St. Elizabeths Hospital

Recent research on schizophrenia has demonstrated that in this disorder the brain is not, strictly speaking, normal. The findings suggest that nonspecific histopathology exists in the limbic system, diencephalon, and prefrontal cortex, that the pathology occurs early in development, and that the causative process is inactive long before the diagnosis is made. If these findings are valid and not epiphenomena, then the pathogenesis of schizophrenia does not appear to fit either traditional metabolic, posttraumatic, or neurodegenerative models of adult mental illness. The data are more consistent with a neurodevelopmental model in which a fixed "lesion" from early in life interacts with normal brain maturational events that occur much later. Based on neuro-ontological principles and insights from animal research about normal brain development, it is proposed that the appearance of diagnostic symptoms is linked to the normal maturation of brain areas affected by the early developmental pathology, particularly the dorsolateral prefrontal cortex. The course of the illness and the importance of stress may be related to normal maturational aspects of dopaminergic neural systems, particularly those innervating prefrontal cortex. Some implications for future research and treatment are considered.

Automated partial DNA sequencing was conducted on more than 600 randomly selected human brain complementary DNA (cDNA) clones to generate expressed sequence tags (ESTs). ESTs have applications in the discovery of new human genes, mapping of the human genome, and identification of coding regions in genomic sequences. Of the sequences generated, 337 represent new genes, including 48 with significant similarity to genes from other organisms, such as a yeast RNA polymerase II subunit; Drosophila kinesin, Notch, and Enhancer of split; and a murine tyrosine kinase receptor. Forty-six ESTs were mapped to chromosomes after amplification by the polymerase chain reaction. This fast approach to cDNA characterization will facilitate the tagging of most human genes in a few years at a fraction of the cost of complete genomic sequencing, provide new genetic markers, and serve as a resource in diverse biological research fields.

The Premorbid Adjustment Scale (PAS) is a rating scale which was developed to be applicable in a research setting. It is designed to evaluate the degree of achievement of developmental goals at each of several periods of a subject's life before the onset of schizophrenia. A description of the scale and its use is presented, along with a discussion of psychometric properties. The PAS has been found to be useful in identifying patients likely to become chronically hospitalized or at high risk for readmission. It may also serve as a possible predictor of patients with brain abnormalities on a computerized tomography (CT) scan.

Recent neuroradiologic and neuropathological studies indicate that at least some patients with schizophrenia have slightly enlarged cerebral ventricles and subtle anatomical abnormalities in the region of the anterior hippocampus. Using magnetic resonance imaging (MRI), we studied 15 sets of monozygotic twins who were discordant for schizophrenia (age range, 25 to 44 years; 8 male and 7 female pairs). For each pair of twins, T1-weighted contiguous coronal sections (5 mm thick) were compared blindly, and quantitative measurements of brain structures were made with a computerized image-analysis system. In 12 of the 15 discordant pairs, the twin with schizophrenia was identified by visual inspection of cerebrospinal fluid spaces. In two pairs no difference could be discerned visually, and in one the twin with schizophrenia was misidentified. Quantitative analysis of sections through the level of the pes hippocampi showed the hippocampus to be smaller on the left in 14 of the 15 affected twins, as compared with their normal twins, and smaller on the right in 13 affected twins (both P less than 0.001). In the twins with schizophrenia, as compared with their normal twins, the lateral ventricles were larger on the left in 14 (P less than 0.003) and on the right in 13 (P less than 0.001). The third ventricle also was larger in 13 of the twins with schizophrenia (P less than 0.001). None of these differences were found in seven sets of monozygotic twins without schizophrenia who were studied similarly as controls. We conclude that subtle abnormalities of cerebral anatomy (namely, small anterior hippocampi and enlarged lateral and third ventricles) are consistent neuropathologic features of schizophrenia and that their cause is at least in part not genetic. Further study is required to determine whether these changes are primary or secondary to the disease.

In order to determine if brain tissue grafts can provide functional input to recipient central nervous system tissue, fetal rat dopamine-containing neurons were implanted adjacent to the caudate nucleus of adult recipients whose endogenous dopaminergic input had been destroyed. The grafts showed good survival and axonal outgrowth. Motor abnormalities, which had been induced by the destruction of the endogenous dopaminergic input to the caudate, were significantly reduced after grafting of the fetal brain tissue. These data suggest that such implants may be potentially useful in reversing deficits after circumscribed destruction of brain tissue.

Patients with schizophrenia exhibit an exceedingly wide range of symptoms from a variety of domains. The cardinal features are abnormal ideas (such as delusions); abnormal perceptions (such as hallucinations); formal thought disorder (as evidenced by disorganized speech); motor, volitional, and behavioral disorders; and emotional disorders (such as affective flattening or inappropriateness). In addition to these diverse, and sometimes bizarre symptoms, it has become increasingly apparent that the disorder is, to variable degrees, accompanied by a broad spectrum of cognitive impairments. This review addresses the question of whether the cognitive deficits seen in schizophrenic patients are the core features of the disorder. In other words, we explore whether schizophrenia is best characterized by symptoms or cognitive deficits (we suggest the latter) and moreover, whether there is a specific cognitive deficit profile that may assist in diagnosis. First, we discuss what the cognitive deficits are. Then we address in turn the reality, frequency, predictive validity, specificity, course and susceptibility to neuroleptic effects of these cognitive impairments. In brief, we argue that various cognitive deficits are enduring features of the schizophrenia illness, that they are not state-related and are not specific to subtypes of the illness, and, more specifically, that working memory and attention are characteristically impaired in patients with schizophrenia, irrespective of their level of intelligence. Last, we conclude that problems in these cognitive domains are at the very core of the dysfunction in this disease.

To determine if neuroleptic treatment changes the natural course of schizophrenia, 22 studies were reviewed in which relatively similar patients were or were not given neuroleptics at specific times during the course of their illness. Nineteen of the studies were from first- or predominantly first-break populations. While there was little consensus among the authors of the studies reviewed, a reanalysis of the data indicates that early intervention with neuroleptics in first-break schizophrenic patients increases the likelihood of an improved long-term course. This finding is similar to that of earlier investigators who indicated there was a decrease in patients with the more severe forms of the illness following the introduction of convulsive therapies. Furthermore, there is evidence that stable schizophrenic patients whose neuroleptics are discontinued and have relapses may have a difficult time returning to their previous level of function. The findings describe in this paper have implications for both the treatment of schizophrenia and for understanding the pathophysiological processes that determine the course of the disorder.

The clinical syndrome of multiple personality disorder (MPD) is an unusual dissociative condition that has been poorly characterized. In an attempt to better delineate the clinical phenomenology of MPD, 100 recent cases were collected on a 386-item questionnaire completed by clinicians involved in the treatment of MPD patients. This study documents the existence of a clinical syndrome characterized by a core of depressive and dissociative symptoms and a childhood history of significant trauma, primarily child abuse.

OBJECTIVE: The authors previously reported that in monozygotic twins discordant for schizophrenia the affected twin almost invariably had a smaller anterior pes hippocampus, measured with magnetic resonance imaging (MRI), and invariably had less regional cerebral blood flow (rCBF) in the dorsolateral prefrontal cortex during performance of the Wisconsin Card Sorting Test. The present study was an investigation of the relationship between hippocampal pathology and prefrontal hypofunction in the same twin pairs. METHOD: Nine pairs of monozygotic twins discordant for schizophrenia underwent MRI scanning for determination of anterior hippocampal volume and xenon-inhalation rCBF testing for determination of prefrontal physiological activation associated with the Wisconsin Card Sorting Test. RESULTS: The differences within twin pairs on the MRI and rCBF measures were strongly and selectively correlated. Specifically, the more an affected twin differed from the unaffected twin in left hippocampal volume, the more they differed in prefrontal physiological activation during the Wisconsin Card Sorting Test. In the affected twins as a group, prefrontal activation was strongly related to both left and right hippocampal volume. These relationships were not found in the group of unaffected twins. CONCLUSIONS: This finding is consistent with the notion that schizophrenia involves pathology of and dysfunction within a widely distributed neocortical-limbic neural network that has been implicated in, among other activities, the performance of cognitive tasks requiring working memory.

Abstract The onset of cell differentiation in the locus coeruleus, dorsal and medial raphe nuclei, and substantia nigra (zona compacta) was studied using the technique of long‐survival H 3 ‐thymidine autoradiography to date neurogenesis. Pregnant female rats were injected with isotope on day 10, 11, 12, 13, 14, 15, 16 or 17 of gestation. Litters were born on day 22 and allowed to survive for 30 days. Brains were prepared for the fluorescence histochemical demonstration of monoamines or fixed by formalin perfusion. Autoradiography was carried out on sections adjacent to those in which monoamine‐nuclear groups were identified by the fluorescence method and also on sections from perfused brains, which were used to facilitate cell counting. The norepinephrine cells of the locus coeruleus began to differentiate (presence of heavily labelled cells) on days 10–13 of gestation, with a peak of heavy labelling on day 12, whereas the 5‐HT cells of the raphe nuclei and the dopamine cells of the substantia nigra began differentiating on days 11–15. In the dorsal raphe nucleus, the peak of heavy labelling occurred on day 14, whereas in the medial nucleus this took place on days 13–14. The substantia nigra, on the other hand, peaked on day 13. Cell differentiation was also studied in the cerebellar Purkinje cells and hippocampal macroneurons (pyramidal and polymorph cells) of areas CA3 and CA4, to which the locus coeruleus has been reported to project. Differentiation of these cells commenced on days 14–15 (Purkinje cells) and 13–18 (hippocampal cells), with both cell types peaking on day 15, a full three days after the peak of heavy labelling in the locus coeruleus. Evidence is discussed for the possible neurotrophic role of monoamine neurons in the neurogenesis of monoaminergic receptive cells.

More than 250 studies, covering 29 Northern and five Southern Hemisphere countries, have been published on the birth seasonality of individuals who develop schizophrenia and/or bipolar disorder. Despite methodological problems, the studies are remarkably consistent in showing a 5-8% winter-spring excess of births for both schizophrenia and mania/bipolar disorder. This seasonal birth excess is also found in schizoaffective disorder (December-March), major depression (March-May), and autism (March) but not in other psychiatric conditions with the possible exceptions of eating disorders and antisocial personality disorder. The seasonal birth pattern also may shift over time. Attempts to correlate the seasonal birth excess with specific features of schizophrenia suggest that winter-spring births are probably related to urban births and to a negative family history. Possible correlations include lesser severity of illness and neurophysiological measures. There appears to be no correlation with gender, social class, race, measurable pregnancy and birth complications, clinical subtypes, or neurological, neuropsychological, or neuroimaging measures. Virtually no correlation studies have been done for bipolar disorder. Regarding the cause of the birth seasonality, statistical artifact and parental procreational habits are unlikely explanations. Seasonal effects of genes, subtle pregnancy and birth complications, light and internal chemistry, toxins, nutrition, temperature/weather, and infectious agents or a combination of these are all viable possibilities.

Two peptides that crossreact with an antiserum raised against Phe-Met-Arg-Phe-NH2 were purified from bovine brain extract. Their structures were determined to be Ala-Gly-Glu-Gly-Leu-Ser-Ser-Pro-Phe-Trp-Ser-Leu-Ala-Ala-Pro-Gln-Arg-Phe- NH2 and Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-NH2. The sequences were determined by gas-phase sequencing, except for the COOH-terminal phenylalaninamides. These were assigned on the basis of the reactivity of the peptides with the anti-Phe-Met-Arg-Phe-NH2 antiserum, which appears to recognize the determinant -Arg-Phe-NH2. Both peptides were synthesized, and the synthetic peptides were found to have the same HPLC retention times as the endogenous Phe-Met-Arg-Phe-NH2-immunoreactive peptides, thus confirming the assignment of phenylalaninamide to the COOH-terminal positions. Both of the synthetic peptides were found to decrease tail-flick latency in rats, and the octapeptide was more active than the octadecapeptide. The octapeptide was found also to attenuate the prolongation of the tail-flick latency induced by morphine.

We previously reported that compared with normals, patients with chronic schizophrenia have reduced regional cerebral blood flow (rCBF) in dorsolateral prefrontal cortex (DLPFC) during performance of the Wisconsin Card Sort Test (WCS), a DLPFC-related cognitive task, but not during nonprefrontal tasks, such as a simple number-matching (NM) test. We also found that unlike normals, patients failed to activate DLPFC during the WCS over their own baseline (NM) level. To explore the reproducibility of these findings, a new cohort of 16 medication-free patients underwent a series of xenon 133 inhalation rCBF studies under the following conditions: at rest, while performing the WCS, and while performing NM. The results confirmed our earlier findings. In addition, the concentrations in cerebrospinal fluid of homovanillic acid and 5-hydroxyindoleacetic acid correlated with prefrontal rCBF during the WCS but not during the NM test or at rest. The results show that behavior-specific hypofunction of DLPFC in schizophrenia is reproducible, and they implicate a monoaminergic mechanism.

The effect of mouse nerve growth factor (NGF) on cultured human fetal sensory neurons was assayed by measuring neurite length, density and rate of growth. Addition of NGF increased adhesion of dissociated sensory neurons cultured on collagen coated surfaces. Almost all neurons of 9 to 10 week old fetuses are postmitotic, contain neuron-specific enolase, (an enzyme linked to differentiation), and require NGF for optimal neurite growth. Sensory ganglia re-explanted on collagen showed maximal neurite length and density when treated with 1 ng/ml of NGF. Neurite density was reduced considerably in the absence of mouse NGF and was almost abolished by addition of antimouse NGF antibodies. Surfaces coated with the matrix glycoproteins laminin or fibronectin further stimulated neurite growth of ganglia in the presence of NGF. Increasing amounts of matrix proteins could partly compensate for the absence of mouse NGF or the inhibition of NGF activity by antibodies. Stimulation of neurite growth by matrix proteins was time-dependent, and neurites showed maximum length at 10 days (2 to 3 mm). Neurite growth was more pronounced with laminin than with fibronectin and collagen, and antibodies to laminin suppressed all neurite growth. In the presence of a constant amount of NGF, mean neurite growth reached 26 microns/hr (at 1 day), and was 2.1 and 1.7 times faster on laminin and fibronectin (respectively) than on collagen. Thus, laminin, and to a lesser degree fibronectin, may enhance neurite growth of human sensory neurons in synergy with NGF.

Arecholine (4 milligrams), a cholinergic agonist, and choline (10 grams), a precursor of acetylcholine, significantly enhanced serial learning in normal human subjects. The subjects received methscopolamine prior to both arecholine and placebo injections. Conversely, scopolamine (0.5 milligram), a cholinergic antagonist, impaired learning and this impairment was reversed by arecholine and choline and the impairment after scopolamine were inversely proportional to the subject's performance on placebo; that is, "poor" performers were more vulnerable to both the enhancing effect of cholinergic agonist and precursor and the impairment after cholinergic antagonist than "good" performers.

A series of studies demonstrated a possible relationship between eye-blink rate and central dopamine activity. First, apomorphine and other dopamine agonists acutely increased blink rate in monkeys, an effect blocked by sulpiride. Secondly, parkinsonian patients with levodopa-induced dyskinesia exhibited twice the mean blink rate (21 blinks/min) of other parkinsonians (11 blinks/min, P less than 0.002) whereas the more symptomatic of the nondyskinetic patients had a very slow rate (3 blinks/min, P less than 0.01). Thirdly, schizophrenic patients had an elevated mean blink (31 vs 23 blinks/min for normals, P less than 0.05) which was normalized by neuroleptic treatment. Thus, the correlation with central dopamine activity may also prove clinically useful in selected neuropsychiatric disorders.

Recent physiological and cognitive studies of schizophrenia have implicated dysfunction of prefrontal cortex as a possible explanation for some of the disabling intellectual and social aspects of the disorder. To investigate the potential reversibility of cognitive deficits and the role of state variables, eg, attention and motivation, three groups of patients with schizophrenia were administered the Wisconsin Card Sorting Test on six consecutive occasions. Two of the groups received incremental information on how to do the test, including explicit card-by-card instruction. The third group served as a control. Regardless of the degree of instruction, patients who could not do the test could not learn it. The deficit did not appear generalized, as patients were able to learn word lists on the Selective Reminding memory test and were not globally demented on the Mini-Mental State Examination. These data suggest that prefrontal-type cognitive deficits in schizophrenia may be more profound than is generally appreciated.

The increased prevalence of multidrug-resistant bacterial pathogens motivated us to attempt to enhance the therapeutic efficacy of bacteriophages. The therapeutic application of phages as antibacterial agents was impeded by several factors: (i) the failure to recognize the relatively narrow host range of phages; (ii) the presence of toxins in crude phage lysates; and (iii) a lack of appreciation for the capacity of mammalian host defense systems, particularly the organs of the reticuloendothelial system, to remove phage particles from the circulatory system. In our studies involving bacteremic mice, the problem of the narrow host range of phage was dealt with by using selected bacterial strains and virulent phage specific for them. Toxin levels were diminished by purifying phage preparations. To reduce phage elimination by the host defense system, we developed a serial-passage technique in mice to select for phage mutants able to remain in the circulatory system for longer periods of time. By this approach we isolated long-circulating mutants of Escherichia coli phage lambda and of Salmonella typhimurium phage P22. We demonstrated that the long-circulating lambda mutants also have greater capability as antibacterial agents than the corresponding parental strain in animals infected with lethal doses of bacteria. Comparison of the parental and mutant lambda capsid proteins revealed that the relevant mutation altered the major phage head protein E. The use of toxin-free, bacteria-specific phage strains, combined with the serial-passage technique, may provide insights for developing phage into therapeutically effective antibacterial agents.

Abstract The projections of neurons in the nucleus locus coeruleus (LC) of the rat were traced by radioautography following stereotaxic injections of 3 H‐proline. An ascending bundle consisting of a dense cluster of labeled axons accompanied the medial forebrain bundle (MFB) into the lateral hypothalamus. Rostral to the anterior commissure, the labeled fibers contributed to other major pathways: the stria terminalis to the amygdala, and the cingulum bundle and the supracallosal stria to the cingulate cortex, subiculum, and hippocampus. The rest of the ascending fibers terminated diffusely in the pyriform cortex and frontal neocortex. In addition, a lateral group of labeled fibers entered the cerebellum through the superior cerebellar peduncle and terminated around the Purkinje cell somata and in the molecular layer. Descending fibers which entered the medulla either terminated around brainstem nuclei or passed into the ventral portion of the spinal cord. In all areas except the brainstem, the labeling was unilateral with respect to the injection site. This distribution of label from LC provides direct confirmation for connections which have been difficult to visualize in their entirety by any other histological or cytochemical method.

OBJECTIVE: Anemia is a complication of chronic kidney disease and may contribute to adverse clinical outcomes. Early identification and treatment of anemia may improve cardiovascular morbidity and mortality. No large-scale population data are available specifically for patients with chronic kidney disease regarding prevalence of anemia, subpopulations at risk, and relationships between anemia and kidney function. This study was undertaken to address these questions in patients with chronic kidney disease, and investigate the relationship between anemia and glomerular filtration rate. RESEARCH DESIGN AND METHODS: Large-scale, cross-sectional, US multicenter survey; 5222 patients (mean age, 68.2 years; 46.6% male); 237 physician practices. Eligible patients: > or = 18 years of age; serum creatinine: 1.5 mg/dL-6.0 mg/dL (females), 2.0 mg/dL-6.0 mg/dL (males). MAIN OUTCOME MEASURES: Primary study end point: prevalence and severity of anemia (hemoglobin < or = 12 g/dL). Data further stratified by hemoglobin (< or = 12 g/dL, < or = 10 g/dL). RESULTS: Primary etiologies of chronic kidney disease (5222 evaluable patients): diabetes (49.5%); hypertension (33.0%). Glomerular filtration rate: < 60 mL/min/1.73 m2 for 97.7% of evaluable patients. Mean +/- SD serum creatinine level: 2.2 mg/dL +/- 0.9 mg/dL; 2.5 mg/dL +/- 1.0 mg/dL for males, 2.0 mg/dL +/- 0.8 mg/dL for females. Mean +/- SD hemoglobin: 12.2 g/dL +/- 1.6 g/dL (47.7% had hemoglobin < or = 12 g/dL; 8.9% had hemoglobin < or = 10 g/dL). Prevalence of anemia was strongly associated with declining glomerular filtration rate. Percentage of patients with hemoglobin < or = 12 g/dL increased from 26.7% to 75.5% when glomerular filtration rate decreased from > or = 60 mL/min/1.73 m2 to < 15 mL/min/1.73 m2. Prevalence of hemoglobin < or = 10 g/dL increased substantially from 5.2% to 27.2% when glomerular filtration rate diminished from > or = 60 mL/min/1.73 m2 to < 15 mL/min/1.73 m2. After controlling for other patient characteristics associated with increased prevalence of anemia, the prevalence odds ratio for hemoglobin < or = 10 g/dL was 0.54 (0.49-0.60) and for hemoglobin < or = 12 g/dL was 0.68 (0.65-0.72), with each 10-mL/min/1.73 m2 increase in glomerular filtration rate. Predictors of anemia: diabetes, female sex, and race/ethnicity. CONCLUSIONS: Anemia was present in 47.7% of 5222 predialysis patients with chronic kidney disease. Prevalence of anemia increased as kidney function decreased. Certain subgroups are at increased risk for anemia.