A randomized, double-blind, placebo-controlled trial of antidepressants in Parkinson disease.

OBJECTIVE: To evaluate the efficacy and safety of a selective serotonin reuptake inhibitor (SSRI) and a serotonin and norepinephrine reuptake inhibitor (SNRI) in the treatment of depression in Parkinson disease (PD). METHODS: A total of 115 subjects with PD were enrolled at 20 sites. Subjects were randomized to receive an SSRI (paroxetine; n = 42), an SNRI (venlafaxine extended release [XR]; n = 34), or placebo (n = 39). Subjects met DSM-IV criteria for a depressive disorder, or operationally defined subsyndromal depression, and scored >12 on the first 17 items of the Hamilton Rating Scale for Depression (HAM-D). Subjects were followed for 12 weeks (6-week dosage adjustment, 6-week maintenance). Maximum daily dosages were 40 mg for paroxetine and 225 mg for venlafaxine XR. The primary outcome measure was change in the HAM-D score from baseline to week 12. RESULTS: Treatment effects (relative to placebo), expressed as mean 12-week reductions in HAM-D score, were 6.2 points (97.5% confidence interval [CI] 2.2 to 10.3, p = 0.0007) in the paroxetine group and 4.2 points (97.5% CI 0.1 to 8.4, p = 0.02) in the venlafaxine XR group. No treatment effects were seen on motor function. CONCLUSIONS: Both paroxetine and venlafaxine XR significantly improved depression in subjects with PD. Both medications were generally safe and well tolerated and did not worsen motor function. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that paroxetine and venlafaxine XR are effective in treating depression in patients with PD.

Cognitive slowing in Parkinson's disease resolves after practice.

OBJECTIVE: To assess the effect of dopaminergic repletion on working memory in Parkinson's disease. METHODS: The role of dopaminergic state on working memory in patients with Parkinson's disease was determined using the Sternberg item recognition paradigm, a continuous performance task that dissociates the motor and cognitive components of response time. Ten patients with Parkinson's disease were tested in an "on" state (on dopaminergic drug treatment) and a practical "off" state in two sessions held one week apart in counterbalanced order; 10 controls matched for age and education were studied at the same time points. RESULTS: Patients with Parkinson's disease showed impaired working memory, independent of motor slowing. During session 1, the performance of the patients was worse than the controls, regardless of dopaminergic state. The patients showed a significant improvement in the cognitive component of task performance during the second session, such that they no longer differed from the controls. The performance of the control subjects remained stable over the two sessions. CONCLUSIONS: Working memory performance of patients with Parkinson's disease did not change in association with dopaminergic state; rather, the performance improved over time. The pattern of improvement over time suggests a delay in proceduralising the task, similar to the deficits shown by such patients in procedural learning of other tasks.

Neuropsychological evidence for a topographical learning mechanism in parahippocampal cortex.

The Parahippocampal Place Area (PPA; Epstein & Kanwisher, 1998) is a region within posterior parahippocampal cortex that responds selectively to visual stimuli that convey information about the layout of local space. Here we describe two patients who suffered damage to the PPA after vascular incidents. Both subsequently exhibited memory problems for topographical materials and were unable to navigate unassisted in unfamiliar environments. Performance on a continuous n-back visual memory test was significantly lower for novel scene-like stimuli than for novel object-like stimuli. In contrast, performance was normal on a famous landmark recognition task and on two perceptual tasks that required on-line analysis of scene geometry. Both patients were able to produce accurate maps of premorbidly learned places but were unable to produce accurate maps of new places. These results converge with previous neuroimaging work to demonstrate that the PPA (1) is selectively involved in processing information about the geometry of surrounding space, and (2) may play a more critical role in the encoding of this information into memory than in the initial perceptual processing, recognition, or recall of this information.

[Cognitive and behavioral disorders in Parkinson disease]. / Trastornos cognitivos y comportamentales en la enfermedad de Parkinson.

INTRODUCTION: Most patients with Parkinson's disease have cognitive and behavior disorders during the course of their illness. OBJECTIVE: In this study we consider practical aspects of the treatment of patients with Parkinson's disease who have such problems. DEVELOPMENT: Better understanding of both normal and abnormal physiology of the basal ganglia and their connections makes it possible to suggest hypotheses regarding the cause of these disorders. The combination of lesions of multiple subcorticocortical systems with different degrees of direct cortical pathology due to Lewy bodies and neuritic plaques may explain most of the changes, from depression to dementia. CONCLUSIONS: It is necessary to test these concepts using studies based on specific predictions derived from pathophysiological models. Until this is done, the clinical treatment of cognitive and compartmental disorders in Parkinson's disease will continue to be symptomatic, complex and controversial.

Correlation of two bioadhesion assays: the everted sac technique and the CAHN microbalance.

This contribution correlates two in vitro methods utilized to determine bioadhesion. One method, the everted intestinal sac technique, is a passive test for bioadhesion involving several polymer microspheres and a section of everted intestinal tissue. The other method, the CAHN microbalance, employs a CAHN dynamic contact angle analyzer with modified software to record the tensile forces measured as a single polymer microsphere is pulled from intestinal tissue. This study demonstrates that CAHN and everted sac experiments yield similar results when used to quantify the bioadhesive nature of polymer microsphere systems. A polymer showing high adhesion in one method also demonstrates high bioadhesion in the other method; polymers that exhibit high fracture strength and tensile work measurements with the CAHN microbalance also yield high binding percentages with the everted sac method. The polymers tested and reported here are poly(caprolactone) and different copolymer ratios of poly(fumaric-co-sebacic anhydride). The results of this correlation demonstrate that each method alone is a valuable indicator of bioadhesion.

Poly(fumaric-co-sebacic anhydride). A degradation study as evaluated by FTIR, DSC, GPC and X-ray diffraction.

The degradation of three poly(fumaric-co-sebacic anhydride) [P(FA:SA)] copolymers is examined in a composition of microspheres made by the hot melt encapsulation process. The emergence of low molecular weight oligomers occurs during degradation of the copolymer microspheres, as evidenced by a variety of characterization methods. Characterization was conducted to determine the extent of degradation of the polyanhydride microspheres using Fourier-transform infrared spectroscopy (FTIR), gel permeation chromatography (GPC), differential scanning calorimetry (DSC) and X-ray diffraction. It is demonstrated that degradation of P(FA:SA) is greatly accelerated at basic pH, yet there is little difference between degradation in neutral and acidic buffers. A good correlation exists between the results of each characterization method, which allows a better understanding of the degradation process and the resulting formation of low molecular weight oligomers in poly(fumaric-co-sebacic anhydride).

Schizophrenic subjects activate dorsolateral prefrontal cortex during a working memory task, as measured by fMRI.

BACKGROUND: Neuroimaging studies of schizophrenic subjects performing working memory (WM) tasks have demonstrated a relative hypoactivity of prefrontal cortex compared with normal subjects. METHODS: Using functional magnetic resonance imaging (fMRI), we compared dorsolateral prefrontal cortex (DLPFC) activation in 12 schizophrenic and 10 normal subjects during rewarded performance of a WM task. Subjects performed a modified version of the Sternberg Item Recognition Paradigm (SIRP), a continuous performance, choice reaction time (RT) task that requires WM. We compared a high WM load condition with a nonWM choice RT condition and with a low WM load condition. RESULTS: Schizophrenic subjects performed the tasks better than chance but worse than normal subjects. They showed greater activation than normal subjects in the left DLPFC but did not differ in the right DLPFC or in the control region. In the schizophrenic group, left DLPFC activation was inversely correlated with task performance, as measured by errors. CONCLUSIONS: These findings contrast with previous studies that demonstrated task-related hypofrontality in schizophrenia. Task parameters that may contribute to this difference are discussed. We hypothesize that the performance and activation differences we observed are also manifestations of prefrontal dysfunction in schizophrenia. They reflect inefficient functioning of the neural circuitry involved in WM.

Dyspnea in patients with chronic obstructive pulmonary disease: does dyspnea worsen longitudinally in the presence of declining lung function?

OBJECTIVE: To determine the direction and rate of change in the symptom of dyspnea in patients with chronic obstructive pulmonary disease (COPD) whose lung function has worsened over time. DESIGN: Secondary analysis of a longitudinal data set. SETTING: Outpatient clinic. PATIENTS: Thirty-four medically stable male subjects with chronic obstructive pulmonary disease studied for 5.3 +/- 3.5 years, with a mean reduction in FEV1 over the period studied of 330.9 +/- 288.0 mL. Subjects were 63.3 +/- 5.5 years of age at entry into the study. OUTCOME MEASURES: Dyspnea and functional status scores were obtained using the Pulmonary Functional Status and Dyspnea Questionnaire. RESULTS: There was no significant difference in reports of dyspnea from the beginning to the end of the study, despite significant reductions in lung function. Of all activities studied, dyspnea when raising arms overhead was the only activity showing a relationship to the slope of change in FEV1 %. CONCLUSION: These findings suggest that, although patients with chronic lung disease experience varying degrees of deterioration in lung function longitudinally, there is no evidence that they report worsening of dyspnea in tandem with these physiologic changes. In this study, patient ratings of dyspnea longitudinally were not directly linked to changes in lung impairment.

Market concentration in secondary health services under a purchaser-provider split: the New Zealand experience.

The separation of purchaser and provider in government-funded health systems enables competition to develop between providers. Competition is seen as a means to drive technical efficiencies by providers. While it is difficult to assess comprehensively the level of competition in a market taking into account contestability and substitutability effects, it is possible to measure the degree of market concentration. This paper employs the Hirschman-Herfindahl index to provide measures of market concentration in selected secondary health care markets in New Zealand immediately prior to (1992) and following (1994) implementation of a purchaser-provider split. The results show that, generally, the selected markets are highly concentrated and that there has been little change in the degree of concentration over the 2 year period under investigation. The paper also discusses some of the methodological problems associated with the measurement of market concentration and acknowledges the limitations of such measures as indicators of competition.

Toxic Releases from Paper Made with Recovered Wastepaper versus Virgin Wood Fiber: A Research Note

Toxic Release Inventory (TRI) data were used to compare average releases (kilograms per metric ton) of paper mills using primarily recovered wastepaper versus mills using primarily virgin wood fiber. Annual releases, for 79 mills, of chlorine, chlorine dioxide, chloroform, acids (hydrochloric and sulfuric), volatile organics (methyl ethyl ketone, methanol, and acetone), and ammonia were compared over the years 1987-1992. Both types of mills reported generally lower toxic releases in 1992 than in 1987; however, toxic releases in all categories were significantly lower from mills using recovered wastepaper than from mills using virgin wood fiber, strongly demonstrating that recycling has added benefits beyond reduced resource consumption. These results suggest that environmental policy should concentrate as much on increasing demand for recycled paper and developing wastepaper collection infrastructure as it does on end-of-pipe pollution abatement.KEY WORDS: Recycled paper; Toxic Release Inventory

Measurement of brain activity with bolus administration of contrast agent and gradient-echo MR imaging.

This study was performed to measure changes in cerebral blood volume (CBV) associated with visual activation by use of bolus administration of contrast agent and conventional, clinically configured magnetic resonance (MR) hardware and software. Fast gradient-recalled acquisition in the steady state technique was used to study five healthy subjects during visual activation and a control dark state. MR images were obtained every 2.048 seconds for 2 minutes. A bolus of gadopentetate dimeglumine was injected during visual stimulation and darkness. Cine images produced from the series of rapid images clearly depicted arterial, capillary, and venous phases. Analysis of serial concentration maps derived from the rapid images revealed expected differences between the relative CBV of gray matter and that of white matter, as well as significantly increased relative CBV in calcarine cortex during visual activation versus the control state (mean increase, 15.24%; range, 6.41%-27.78%; P < .05). These results confirm those reported in echo-planar imaging studies and demonstrate that brain function can be assessed with the bolus method by means of MR imaging hardware and software with conventional clinical configurations.

The development of induced cerebrocortical microgyria in the rat.

Placement of a freezing probe on the skull of neonatal rats produces four-layered microgyria, complete with a lamina dissecans and microsulcus. We studied the developmental course of this induced microgyria under light microscopy by examining changes in neurons, glia, and macrophages following a focal freezing insult on the day of birth (postnatal day [P]0). The destruction of neurons and glia induced by the freezing probe extends through the cortical plate and occasionally through the subplate, but the pial membrane appears undamaged and radial glial cells, while damaged, are not eliminated. Reactive astrocytes and macrophages arrive in the damaged area within 24 hours of the injury, and repair of the damaged tissue peaks within the first week. Damaged radial glial fibers regrow, and supragranular neurons migrate through this damaged area, also within the first week. The newly formed supragranular layer overlies the cell-free area. The damaged cortex begins to assume its adult-like microgyric appearance from P5 to P10. On P15 and P32, long glial fibers, resembling radial glia, are present and are immunoreactive for glial fibrillary acidic protein and radial glial fiber antibodies (vimentin and Rat-401). No such fibers appear at this age in the non-microgyric areas or in normal brains. We conclude that microgyria formation may be the consequence of brain repair mechanisms occurring during neuronal migration to the neocortex, and that it appears to preserve primitive features characteristic of the developing cortex.

The organization of radial glial fibers in spontaneous neocortical ectopias of newborn New Zealand black mice.

Forty percent of New Zealand Black (NZB) mice, a strain that develops severe autoimmune disease, have ectopic collections of neurons in layer I of the neocortex. This strain is used as a model for similar anomalies seen in the dyslexic brain. In the present study we immunohistochemically stained radical glial fibers and their anchoring processes (which form the glial external limiting membrane) in the region of ectopias in NZB mice. The organization of glial fibers was abnormal in and around the ectopic region. Radial glial fibers underlying the ectopia were denser than in the surrounding cortex, and within the ectopia there was a disorganized matrix of glial fibers. Most glial fibers, however, did not enter the ectopia, but instead curved towards the edge of the ectopia and attached there. The glial limiting membrane was breached in the area of the ectopia, indicating that an insult to this membrane may have allowed neurons to migrate into layer I and the overlying subarachnoid space. This finding along with the results of the accompanying paper on puncture wounds of the cortex of newborn rodents supports the view that rupture of the external limiting glial membrane is responsible for the inappropriate migration of neurons into the molecular layer.

Freezing lesions of the developing rat brain: a model for cerebrocortical microgyria.

Cerebrocortical microgyri were induced by placing a freezing probe on the skull of P0 and P1 rat pups. Freezing lesions resulted in laminar necrosis of the infragranular layers and the subsequent migration of supragranular neurons through the region of damage. The result was most often a region of four-layered microgyric cortex consisting of a molecular layer, a thickened layer ii, a lamina dissecans (corresponding to the necrotized layers IV, V, and VIa), and a neuronal layer iv which corresponded to layer VIb of the intact cortex. Immunocytochemical investigation of the microgyric cortex with antibodies to neurofilament, glial fibrillary acidic protein and glutamate showed more widespread disruption of neocortical architecture than could be seen from Nissl preparations. In contrast, vasoactive intestinal peptide-containing neuronal bodies appeared to be distributed normally in the microgyric region although their processes were sometimes distorted. These results are considered in the light of previous research on induced microgyria, and possible implications for the behavioral consequences of focal, developmental neuropathologic lesions are discussed.

Assessment of olfactory deficits in detoxified alcoholics.

Olfactory functioning was evaluated in 37 male detoxified alcoholics and in 21 age-matched nonalcoholic controls using the University of Pennsylvania Smell Identification Test (UPSIT). Of the original subjects, 23 alcoholics and 14 controls returned for reevaluation 3-4 months following initial testing. The results showed that alcoholics had significantly lower UPSIT scores than did the controls, both at baseline and follow-up testing. Thirty-two percent of the alcoholics' UPSIT scores, in comparison to five percent of the controls' scores, fell into the clinically impaired range. Although current smoking patterns correlated significantly with UPSIT indices, comparisons limited to nonsmokers still indicated that the alcoholics were significantly impaired on this olfactory task. Correlational analyses indicated that olfactory performance was unrelated to alcoholics' scores on visuoconceptual and language tasks. Correlations with MR-derived indices of CSF volume showed a highly significant relationship between UPSIT scores and cortical sulcal volumes. Additionally, alcoholics (N = 15) who remained abstinent had significantly higher scores at follow-up than those who were not abstinent (N = 8). These findings demonstrate that alcoholism is associated with basic olfactory impairments which are only partially reversible with abstinence and that cortical structures play an important role in this sensory loss.

Abnormal architecture and connections disclosed by neurofilament staining in the cerebral cortex of autoimmune mice.

Routine cell stains disclose abnormal, usually single, nests of ectopic neurons in neocortical layer I of New Zealand Black (NZB) and BXSB autoimmune mice. We have suggested that these anomalies represent only the most visible part of more widespread cortical disorganization. In an attempt to determine the true magnitude of cellular and fiber disruption associated with the presence of ectopias, we stained cortical sections containing ectopias in layer I from NZB and BXSB mice with an antibody directed against the 68 kDa subunit of neurofilament protein. The neurofilament-stained sections revealed substantial disruption of the cortical layers underlying the ectopic neurons. This resulted primarily from the existence of dense, radially oriented fiber bundles spanning the thickness of the cortex underlying the ectopias. In some instances these fiber bundles could be seen to join the corpus callosum. Even in a small ectopia, where standard stains show no associated cortical dysplasia, dense neurofilament staining was present in layers II and III. It was concluded that the brains of autoimmune mice have severe developmental cortical disorganization, which could account for the behavioral differences displayed by these animals.

Effects of hypophysectomy and ovariectomy on hepatic estrogen receptor content in the turtle, Chrysemys picta.

Estrogen receptor (ER) content in the cytosol and nuclear extract of the liver of adult female Chrysemys picta (control females) was measured in February, May, early June, and late June. Both cytosolic (C) and nuclear (N) hepatic ER content rose from low levels (C: 189 +/- 19; N: 52 +/- 23 fmol/g tissue) in February to significantly higher levels in May (C: 437 +/- 15; N: 124 +/- 25 fmol/g tissue) before declining to lower values in early June (C: 298 +/- 19; N: 118 +/- 20 fmol/g tissue) and late June (C: 274 +/- 22; N: 89 +/- 13 fmol/g tissue). This pattern of seasonal variation in hepatic ER content was also observed in gonadectomized females. Levels of hepatic ER content in ovariectomized turtles fluctuated in the same manner as those found in control females. However, elevations in hepatic ER contents were not observed in hypophysectomized females. Removal of the pituitary resulted in a drastic reduction in the May value (316 +/- 49 fmol/g tissue) of cytosolic ER content and a complete blockade in a rise of nuclear ER content in the liver of the turtle. Nuclear hepatic ER content remained at around 50 fmol/g tissue throughout the months of May and June. The two surgeries procedures caused no significant changes in the ER's affinity for estrogen. The present findings demonstrate a direct control of the pituitary over hepatic ER content which signifies important pituitary regulation of the vitellogenic process, at the liver level, during the spring reproductive season.

High-affinity binding of [3H]estradiol-17 beta by an estrogen receptor in the liver of the turtle.

Specific [3H]estradiol-17 beta ([3H]E2) binding activity (EBA) with characteristics of an estrogen receptor (ER) was demonstrated in cytosols and nuclear extracts of the female turtle, Chrysemys picta. Three different receptor assays (dextran-coated charcoal assay, hydroxylapatite batch procedure, and DNA-cellulose chromatography) were evaluated in terms of their applicability in analyzing large numbers of samples. For the measurement of cytosolic EBA, the hydroxylapatite batch procedure was found to be the most reliable assay. On the other hand, the dextran-coated charcoal assay was found to be the most appropriate method for the measurement of nuclear EBA. Turtle hepatic EBA binds [3H]E2 with high affinity (cytosolic, 17.4 +/- 2.8 X 10(9) M-1; nuclear, 17.7 +/- 1.9 X 10(9) M-1), limited capacity (cytosolic, 133.7 +/- 4.6 fmol/g tissue; nuclear, 81.1 +/- 9.0 fmol/g tissue), and strict steroid specificity. The EBA bound natural estrogens (E2, estrone, estriol) as well as the nonsteroidal estrogen, diethylstilbestrol, but exhibited little affinity for androgens, progesterone, or corticosterone. The turtle hepatic EBA resembled mammalian and avian ERs in terms of binding characteristics; however, unlike mammalian and avian ERs it was shown to be heat-labile. Incubation at 30 degrees caused rapid loss of [3H]E2 binding activity in both cytosolic and nuclear fractions. The exchange between [3H]E2 and the endogenously bound estrogen was slow at 4 and 15 degrees, but the exchange process was facilitated in the presence of the chaotropic salt, NaSCN. Establishment of quantitation methods for both cytosolic and nuclear forms of EBA will enable future investigation of the mechanism and regulation of estrogen action in the liver of this turtle species.

Identification of an estrogen receptor in the testis of the sea lamprey, Petromyzon marinus.

Employing a hydroxylapatite batch assay, estrogen-binding activities (EBAs) were demonstrated in the cytosol and nuclear extract of the testis of the anadromous sea lamprey, Petromyzon marinus. The lamprey testicular EBAs are sensitive to trypsin digestion and bind [3H]estradiol-17 beta with high affinities (cytosolic Kd = 0.52 nM; nuclear Kd = 0.39 nM) and limited capacities (cytosolic: 56.2 fmol/g tissue; nuclear: 68.2 fmol/g tissue). Androgens, progesterone, and corticosterone displayed little affinities for lamprey EBAs. Thus, lamprey testicular EBA possessed many definitive properties of an estrogen receptor as described in amphibian, reptilian, and mammalian studies. No specific binding to androgens was detected in either testicular subcellular fraction. The presence of a putative estrogen receptor in lamprey testis suggests a functional role of estrogen in testicular regulation in this ancient vertebrate.

The problem-oriented medical record applied to communicative disorders.

A continuing interest in clarity of reporting generated a change in our reporting format from the traditional report to the problem-oriented structure. This article discusses the differences and the advantages and disadvantages of each.