, for a candidate endophenotype—that is cheap 100 mg clomid with mastercard, a candidate endo- or smooth pursuit buy clomid 100 mg with visa, and the antisaccade task. Eye-tracking phenotype should appear in clinically unaffected family dysfunction in schizophrenic patients was first reported by members of schizophrenic patients (and perhaps in schi- Diesendorf and Dodge (83), and their work was later ex- zotypal patients). Across quantitative and qualitative stud- ies, the eye-tracking deficits seen in schizophrenia have been Neuropsychological Tasks well documented (86–89). A plethora of candidate endophenotypes have been derived from the neuropsychological literature. It is well-known that Smooth-Pursuit Eye Movement schizophrenic patients exhibit a wide range of neuropsycho- In a typical study of smooth-pursuit eye movement, a signal logical deficits (105,106) and that these deficits extend to is presented to subjects on a computer screen and their clinically unaffected family members (107). Deficits have Chapter 51: Endophenotypes in the Genetics of Schizophrenia 709 been reported in several important domains: (a) executive of information-processing deficits in schizophrenia. These function, as assessed by the Wisconsin Card Sorting Test deficits appear to measure stable markers of schizophrenia (108); (b) working memory, as assessed by the Letter–Num- that may be associated with a genetic vulnerability to the ber Span (109), and (c) thought disorder, commonly derived illness and are seen in neuroleptic-naıve,¨ first-break, and from the processing of stimuli from the Rorschach Test neuroleptic-withdrawn schizophrenic patients and their sib- to yield the Thought Disorder Index (110) and the Ego lings (142). These cognitive dysfunctions are frequently found in family and twin studies in clinically Span of Apprehension unaffected family members (112–121), schizotypal patients (122–126), and clinically unaffected monozygotic twins The utility of Span of Apprehension as a candidate endo- discordant for schizophrenia itself (127). The neural sub- phenotype, like that of the others measures discussed in this strates of many of these abnormalities are well understood chapter, is supported by a vast amount of literature, only a and are being rapidly explicated because these tasks are very brief summary of which can be presented here. In its most well suited to performance during functional brain imaging simplified form, Span of Apprehension refers to the number (e. For example, it appears that the Wisconsin Card of items that can be apprehended or attended to and subse- Sorting Test relies on dorsolateral prefrontal cortex quently recalled at one time from an array of stimuli. The (128–131) and related distributed circuit structures. Work- interested reader is referred to a particularly scholarly discus- ing memory utilizes a complex neural substrate that includes sion by Asarnow et al. As in the other measures dis- the prefrontal cortex and related structures. It important cussed here, the Span of Apprehension has yielded a pattern when working memory is utilized to be clear about whether of interesting results that makes the task another excellent the test assesses simple delayed recall (transient online stor- candidate endophenotype in schizophrenia. Additionally, age) or the more complex storage, manipulation, and recall Span of Apprehension deficits have been found in clinically (executive functioning) of visuospatial or verbal memory; unaffected family members of schizophrenic patients these are two distinct neuropsychological processes that (150–152) and in patients with schizotypal disorder (153, probably utilize at least partially distinct neural substrates 154). Recently, in a study of normal twins, Bartfai et al. Visual Backward Masking Continuous Performance Task In Visual Backward Masking, a simple target stimulus pre- The Continuous Performance Task (CPT) is another mea- sented with a tachistoscope (156–158) or, more recently, sure that has been widely applied in the study of schizo- a computer (159,160) is followed by a complex, usually phrenic patients (133–136). In the basic form of this task, powerful masking stimulus of interlocking Xs that overlap the subject is presented with a string of stimuli and asked the area of target presentation. A subject reports the target to identify target stimuli from among background or noise stimulus when it is presented alone. The CPT is thought to tap into the function of appears closer in time to the target (e. The CPT also has the advantage that ments), the subject is no longer able identify the target stim- it can be presented in a variety of 'degraded' forms in which ulus. Schizophrenic patients are subjected to the effects of the signal-to-noise ratio of the stimulus to be identified is the mask on target identification at an interstimulus interval attenuated through a variety of parametric manipulations; at which normal subjects have little trouble distinguishing these make the vigilance and identification task more diffi- the target stimulus (161). Explanations for the masking ef- cult to perform and may correspondingly increase group fect extend from integration of the mask with the target separation between schizophrenic patients, their clinically stimulus to interruption of target stimulus processing by unaffected relatives, and appropriate comparison subjects. Whatever the mechanism, the phe- The CPT is one of the most thoroughly studied tasks in nomenon is readily identified as a marker in schizophrenic schizophrenia, in no small degree because of the pioneering patients (158,165–168), family members of schizophrenic work of Nuechterlein et al. The specificity of the deficit is unclear, although phrenic patients. The fact that unaffected relatives of pa- in one study, manic patients at the height of psychosis tients with schizophrenia (139–145) and schizotypal disor- showed visual masking deficits that were reversible over time der (146–148) have parallel deficits supports the utility of with treatment. In this study, it was reported that the defi- the task as a candidate endophenotype for genetic studies cits of schizophrenic patients with a good prognosis, who 710 Neuropsychopharmacology: The Fifth Generation of Progress typically respond to treatment, may also be reversible over deficits and closely related inhibitory abnormalities as excel- time (174). The underlying neural mechanism linked to lent candidate endophenotypes for genetic studies of schizo- masking deficits involves the dorsal and ventral informa- phrenia. The heritability of several of these candidate endo- tion-processing substrates that are supported by magnocel- phenotypes has already been assessed in genetic studies. Because both addition, the neuronal mechanisms of many of the endo- clinically unaffected family members and schizotypal pa- phenotypes are currently being investigated through neuro- tients exhibit deficits of Visual Backward Masking, it may physiologic studies in both humans (e.

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First buy 100 mg clomid with mastercard, angiotensin II FIGURE 11-16 increases arterial pressure— directly and Soon after the release of this useful class of antihypertensive drugs buy 50mg clomid amex, the syndrom e of func- acutely by causing vasoconstriction and tional acute renal insufficiency was described as a class effect generic clomid 50mg online. This phenom enon was first m ore “chronically” by increasing body fluid observed in patients with renal artery stenosis order clomid 50mg without a prescription, particularly when the entire renal m ass was volum es through stim ulation of renal sodi- affected discount 25mg clomid mastercard, as in bilateral renal artery stenosis or in renal transplants with stenosis to a soli- um retention; directly through an effect on tary kidney. Acute renal dysfunction appears to be related to loss of postglom erular the tubules, as well as by stim ulating thirst (Continued on next page) 11. Normal condition depletion as during diuretic therapy, con- Autoregulation gestive heart failure, cirrhosis, and +– +– nephrotic syndrom e. W hen activated, this Afferent Efferent reninangiotensin system plays an im por- arteriole Glomerulus arteriole tant role in the m aintenance of glom erular pressure and filtration through preferen- M yogenic reflex (Laplace) tial angiotensin II–m ediated constriction Tubuloglomerular feedback of the efferent arteriole. Thus, under such Tubule conditions the kidney becom es sensitive B2. Perfusion pressure reduced to the effects of blockade of the renin- but still within autoregulatory range PGE2 (congestive heart failure, angiotensin system by angiotensin I–con- – renal artery stenosis, verting enzym e inhibitor or angiotensin II diuretic therapy, receptor antagonist. Perfusion pressure com prom ised renal function and congestive seriously reduced PGE2 heart failure, the incidence of serious (prerenal azotemia) – changes in serum creatinine during ACE Intra- glomerular inhibition depends on the severity of the pressure pretreatm ent heart failure and renal failure. Second, angiotensin II preferentially constricts the efferent am ong the appropriate m easures for arteriole, thus helping to preserve glom erular capillary hydrostatic pressure and, conse- patients at risk. Acute interstitial nephritis associated with W hen arterial pressure or body fluid volum es are sensed as subnorm al, the renin- angiotensin I–converting enzym e inhibition angiotensin system is activated and plasm a renin activity and angiotensin II levels has been described. This m ay occur in the context of clinical settings such as renal artery stenosis, O pie; with perm ission. M ost of the renal abnorm alities encountered clinically as a result of N SAIDs can be attributed to the action of these com pounds on prostaglandin production in the kidney. Renal vasoconstriction Sodium chloride and water retention are the m ost com m on side ↓Renal function effects of N SAIDs. This should not be considered drug toxicity because it represents a m odification of a physiologic control "Normalized" renal function m echanism without the production of a true functional disorder in the kidney. Inhibition – – by NSAID Compensatory vasodilation induced by renal prostaglandin synthesis Renal Injury Due To Environmental Toxins, Drugs, and Contrast Agents 11. N SAIDs can induce acute renal decom pensation in patients with various renal and extrarenal clinical conditions that cause a decrease in blood perfu- Severe heart disease (congestive heart failure) sion to the kidney. Renal prostaglandins play an im portant Severe liver disease (cirrhosis) role in the m aintenance of hom eostasis in these patients, so disrup- tion of counter-regulatory m echanism s can produce clinically Nephrotic syndrome (low oncotic pressure) im portant, and even severe, deterioration in renal function. Chronic renal disease Age 80 years or older Protracted dehydration (several days) FIGURE11-19 Physiologic stimulus Inflammatory stimuli Inhibition by nonsteroidal anti-inflam m atory drugs (N SAIDs) on pathways of cyclo-oxygenase (CO X) and prostaglandin synthesis Inhibition - by NSAID -. The recent dem onstration of the existence of functionally dis- tinct isoform s of the cox enzym e has m ajor clinical significance, as COX-1 it now appears that one form of cox is operative in the gastric COX-2 constitutive inducible m ucosa and kidney for prostaglandin generation (CO X-1) whereas Stomach Kidney Inflammatory sites an inducible and functionally distinct form of cox is operative in Intestine Platelets (macrophages, the production of prostaglandins in the sites of inflam m ation and Endothelium synoviocytes) pain (CO X-2). The clinical therapeutic consequence is that an N SAID with inhibitory effects dom inantly or exclusively upon the - cox isoenzym e induced at a site of inflam m ation m ay produce the PGE2 TxA2 PGI2 Inflamma- Proteases O2 tory PGs desired therapeutic effects without the hazards of deleterious effects on the kidneys or gastrointestinal tract. A focal diffuse inflam m atory infiltrate Renal Syndrome Mechanism Risk Factors Prevention/Treatment can be found around the proxim al and dis- Sodium retension ↓ Prostaglandin NSAID therapy (most Stop NSAID tal tubules. The infiltrate consists prim arily and edema common side effect) of cytotoxic T lym phocytes but also con- Hyperkalemia ↓ Prostaglandin Renal disease Stop NSAID tains other T cells, som e B cells, and plasm a ↓ Potassium to Heart failure Avoid use in high-risk patients cells. Changes in the glom eruli are m inim al distal tubule Diabetes and resem ble those of classic m inim al- ↓ Aldosterone/renin- Multiple myeloma change glom erulonephritis with m arked angiotensin Potassium therapy epithelial foot process fusion. Potassium-sparing H yperkalem ia, an unusual com plication diuretic of N SAIDs, is m ore likely to occur in Stop NSAID Acute deterioration of ↓ Prostaglandin and Liver disease patients with pre-existing renal im pairm ent, Avoid use in high-risk patients renal function disruption of Renal disease cardiac failure, diabetes, or m ultiple m yelo- hemodynamic bal- m a or in those taking potassium supple- Heart failure ance m ents, potassium -sparing diuretic therapy, Dehydration Stop NSAID or intercurrent use of an angiotensin-con- Old age Dialysis and steroids (? The m echanism of Nephrotic syndrome with: ↑ Lymphocyte recruit- Fenoprofen Stop NSAID N SAID hyperkalem ia— suppression of Interstitial nephritis ment and activation prostaglandin-m ediated renin release— leads Avoid long-term Papillary necrosis Direct toxicity Combination aspirin analgesic use to a state of hyporeninem ic hypoaldostero- and acetaminophen nism. In addition, N SAIDs, particularly abuse indom ethacin, m ay have a direct effect on cellular uptake of potassium. The renal saluretic response to loop diuretics is partially a consequence of FIGURE 11-20 intrarenal prostaglandin production. This Summary of effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on renal function. Characteristically, the histology of this form of N SAID–induced nephrotic syndrom e Thus, concurrent use of an N SAID m ay consists of m inim al-change glom erulonephritis with tubulointerstitial nephritis. This is an blunt the diuresis induced by loop diuretics. Contrast M edium–Associated Nephrotoxicity FIGURE 11-21 RISK FACTORS THAT PREDISPOSE TO CONTRAST Risk factors that predispose to contrast-associated nephropathy. In ASSOCIATED NEPHROPATHY random populations undergoing radiocontrast imaging the incidence of contrasts associated nephropathy defined by a change in serum creatinine of more than 0. For confirmed high-risk patients (baseline serum creatinine values greater than 1.

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