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It is interesting to note that NAA signals in NAA signals were found only in the animals with neonatal hippocampal formation buy cheap super p-force 160 mg line, the other region consistently impli- removals quality super p-force 160mg, suggesting that NAA could reflect more complex cated in studies of patients with schizophrenia purchase super p-force 160mg line, do not show plastic neuronal modifications generic 160mg super p-force with mastercard, perhaps at the level of local these predictable relationships generic super p-force 160 mg amex. Chapter 59: Neurochemical and Neuropharmacological Imaging in Schizophrenia 849 (177) may shed some light on this apparent inconsistency. Preliminary studies of fluorinated compounds, such as schizophrenia and found that although NAA signals were fluoxetine and fluphenazine, have demonstrated the feasibil- also reduced in the hippocampal formation of the healthy ity of measuring the concentrations of such compounds in siblings, changes in DLPFC were not found. The potential applications of such measurements will suggest that consistent with other evidence of hippocampal become clearer in the context of improved methodology. In contrast, consistent with the pre- aim to understand the basis for this change, as well as other dictable relationships of NAA in DLPFC with other func- factors that affect NAA signals. The lack of a difference in frontal lobe NAA in healthy relatives of pa- ACKNOWLEDGMENTS tients with schizophrenia has recently been reported by an- other group as well (198). Therefore, these results have This work is supported by the National Institute of Mental added hippocampal NAA measures to the list of potential Health (M. Weinberger has phenotypic markers of genetic risk for further exploration served as a consultant for Janssen and Eli Lilly & Company. Imaging dopamine MRS is a rapidly evolving technology and its future applica- receptors in the human brain by positron tomography. Science tions in schizophrenia research should lead to important 1983;221:1264–1266. The significance of dopamine receptor blockade for emerge from methodologic advances leading to improved the mechanism of action of neuroleptic drugs. Arch Int Pharma- sensitivity and resolution, measurement of novel chemical codyn Ther 1966;160:492–494. Effect of chlorpromazine or haloperi- moieties, indexing neuronal metabolism, and characterizing dol on formation of 3-methoxytyramine and normetanephrine drug effects. The availability of high-field human magnets in mouse brain. Antipsychotic drugs: direct correlation be- and allow for improved reliability and resolution. At the tween clinical potency and presynaptic action on dopamine neu- rons. National Institute of Mental Health (NIMH), proton spec- 5. Dopamine receptor binding tral images are currently acquired at 3 T with 0. London: Chapman and it possible to shim individual slices rather than slabs of tis- Hill, 1958. The phenomenology of experimentally sue, and to acquire both early and late echo spectra within induced amphetamine psychosis-Preliminary observation. Biol the same acquisition, without suppressing the water signal. Clinical studies on the mechanism of action of clo- tor signals) may further improve reliability and make it pos- zapine: the dopamine-serotonin hypothesis of schizophrenia. The current status of the dopamine hypothesis of improved STN and signal acquisition of new methods will schizophrenia. This will improve the potential reliability of A review and meta-analysis. Dopamine in schizophrenia: calculations of the components of the tGlx peak more relia- a review and reconceptualization. Preliminary results using spectral editing approaches to 12. A critical the GABA peak suggest that clinically meaningful data review of the data and their interpretation. Brain 1999;122: about GABA metabolism can be derived from this peak 593–624. Greater sensitivity and SNR also will permit spectral 13. Prefrontal function in schizophre- analyses of externally administered molecules. Functional and anatomical skeleton tracked over time as changing concentrations of aspects of prefrontal pathology in schizophrenia. Implications of the normal brain development 850 Neuropsychopharmacology: The Fifth Generation of Progress for the pathogenesis of schizophrenia. Arch Gen Psychiatry 1987; sured by [(11)C]raclopride continuous infusion PET scans.

With reduction in these trexone was investigated as a potential treatment for the associated target symptoms cheap super p-force 160mg overnight delivery, improvement in some aspects associated behavioral symptoms of autistic disorder super p-force 160mg low cost, as well of social behavior can result secondarily best 160 mg super p-force. Again cheap super p-force 160 mg overnight delivery, results from initial open- Following a brief review of earlier drug studies discount 160mg super p-force overnight delivery, results label reports and small controlled studies suggested possible from more current investigations, including those of atypi- effectiveness for naltrexone. More recent large well-designed cal antipsychotics and serotonin reuptake inhibitors (SRIs), controlled investigations involving children, adolescents, will be presented in some detail. For a more comprehensive and adults with autistic disorder, however, have failed to review of drug treatment of PDDs, the reader is referred to demonstrate improvement in the majority of target symp- other sources (5,6). The most consistent find- ings from these controlled studies were that naltrexone is well tolerated and may be effective for reducing motor hy- Early Drug Treatment Studies peractivity. Beginning in the 1960s, numerous agents, including ly- A number of other drugs have been studied in autistic disorder, although most of the trials were either uncon- sergic acid diethylamide, methysergide, levodopa, triiodo- trolled or contained a small number of subjects (5,6). For thyronine, imipramine, and 5-hydroxytryptophan were example, -adrenergic antagonists have been reported to studied in autistic disorder. Many of these investigations reduce aggression and self-injury in some small open-label were limited by a lack of diagnostic precision and inade- pilot trials in adults with autistic disorder. In general, these initial studies bradycardia were common dose-related adverse effects. Case identified no drug that resulted in consistent target symp- reports and small open-label studies have described mixed tom reduction. Con- Elevated levels of whole blood serotonin (5-hydroxytryp- trolled investigations of mood stabilizers, including lithium, tamine, 5-HT) have long been associated with autistic disor- valproic acid, carbamazepine, and gabapentin, have not der in a large minority of subjects (7). Following reports been reported in well-defined groups of autistic subjects. Despite early enthusiasm generated by PDDs has proven particularly challenging to clinicians and small open-label reports, most controlled studies found no researchers. These symptoms are most prominent in consistent efficacy for fenfluramine as a treatment for autis- younger-aged autistic children. Furthermore, increasing evidence of possi- largely present during a time when educational program- ble neurotoxic effects of the drug on 5-HT neurons in ani- ming and interventions are most critical. The psychostimu- mals and the association of fenfluramine with primary lants, such as methylphenidate and dextroamphetamine, are pulmonary hypertension and (in combination with phenter- effective treatments for these symptoms in individuals with mine) valvular heart disease have eliminated its use as a safe attention-deficit/hyperactivity disorder (ADHD). In a more studied in heterogeneous groups of children that included recent double-blind crossover study of methylphenidate and autistic subjects. Many of these early investigations suffered placebo, ten autistic children, ages 7 to 11 years, received from the lack of adequate diagnostic methods and nonstan- doses of 10 or 20 mg twice daily for 2 weeks (17). Most of these trials were direct cally significant improvement was seen on the Conners comparisons of two drugs, usually low-potency antipsychot- Teacher Questionnaire (18) and on the hyperactivity factor, ics, and did not include a placebo control. A number of irritability factor, and total score of the Aberrant Behavior these agents were found to be effective for behavioral symp- Checklist (19). Due to significant sedation and adverse cognitive ef- modest. Following completion of the study, it was necessary fects secondary to the low-potency drugs, however, studies to add haloperidol to the treatment regimen of two of the of higher potency conventional antipsychotics were next ten children due to continued symptoms of aggression. The 2-adrenergic agonist clonidine has been shown to be an effective treatment for some individuals with ADHD. Clozapine In a small double-blind, placebo-controlled study of cloni- Clozapine has been shown to be effective for treatment- dine (4 to 10 g per kg daily) in eight children with autistic refractory schizophrenia (27). No significant drug–placebo differences were been only one report to date describing the use of clozapine identified on clinician ratings of videotaped observations, in autistic disorder (28). Adverse effects included hypotension, sedation, hyperactivity or aggression were given clozapine after they and irritability. In contrast, transdermal clonidine (5 g per had not responded to typical antipsychotics. The scarcity of reports ment phase) involving nine males (ages 5 to 33 years) with describing the use of clozapine in autistic disorder might autistic disorder (21). Significant improvement was seen reflect concern regarding the risk of agranulocytosis or sei- on the Clinical Global Impression Scale (CGI) (22), and zures in children or adolescents that are associated with the hyperactivity and anxiety were also reduced. Because autistic individuals typically have an impaired mon adverse effects were sedation and fatigue.

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The last step is statistical analysis using the general linear model to identify regions of gray matter con- 1 super p-force 160mg low cost. Each automated warping procedure should be compared centration that are significantly related to the variable under with the results using manual ROI definitions buy super p-force 160 mg visa. Accuracy may be good for subcortical structures (because analysis is used) cheap super p-force 160mg without prescription. Accuracy is questionable for the neocortex super p-force 160mg fast delivery, because of comparisons throughout the whole brain without the re- the irregularity of sulco-gyral patterns purchase super p-force 160 mg amex. They performed manual area onto spatially normalized brains of a large group of schizo- measurements of the head of the caudate in the transverse phrenic patients (n 85) and controls (n 75). They slice 12 mm superior to the intercommissural plane in the then computed the statistical significance of the difference untransformed data. They found Pearson product–moment temporal gyrus and unilateral reductions in the superior and correlations between the area measurement and the voxel middle frontal gyrus, precentral gyrus, lingual gyrus, and gray matter values for the transformed data for the 20 sub- cerebellum. This study forms a good transition to the next jects to be about r 0. These data do not, unfortunately, section because the spatial normalization techniques and the provide information on spatial specificity in terms of a mea- nonlinear registration method, those of SPM99 and Ash- surement of the boundaries of the caudate in the untrans- burner and Friston (27), respectively, are described in the formed data for the 20 subjects and the transformed data. Nor do these data, taken from the center point of a regular structure, provide any clear information on how well the transformation would work on the much more irregular Voxel-Based Morphometry cerebral cortex. Because one of the findings with trans- Ashburner and Friston (27) define this technique as 'a formed data was decreased gray matter in the schizophrenic voxel-wise comparison of the local concentration of gray group in the voxels corresponding to the right amygdala, matter between two groups of subjects,' and have provided one would have liked to see a comparison with manually a detailed description of this methodology, closely related drawn ROI in this structure as a way of validating the voxel to that of SPM99. As a first step, this method takes all analysis (and/or a comparison in the other regions found to subject images and normalizes them to the same stereotaxic be abnormal, the temporal pole/insula, and left dorsolateral space, using procedures similar to those used in SPM for prefrontal cortex). Wright and associates did find that voxel fMRI and PET data. This procedure involves an initial lin- analysis could detect artificial 'lesions,' created by setting ear (affine) match (similar to that described for brain warp- gray matter content to zero in a group of voxels, including ing) followed by a nonlinear registration using smooth spa- a4- 4-mm bar and a 12- 25-mm grid. These authors emphasize that this spatial not try more realistic 'lesions' with parametric variation of normalization 'does not attempt to match every cortical degrees of lesser gray matter content; nor did they quantify Chapter 55: Structural MRI Studies in Schizophrenia 767 the spatial specificity. In concluding the discussion of this DIFFUSION TENSOR MR IMAGING technique, Wright and colleagues voiced the important ca- veats that voxel based morphometry may not detect 'very This is a new MRI technology that is able to provide infor- small gray matter reductions, gray matter reduction in areas mation on the orientation and integrity of fiber tracts. In of high variability in gray matter volume or gray matter diffusion tensor imaging (DTI), a tensor describing local reductions with an inconsistent location. Until Diffusion may be 'isotropic,' equal in all directions, as such validation procedures are done, any results with voxel- occurs in CSF, and the diffusion volume (3D representation based morphometry (VBM) will, of necessity, be viewed of diffusion pathways) has a spherical geometry in this case. Because of the Or diffusion may be 'anisotropic' (e. The limiting case for maximal anisotropy is an infi- tional ROI analysis (Kubicki and colleagues, unpublished nitely long and thin cylinder. For VBM applied to whole brain, only the left poste- diffusion is mainly in the direction of the fibers. Factors rior superior temporal gyrus region was significantly differ- that affect the shape of the apparent diffusion tensor (shape ent between schizophrenic and control groups, a finding of the diffusion ellipsoid) in the white matter include the consistent with our ROI analysis. In a less statistically less density of fibers, degree of myelination, average fiber diame- stringent analysis (taking into account peak z values and ter, and directional similarity of the fibers in the voxel. For voxel cluster extent), there was significance bilaterally in the example, the DTI-measured diffusion coefficients are larger anterior cingulate gyri and insula (regions not examined when measured along (parallel to) white matter fibers (in 3 2 with ROI), but not in medial temporal lobe where ROI the range of 1. Taken together, these data suggest the following meth- nature of the measured diffusion tensor within a voxel is odologic conclusions: thus a meaningful measure of fiber tract organization. The degree of anisotropy in schizophrenia has been in- 1. Each VBM study should be compared with manual ROI vestigated in two recent studies. Using DTI, Buchsbaum definitions until validity is established. VBM may be useful for generating hypotheses to be isotropy in some inferior portions of prefrontal white matter validated with traditional ROI analyses. Much work remains to be done in comparing the validity co-workers (32) found that abnormally low white matter of VBM and ROI analysis, and formulating reasons for anisotropy in patients with schizophrenia was present in any differences. For group statistics, Lim and co-workers used the median value of voxel anisotropy (mea- Shape Analysis sured as fractional anisotropy; 1 is maximal and 0 minimal) in each slice within the white matter regions of interest in It is readily apparent that ROI shape as well as volume may the control and schizophrenia groups. These studies raised carry information about pathology.

Figures express cases per m illion persons per year with 95% confidence intervals (CI) purchase super p-force 160mg on-line. Condition Incidence (per million persons per year) 95% CI Acute tubular necrosis 88 79–97 Prerenal acute renal failure 46 40–52 Acute on chronic renal failure 29 24–34 Obstructive acute renal failure 23 19–27 Glomerulonephritis (primary or secondary) 6 buy super p-force 160 mg cheap. This algorithm could help Normal or big kidneys to determ ine the cause of the increase in Small kidneys (excluding amiloidosis and blood urea nitrogen (BUN ) or serum polycystic kidney disease creatinine (SCr) in a given patient order super p-force 160 mg on line. ARF Parenchymatous Data indicating Improvement glomerular or Yes glomerular No with specific systemic ARF or systemic treatment? Great or Vascular small vessel Yes ARF Yes No disease? Prerenal Acute ARF tubulointerstitial Data indicating nephritis Yes interstitial No disease? Tumor lysis Acute Sulfonamides Crystals or tubular Yes tubular No Amyloidosis necrosis Other deposits? Kidney biopsy has had fluctuating roles in the diagnostic work-up of ARF 160 mg super p-force. After extrarenal causes of ARF are excluded super p-force 160mg with mastercard, the most common Disease Patients, n cause is acute tubular necrosis (ATN). Patients with well-established clinical and laboratory features of ATN receive no benefit from renal Primary GN 12 Extracapillary 6 biopsy. By that time, most cases of ATN have Focal sclerosing 1 resolved, so other causes could be influencing the poor evolution. Secondary GN 6 Biopsy is mandatory when a potentially treatable cause is suspected, Antiglomerular basement membrane 3 such as vasculitis, systemic disease, or glomerulonephritis (GN) in Acute postinfectious 2 adults. Other parenchymatous forms of ARF can be accurately Acute tubular necrosis 4* diagnosed without a kidney biopsy. This is true of acute post-strepto- Acute tubulointerstitial nephritis 4 coccal GN and of hemolytic-uremic syndrome in children. Kidney Atheroembolic disease 2 biopsy was performed in only one of every 16 ARF cases in the Kidney myeloma 2* M adrid ARF Study. All patients with primary GN, 90% with Cortical necrosis 1 vasculitis and 50% with secondary GN were diagnosed by biopsy at Malignant hypertension 1 the time of ARF. As many as 15 patients were diagnosed as having ImmunoglobulinA GN + ATN 1 acute tubulointerstitial nephritis, but only four (27% ) were biopsied. Hemolytic-uremic syndrome 1 Only four of 337 patients with ATN (1. Predisposing Factors for Acute Renal Failure Other figure shows the Renal insult Very Obstructive m ain causes of elderly Elderly Young Prerenal ARF, dividing a Advanced age Acute tubular population diag- 11% 12% 17% necrosis nosed with ARF Proteinuria 11% 7% into the very elder- 20% ly (at least 80 Volume 21% years), elderly (65 depletion 29% to 79), and young 30% (younger than 65). M yeloma Essentially, acute tubular necrosis 56% (ATN ) is less Diuretic use 48% 39% frequent (P=0. Although the cause of ARF is diseases appear Higher probability usually m ultifactorial, one can define the with sim ilar for ARF cause of each case as the m ost likely con- frequency in the tributor to im pairm ent of renal function. FIGURE 8-11 O ne interesting approach is to distribute (D ata from Pascual the causes of ARF according to age. Som e of them act synergistically when they occur in the sam e patient. Advanced age and volum e depletion are particularly im portant. Prospective epidemiologic studies of acute renal failure (ARF) in large populations have not often been published. Study Period Study Population Incidence The first study reported by Eliahou and Investigator, Year Country (City) (Study Length) (millions) (pmp/y) colleagues was developed in Israel in the Eliahou et al. No data about ARF incidence are (Bristol and Devon) available from undeveloped countries. This has been another way of assessing the incidence of the m ost severe cases of ARF. Local situations, m ainly econom ics, have an effect on dialy- Investigator, Year Country Cases (pmp/y) sis facilities for ARF m anagem ent.

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