The resultant hyperkalem ia ference and thus the secretion of potassium and hydrogen ions causes im paired am m onium excretion that is an im portant contri- (voltage-m ediated defect); inhibition of the basolateral sodium ion quality 50 mcg thyroxine, bution to the generation of the m etabolic acidosis cheap thyroxine 100mcg mastercard. The causes of potassium ion–adenosine triphosphatase; and enhanced chloride this syndrom e are broadly classified into disorders resulting in ion perm eability in the collecting tubule order thyroxine 50 mcg with visa, with consequent shunting aldosterone deficiency and those that im pose resistance to the of the transepithelial potential difference 200mcg thyroxine mastercard. Aldosterone deficiency can arise from com bined aldosterone deficiency and resistance purchase thyroxine 75 mcg online. W henever possible, cause- specific m easures should be at the center of treatm ent of m etabolic acidosis. In the presence of severe acidem ia, such m easures should be supplem ented by judicious adm inistration of sodium bicarbon- Alkali therapy for severe ate. The goal of alkali therapy is to return the blood pH to a safer Cause-specific measures acidemia (blood pH<7. Anticipated benefits and potential risks of alkali therapy are depicted here. Benefits Risks • Prevents or reverses acidemia- • Hypernatremia/ related hemodynamic compromise. The mm Hg resultant alkalem ia dam pens alveolar ventilation and leads to the 40 50 secondary hypercapnia characteristic of the disorder. Available observations in hum ans suggest a roughly linear relationship between the steady-state increase in bicarbonate concentration 40 and the associated increm ent in the arterial carbon dioxide ten- 30 sion (PaCO 2). Although data are lim ited, the slope of the steady- - state PaCO 2 versus [H CO 3] relationship has been estim ated as 30 about a 0. The value of this slope is virtually identical to Normal that in dogs that has been derived from rigorously controlled 20 observations. Em piric observations in hum ans have been used for construction of 95% confidence intervals for graded 10 degrees of m etabolic alkalosis represented by the area in color in 10 the acid-base tem plate. The black ellipse near the center of the figure indicates the norm al range for the acid-base param eters. Assum ing a steady state is present, values falling within the area in color are consistent with but not diagnostic of sim ple 6. Acid-base values falling outside the area in Arterial blood pH color denote the presence of a m ixed acid-base disturbance. Two Alkali gain Calcium supplements Enteral crucial questions m ust be answered when Absorbable alkali + evaluating the pathogenesis of a case of Nonabsorbable alkali plus K exchange resins m etabolic alkalosis. Answering this question addresses the pathophysiologic events that m aintain Vomiting the m etabolic alkalosis. Gastric H+ loss Suction Villous adenoma Intestinal Congenital chloridorrhea Chloruretic diuretics Renal Inherited transport defects Mineralocorticoid excess + Posthypercapnia H shift + K depletion Reduced GFR Mode of perpetuation? Increased – renal acidification Cl responsive defect Cl–resistant defect FIGURE 6-32 Baseline Vomiting Maintenance Correction Changes in plasm a anionic pattern and body electrolyte balance Low NaCl and KCl intake High NaCl and KCl intake 45 during developm ent, m aintenance, and correction of m etabolic alkalosis induced by vom iting. Loss of hydrochloric acid from the 40 stom ach as a result of vom iting (or gastric drainage) generates the 35 hypochlorem ic hyperbicarbonatem ia characteristic of this disorder. During the generation phase, renal sodium and potassium excre- 30 tion increases, yielding the deficits depicted here. Renal potassium 25 losses continue in the early days of the m aintenance phase. Subsequently, and as long as the low-chloride diet is continued, a new steady state is achieved in which plasm a bicarbonate concen- 105 - tration ([HCO3]) stabilizes at an elevated level, and renal excretion 100 of electrolytes m atches intake. Addition of sodium chloride (N aCl) and potassium chloride (KCl) in the correction phase repairs the 95 electrolyte deficits incurred and norm alizes the plasm a bicarbonate and chloride concentration ([Cl-]) levels [22,23]. During acid rem oval from the stom ach as well as early in the phase –2 0 2 4 6 8 10 12 after vom iting (m aintenance), an alkaline urine is excreted as acid Days excretion is suppressed, and bicarbonate excretion (in the com pany of sodium and, especially potassium ; see Fig. FIGURE 6-34 This acid-base profile m oderates the steady-state level of the result- Changes in plasm a anionic pattern, net acid excretion, and body ing alkalosis. In the steady state (late m aintenance phase), as all fil- electrolyte balance during developm ent, m aintenance, and correc- tered bicarbonate is reclaim ed the pH of urine becom es acidic, and tion of diuretic-induced m etabolic alkalosis. Adm inistration of a the net acid excretion returns to baseline. Provision of sodium loop diuretic, such as furosem ide, increases urine net acid excretion chloride (N aCl) and potassium chloride (KCl) in the correction (largely in the form of am m onium ) as well as the renal losses of phase alkalinizes the urine and suppresses the net acid excretion, as - + + chloride (Cl ), sodium (N a ), and potassium (K ). The resulting bicarbonaturia in the com pany of exogenous cations (sodium and - hyperbicarbonatem ia reflects both loss of excess am m onium chlo- potassium ) supervenes [22,23]. During the phase after diure- sis (m aintenance), and as long as the low-chloride diet is continued, a new steady state is attained in which the plasm a bicarbonate con- - centration ([HCO3]) rem ains elevated, urine net acid excretion returns to baseline, and renal excretion of electrolytes m atches intake. Addition of potassium chloride (KCl) in the correction phase repairs the chloride and potassium deficits, suppresses net acid excretion, and norm alizes the plasm a bicarbonate and chloride concentration ([Cl-]) levels [23,24]. If extracellular fluid volum e has becom e subnorm al folllowing diuresis, adm inistration of N aCl is also required for repair of the m etabolic alkalosis. N otwithstanding, here Increased renal bicarbonate reabsorption frequently coupled depicted is our current understanding of the participation of with a reduced glom erular filtration rate are the basic m echa- each of these factors in the nephronal processes that m aintain nism s that m aintain chloride-responsive m etabolic alkalosis. In addition to These m echanism s have been ascribed to three m ediating fac- these factors, the secondary hypercapnia of m etabolic alkalosis tors: chloride depletion itself, extracellular fluid (ECF) volum e contributes im portantly to the m aintenance of the prevailing depletion, and potassium depletion.
Proteins binding at each of these sites are constitutively present in cells and are activated by phosphorylation discount 200mcg thyroxine overnight delivery. CREBcan be activated by protein kinase A discount thyroxine 75 mcg free shipping, CaM kinases (CaM-Ks) proven thyroxine 75mcg, or RSKs (ribosomal S6 kinases) (Fig 200mcg thyroxine with amex. Thus purchase thyroxine 25 mcg otc, activation of the c-fos gene—by any of multiple signaling pathways—depends only on signal-induced phosphorylation rather than on new protein synthe- sis. This explains the rapidity of its induction by a wide array of stimuli. MEK, MAP kinase and ERK kinase; PKA, protein kinase A; RTKs, receptor tyrosine kinases. However, the STAT activation of certain MAP kinases called extracellular signal site in c-fos had already been named the SIE or SIF-inducible regulated kinases (ERKs). These ERKs can phosphorylate element (SIF itself is an acronym for sis-inducible factor, and activate additional protein kinases, such as RSK, which, i. STATs are activated by the class of CREB, as described earlier. However, an additional mecha- cytokines that interact with gp130-linked receptors, which nism exists whereby ERK can induce the c-fos gene, and include ciliary neurotrophic factor, LIF (leukemia inhibi- this mechanism appears to predominate in many cell types tory factor), interleukin-6, leptin, and prolactin, to name a (41). Here, the ERKs translocate into the nucleus where few (16,43). These receptors activate a cytoplasmic protein they phosphorylate the transcription factor Elk-1 (also tyrosine kinase called JAK (Janus kinase), which then phos- called the ternary complex factor or TCF). SREs are present within many other Most other Fos and Jun family proteins are also induced growth factor-inducible genes as well. In comparison with rapidly in response to diverse acute stimuli and, presumably, cAMP- or Ca2 -dependent phosphorylation of CREB, the many of the same mechanisms operate for the genes encod- Ras/MAP kinase pathway depends on a complex chain of ing these proteins. However, the response elements within phosphorylation events. Nonetheless, these events can occur these genes are not as well characterized as are those for very rapidly to induce gene expression. As stated earlier, STATs are activated on their phos- Regulation by Phosphorylation phorylation by certain protein tyrosine kinases. This permits STATs to form multimeric complexes, translocate to the Several AP-1 proteins are regulated at the post-translational nucleus, and bind to their specific DNA response elements, level by phosphorylation. The best-established example is Chapter 17: Regulation of Gene Expression 225 the phosphorylation of c-Jun, which provides a critical mechanism of regulation of AP-1-mediated signaling (44, 45). In this pathway, a Ras- like G protein is activated by any of several insults (e. The culmination of this pathway is the phosphoryla- tion and activation of certain MAP kinases called SAP ki- nases (stress-activated protein kinases)or alternatively JNKs (for Jun N-terminal kinases). JNKs phosphorylate c-Jun on serines 63 and 73 in its transcriptional activation domain and increase the ability of c-Jun to activate transcription. Phosphorylation and activation of c-Jun have been impli- cated in the regulation of apoptosis (programmed cell death) pathways (45). Scheme showing the composition of AP-1 com- Repeated Stimulation plexes changing over time. Top: There are several waves of Fras (Fos-related antigens) induced by many acute stimuli in neurons. Thus, under resting conditions, c-fos mRNA isoforms of FosB; they, too, are induced (although at low levels) and protein are barely detectable in most neurons, but c- after a single acute stimulus but persist in brain because of their fos expression can be induced dramatically in response to enhanced stability. In complexes with Jun family proteins, these wavesofFras formAP-1bindingcomplexes withshiftingcomposi- numerous stimuli. As just one example, experimental induc- tion over time. Bottom: With repeated stimulation, each acute tion of a grand mal seizure causes marked increases in levels stimulus induces a low level of FosBisoforms. This is indicated by the lower set of overlapping lines, which indicate FosB-in- of c-fos mRNA in brain within 30 minutes and induces duced by each acute stimulus. The result is a gradual increase in substantial levels of c-Fos protein within 2 hours. This is indicated by the increasing stepped line in the graph. The increasing levels of FosBwith within 4 to 6 hours (46). Administration of cocaine or am- repeated stimulation would result in the gradual induction of phetamine causes a similar pattern of c-fos expression in significant levels of a long-lasting AP-1 complex, which could un- striatum (47,48). In either of these stimulus paradigms, derlie persisting forms of neural plasticity in the brain.
Liver involvem ent cheap 125mcg thyroxine with visa, occurring Periungual fibromas 30 ≥15 in 40% of cases thyroxine 200mcg overnight delivery, includes angiom yolipom as and cysts order 125mcg thyroxine overnight delivery. Involvem ent Central nervous system of other organs is m uch rarer [31 order 75mcg thyroxine amex, 32] buy 50mcg thyroxine. Cortical tubers 90 Birth Subependymal tumors 90 Birth (may be calcified) focal or generalized seizures 80 0–1 Mental retardation/ 50 0–5 behavioral disorder Kidney Angiomyolipomas 60 Childhood Cysts 30 Childhood Renal cell carcinoma 2 Adulthood Eye Retinal hamartoma 50 Childhood Retinal pigmentary abnormality 10 Childhood Liver (angiomyolipomas, cysts) 40 Childhood Heart (rhabdomyoma) 2 Childhood Lung (lymphangiomyomatosis; 1 ≥20 affects females) B FIGURE 9-32 (see Color Plate) Tuberous sclerosis com plex (TSC): skin involvem ent. Facial angiofibrom as, forehead plaque, A, and ungual fibrom a, B, characteristic of TSC. Previously (and inappropriately) called adenom a sebaceum , facial angiofibrom as are pink to red papules or nodules, often concentrated in the nasolabial folds. Forehead fibrous plaques appear as raised, soft patch- es of red or yellow skin. Ungual fibrom as appear as peri- or subungual pink tum ors; they are found m ore often on the toes than on the fingers and are m ore com m on in fem ales. Other skin lesions include hypomelanotic macules and “shagreen patches” (slightly elevated A patches of brown or pink skin). Brain CT shows several subependymal, periventricular, calcified nodules characteristic of TSC. Subependymal tum ors and cortical tubers are the two characteristic neurologic features of TSC. Calcified nodules are best seen on CT, whereas noncalcified tum ors are best detected by m agnetic resonance im aging. Clinical m anifestations are seizures (including infantile spasm s) occur- ring in 80% of infants, and varying degrees of intellectual disability or behavioral disorder, reported in 50% of children. A B FIGURE 9-34 Tuberous sclerosis com plex (TSC): kidney involvem ent. Contrast- of fat into the tumor, but it is not always possible to distinguish enhanced CT, A, and gadolinium -enhanced T1 weighted m agnetic between AM L and renal cell carcinoma. The main complication of resonance im ages, B, of a 15-year-old wom an with TSC, show AM L is bleeding with subsequent gross hematuria or potentially life- both a large, hypodense, heterogeneous tum or in the right kidney threatening retroperitoneal hemorrhage. O ccasionally, AM L is a benign tum or com posed of atypical blood vessels, polycystic kidneys are the presenting m anifestation of TSC2 in early sm ooth m uscle cells, and fat tissue. W hile single AM L is the m ost childhood: in the absence of renal AM L, the im aging appearance is frequent kidney tum or in the general population, m ultiple and bilat- indistinguishable from ADPKD. Polycystic kidney involvem ent leads eral AM Ls are characteristic of TSC. In TSC, AM Ls develop at a to hypertension and renal failure that reaches end stage before age younger age in fem ales; frequency and size of the tum ors increase 20 years. Though the frequency of renal cell carcinom a in TSC is with age. Diagnosis of AM L by imaging techniques (ultrasonography sm all, the incidence is increased as com pared with that of the gener- [US], CT, magnetic resonance imagine [M RI]) relies on identification al population. Representative examples Endolymphatic sac tumor Rare of various contiguous deletions of the PKD1 and TSC2 genes in Eye/Retinal hemangioblastoma 60 25 (8–70) five patients with TSC and prom inent renal cystic involvem ent (the Kidney size of the deletion in each patient is indicated). Clear cell carcinoma 40 40 (18–70) TSC is genetically heterogeneous. Cysts 30 35 (15–60) The TSC1 gene is on chromosome 9, and TSC2 lies on chromosome Adrenal glands/ 15 20 (5–60) 16 immediately adjacent and distal to the PKD1 gene. Half of affect- Pheochromocytoma ed families show linkage to TSC1 and half to TSC2. Nonetheless, Pancreas 30 (13–70) 60% of TSC cases are apparently sporadic, likely representing new Cysts 40 mutations (most are found in the TSC2 gene). The proteins Microcystic adenoma 4 encoded by the TSC1 and TSC2 genes are called hamartin and Islet cell tumor 2 tuberin, respectively. They likely act as tumor suppressors; their pre- Carcinoma 1 cise cellular role remains largely unknown. VHL is an autosomal-dominant multisystem disorder with a prevalence rate of roughly 1 in 40,000 [32, 35]. It is characterized by the development of tumors, benign and malignant, in various organs. VHL-associated tumors tend to arise at an earlier age and more often are multicentric than the sporadic varieties. M orbidity and mortality are mostly relat- ed to central nervous system hemangioblastoma and renal cell carci- noma. Involvement of cerebellum, retinas, kidneys, adrenal glands, and pancreas is illustrated (see Figures 9-37 to 9-41). The VH L gene is located on the short arm of chrom osom e 3 and exhibits characteristics of a tum or suppressor gene. M utations are now identified in 70% of VH L fam ilies. FIGURE 9-37 Von H ippel-Lindau disease (VH L): central nervous system involve- m ent.
The data with respect to high-energy phosphodiesters (PDE purchase thyroxine 50 mcg online, 2 buy 125mcg thyroxine free shipping. Studies that have looked outside the frontal lobe buy 25mcg thyroxine, ious membrane phospholipids; (c) phosphate residues on at parietal and temporal lobes and at the basal ganglia generic thyroxine 100mcg overnight delivery, also adenosine triphosphate (ATP) ( 16 discount 50mcg thyroxine fast delivery. The reasons for the inconsistencies are un- shift standard, has a resonance set at 0 ppm. The usual explanations—differences in patient trations, which are thought to reflect in part membrane sample (e. In white matter, positive and negative reports have appeared regardless of however, PMEs are metabolites of both synthesis and break- the characteristics of the samples and in the context of a down of sphingomyelin. PDEs are thought to reflect in part variety of acquisition parameters. A more likely explanation products of membrane breakdown and have been shown to for the inconsistencies involves the low sensitivity and repro- be decreased in certain brain tumors and to increase shortly ducibility of 31Pspectroscopy and problems in achieving a after birth. However, both PME and PDE peaks include standardized placement of a region of interest (ROI) or of other phosphorylated proteins associated with cell organ- an acquisition plane. There are very limited data about the elles and with membrane phospholipids that are not clearly reliability of 31Pmeasurements in patients, with one study related to membrane turnover. Thus, unavoidable error in the localization process, which is fur- changes in PME and PDE peaks are not easily interpreted. Large The phosphocreatine (PCr), ATP, and Pi peaks confer in- voxel sizes also introduce error in terms of partial volume formation about the state of high-energy phosphate metabo- effects. The small differences that have been reported in lism and pH in the tissue. It also should be noted that most of the positive studies, on the order of 10% to 25%, 31 because Pspectra are acquired with large voxels (i. They used a surface coil to each, and drew ROIs on an anatomic reference scan that acquire data from 87-cm3 voxels arbitrarily placed in both was acquired in a coplanar orientation, on 11 medication- temporal lobes. There were no differences found in any of free patients, including seven acute patients who were medi- the peaks. Though the planes are not strictly registered in study of 11 first-episode patients, using a surface coil placed space, because subject motion may have tilted their relative over the front of the head. With higher field magnets, with better sensitivity and resolution, the exception of one mesial prefrontal voxel having a de- combined with signal enhancement and peak separation creased PDE peak and one voxel localized to the basal gan- procedures may lead to more reliable methods. Four prefrontal voxels Proton Spectroscopy: Assays of Cells and having decreases in ATPand PCr also were found. The Cellular Metabolism authors argued that their data suggested decreased mem- brane catabolism, but, given the number of voxels analyzed, Proton spectroscopy has been a more widely applied tech- chance results cannot be excluded. In an earlier study of nique in schizophrenia research and the results are much chronic, medicated patients, they also found a decreased more consistent. A variety of chemicals in the proton spec- prefrontal PDE peak, but the high-energy phosphate data trum can be assayed with clinical magnets, including several were in the opposite direction (147). Finally, Potwarka et amino acids, membrane and myelin metabolites, and several al. Although the sensitivity of proton the effects of coupling between phosphorus and proton spectroscopy is approximately 20 times that of phosphorus, spins, were able to separate structural membrane phospho- allowing for much better resolution, the metabolites of in- lipids from other constituents of the PME and PDE peaks, terest need to be resolved in a smaller chemical shift range with 50-cc voxels acquired as part of a plane. Although the (less than 10 ppm), in the presence of large concentrations authors found no decrease in PMEs as reported by Pettegrew of brain water (approximately 104 times greater concentra- et al. Until recently, most 1H MRS techniques erophosphocholine (GPC) and glycerolphosphoethanolam- used special procedures to suppress the signal from water ine (GPE), as suggested by Pettegrew et al. With the Rather, the difference was reflected in the membrane phos- availability of analogue to digital converters having greater pholipid components of the peak. These differences were dynamic range, it is now possible to acquire the water signal not found in motor or occipital cortices, providing some and still resolve the other metabolites (152). This study also found no differ- preservation of neighboring signals, this approach also has ences between patients and controls in total PMEs, again the advantage of making the water signal available as an in contrast to the Pettegrew et al. The metabolite signals acquired with H story even further, Bluml et al. Many of the resolvable elements and GPE acquired with a large (97-cc) voxel in the middle have short T2 (e. GABA) and emit no observable signal with longer echo Several studies have attempted to link 31Pdata to clinical times. On the other hand, long echo time acquisitions pro- characteristics of patients, but these also have been inconsis- duce signals from several compounds that are very distinctly tent. The long echo time metabolite spectrum is domi- tion between prefrontal PME signals and performance on nated by a peak at approximately 2 ppm corresponding the WCST, suggesting that prefrontal membrane abnormal- to the methyl group (CH3) of several N-acetyl containing ities were reflected in prefrontal function. However, in the compounds, principally N-acetylaspartate (NAA) and to a same patient sample, Deicken et al. NAA is correlation between any 31Psignals and WCST perfor- an intracellular neuronal marker, found almost exclusively mance. Its concentration is higher in gray matter than in It is difficult to arrive at a synthetic analysis of the 31P white matter (156), and NAA signals increase during child- data in schizophrenia. Technical error is probably the criti- hood, remaining relatively stable throughout adult life cal factor in the variable results that have been reported.
This idea fits more discount 50mcg thyroxine with amex, it is possible that maternal depression exacerbates with the pharmacotherapy of ADHD because a plausible family conflict and poor parenting buy thyroxine 100 mcg low cost, both of which could model for the effects of stimulants is that buy 75 mcg thyroxine fast delivery, through dopami- exacerbate ADHD symptoms order thyroxine 125 mcg on line. Thus order thyroxine 200mcg on line, they can be con- ies implicate orbitofrontal and dorsolateral prefrontal cortex ceptualized as nonspecific triggers of an underlying or regions projecting to these regions; (b) the monkey model predisposition or as modifiers of the course of illness. Nevertheless, converging evi- callosum; (e) the I/LnJ mouse strain shows total callosal dence from the studies reviewed in this chapter supports agenesis along with behavioral features that resemble several empiric generalizations, which should be useful in ADHD; (f) functional neuroimaging finds hypoactivity of guiding future research and theory. The key data supporting this idea are as follows: (a) striatal DAT functioning, abnormal synaptic plasticity at anti-ADHD medications have noradrenergic and dopami- corticostriatal synapses, and long-term changes in synaptic nergic effects; (b) lesion studies in mouse and monkey efficacy in the striatum; and (j) the coloboma mouse shows models implicate dopaminergic pathways; (c) the SHR rat deficient dopamine release in dorsal striatum. Although rare Although the role of catecholamine systems cannot be cases may have a single cause such as lead exposure, general- disputed, future work must also consider other neurotrans- ized resistance to thyroid hormone, head injury, and frontal mitter systems that exert upstream effects on catechola- lobe epilepsy, most cases of ADHD are probably caused by mines. Two prime candidates are nicotinic and serotonergic a complex combination of risk factors. Nicotinic agonists help to control the symptoms From the many twin studies of ADHD, we know for of ADHD, and nicotinic activation enhances dopaminergic certain that genes mediate susceptibility to ADHD. Serotonergic drugs have not been shown ular genetic studies suggest that two of these genes may be to be effective anti-ADHD agents, but knockout mice stud- the DRD4 gene and the DAT gene. To confirm these find- ies suggest that the paradoxical effects of stimulants on hy- ings, we need much more work because, even if the positive 590 Neuropsychopharmacology: The Fifth Generation of Progress studies are correct, they may implicate neighboring genes us with more accurate assessments of the brain along with instead of those targeted by the studies. It seems unlikely a complete sequence of the human genome. These advances that a single 'ADHD gene' causes ADHD with certainty. When the ADHD-related variants of these genes are dis- covered, they will probably be 'normal' variants and will DISCLAIMERS most certainly not have the devastating effects seen in knockout mouse models. Biederman receives research support from Shire Labora- confirms that the 7-repeat allele is a risk factor for ADHD. In addition, he serves on speaking bu- 20% of people who do not have ADHD carry this version reaus for SmithKline Beecham, Eli Lilly & Company, and of the DRD4 gene. Most of these people do not develop Pfizer Pharmaceuticals. ADHD despite the blunted dopaminergic transmission as- sociated with that allele, and many patients with ADHD do not carry the allele. Thus, the 7-repeat allele cannot be REFERENCES a necessary or sufficient cause of the disorder. Attention deficit hyperactivity disorder: a handbook acts in concert with other genes and environmental risk for diagnosis and treatment. Is attention deficit Like genetic studies, studies of environmental risk factors hyperactivity disorder in adults a valid disorder? Harvard Rev suggest that most of these risks exert small but significant Psychiatry 1994;1:326–335. Age-dependent decline of attention deficit hyperactivity disorder. Comorbidity of attention most children with ADHD do not have a history of ADHD. Comorbidity in child psychopathology: concepts, issues and research strategies. J Child Psychol Psychiatry These considerations lead us to conclude that the origin 1991;32:1063–1080. Estimates of the posits ADHD to arise a pool of genetic and environmental prevalence of childhood maladjustment in a community survey variables—each of small effect—that act in concert to pro- in Puerto Rico: the use of combined measures. DSM-III disorders nerability exceeds a certain threshold, he or she will manifest in preadolescent children: prevalence in a large sample from the the signs and symptoms of ADHD. Pharmacotherapy of cause for ADHD, and each of the etiologic factors is inter- attention deficit hyperactivity disorder across the lifecycle: a changeable (i. J Am Acad Child Adolesc Psychiatry 1996;35: 409–432. Pharmacotherapy of combine in an additive or interactive manner is unknown. J Clin The mouse models of ADHD we described provide ex- Psychopharmacol 1995;15:270–279. A controlled study of model showed that individual differences in the DAT gene nortriptyline in children and adolescents with attention deficit hyperactivity disorder. In: Scientific proceedings of the annual could directly produce a hypodopaminergic state; these meeting of the American Academy of Child and Adolescent studies showed that dopamine transporter variants differ in Psychiatrists XV, Chicago, 1999. A double-blind abnormalities could interact with environmental toxins to trial of bupropion in children with attention deficit disorder. Another line of work shows that cate- Psychopharmacol Bull 1987;23:120–122. Bupropion in cholamines are secreted in response to stress, and catechol- children with attention deficit disorder. Psychopharmacol Bull amine administration produces fetal hypoxia.