Brain atrophy or dystrophy in schizophrenia: when did it happen?
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Biomedical subjects
Publications and source records attributed to J R Stevens.
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This study examines the relationship between epilepsy and psychosis. It compares clinical, EEG, and neuropathologic data from a group of subjects who had both epilepsy and psychosis with similar information from another group of patients who had epilepsy but no evidence of psychotic illness. We examined, blind to clinical diagnosis, gross and microscopic material from whole-brain specimens from 10 patients diagnosed with epilepsy plus schizophrenia-like psychosis, nine subjects diagnosed with epilepsy plus "epileptic psychosis," and 36 individuals with epilepsy (21 from an epileptic colony and 15 from the community at large) who had no history of psychosis (n = 10 + 9 + 21 + 15 = 55). We abstracted case histories without knowledge of pathologic findings. Epileptic colony patients had an earlier age at onset of seizures, while epileptic colony and epileptic psychosis patients had more frequent seizures. Epileptic individuals in the community died at a younger age than did epileptic patients in long-stay hospital care. Psychotic epileptic patients had larger cerebral ventricles, excess periventricular gliosis, and more focal cerebral damage compared with epileptic patients who had no psychotic illness. Epileptic patients with schizophrenia-like psychosis were distinguished from all other groups by a significant excess of pinpoint perivascular white-matter softenings. We found that mesial temporal sclerosis and temporal lobe epilepsy occurred with equal frequency in the psychotic and nonpsychotic groups; generalized seizures occurred more frequently in the psychotic epileptics and the epileptic colony epileptics than in the community epileptic controls.
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In many previous characterization studies of Trypanozoon, isolates have been subpassaged numerous times in laboratory rodents until a quantity of trypanosomes sufficient for analysis has been obtained. In addition to the numerous biochemical effects of such a process on the parasite, it appears probable that adaptation to an unnatural host may also serve to filter out less virulent populations from mixed infections, leading to an underestimate of the true level of genetic diversity. By the early cloning of trypanosomes from susceptible captive flies infected from the primary isolate--the midgut of a wild tsetse--the present study provides evidence of the range of genetically different Trypanosoma brucei populations which may coexist within the midgut of individual tsetse flies in nature. The three primary isolates from tsetse yielded one, five and nine genetically distinct populations. Cloned populations were confirmed as T. brucei using the polymerase chain reaction, and were characterized by karyotype analysis and multilocus isoenzyme electrophoresis. These data allowed a limited assessment of the level of genetic variability in natural populations of T. brucei.
A growth-promoting agent for the human neuroblastoma cell line SK-N-SH(EP) (SH-EP) has been detected in human cerebrospinal fluid (CSF) derived from schizophrenic patients. Following treatment with the CSF, a number of properties of the SH-EP cells changed permanently. These included an accelerated rate of growth, an increased cell density at confluence, a change of cell shape, and an increased ability to form colonies in soft agar. All of these changes are consistent with further cellular transformation of the SH-EP cells. Once the cells' properties had changed following CSF treatment, the growth-promoting activity was found to be present in freeze-thawed cell extracts and in the culture medium, and could be passed to untreated SH-EP cells. The activity could be detected in culture media diluted as high as 10(8). It was inactivated by proteinases, chloroform, or heat but passed through a 0.22-micron filter. The growth-promoting activity can be banded on a Percoll gradient, suggesting that it is particulate rather than a soluble growth factor.
Reproductive processes within the current Ugandan epidemic of sleeping sickness are investigated. Genotype frequencies derived from isoenzyme patterns in 44 stocks of Trypanosoma brucei s.l. collected in 1988 from Tororo, south-east Uganda are analysed by single and multiple loci methods. In the single locus method, the hypothesis of random mating is tested by agreement with Hardy-Weinberg equilibrium. The multiple loci method uses a contingency table approach to detect non-random associations between pairs of loci; this equates to the detection of disequilibrium. The results do not support the concept of a randomly mating population of T. brucei within the current epidemic. Results from the epidemic data set are discussed in relation to the broader problem of genetic exchange in Trypanozoon.
The study characterized 151 Trypanozoon isolates from south-east Uganda by isoenzyme electrophoresis. Stocks were from a range of hosts, including man, cattle, pigs, dogs and Glossina fuscipes fuscipes: 104 isolates were from the Busoga area, 47 were from the Tororo district. Stocks were characterized on thin layer starch gel using eight enzyme systems: ALAT, ASAT, ICD, MDH, ME, NHD, NHI, PGM. Enzyme profiles were generally typical of East Africa; new patterns for ICD and ME were detected. Trypanosomes were classified on the basis of their profile by similarity coefficient analysis and the unweighted pair-group method using arithmetic averages (UPGMA). The majority of trypanosomes were classified in one or other of two genetically distinct groups which corresponded to the strain groups busoga and zambezi, both of which are associated with Rhodesian sleeping sickness in East Africa. Contingency table analyses indicated associations between certain isoenzymes of ICD and PGM, according to host and geographical origin. Significant relationships between trypanosome strain group and geographic origin were also demonstrated for some host groups.
Neuropathologic and neuroimaging studies reveal atrophy or dystrophy of the hippocampal region and enlarged ventricles indicative of tissue loss in many patients with schizophrenia. It is now widely recognized that brain damage can provoke regenerative collateral sprouting of axons, synaptic proliferation, and reorganization, even in the adult mammalian brain. The functional consequences of these plastic regenerative changes are largely unknown; they could be adaptive or cause further impairment. There is evidence of lesion-provoked aberrant synaptic regeneration in epilepsy and Alzheimer's disease. Data suggest that anomalous reinnervation could also have a significant role in the pathophysiology of schizophrenia. Histologic methods to test this hypothesis are in progress.
Numerical analyses of Trypanozoon taxonomy are presented, based on the isoenzyme data of Stevens et al. (1992). The previous study used a reduced range of enzymes compared with earlier work; the analyses indicate the value of this rationalized system. Both recently isolated trypanosome stocks and previously studied populations were included, allowing detailed comparison with earlier studies. Relationships between zymodemes were calculated with an improved similarity coefficient program, using Jaccard's coefficient (1908), and by Nei's method (1972). Dendrograms were constructed from the matrices produced with the group-average method. The groupings produced by both numerical methods were in close agreement, and the clusters of related principal zymodemes largely matched the species, subspecies and strain groups proposed by previous workers. Trypanozoon biochemical taxonomy is reviewed and the groupings reinforced by this study are: the mainly East African strain groups, busoga, zambezi, kakumbi, kiboko and sindo; T.b. gambiense and the bouaflé strain group from West Africa, and T. evansi; an intermediate bouaflé/busoga group was also recognized.
To characterize trypanosomes from the subgenus Trypanozoon, 272 stocks in 111 zymodemes were analysed by the polymorphisms seen in a rationalized range of nine enzymes, resolved by electrophoresis, mostly on cellulose acetate. Several highly polymorphic or invariant enzymes used previously were omitted, while two new enzymes, NHD and SOD were included; the isoenzymes seen for SOD were interpreted as two separate enzymes, SODA and SODB. Isoenzyme band patterns were analysed by two complementary numerical methods to elucide taxonomic relationships within the subgenus; groups of zymodemes corresponding to subspecies and strain groups were defined, which agreed closely with previous studies. Except for one zymodeme, Trypanosoma evansi could not be clearly distinguished from the bouaflé strain group. This strain group had enzymic features that overlapped to some extent those of the busoga group. Trypanosoma brucei gambiense and the zambezi, kakumbi, kiboko and sindo groups were clearly defined. Eight zymodemes could not be classified. A rapid identification system using a limited number of enzymes is presented.
Immunocytochemical staining for glial fibrillary acidic protein (GFAP) allows more specific identification of astrocytes and their processes than classical histochemical techniques and has therefore recently been used by some investigators to quantify gliosis. However, although the immunocytochemical method is superior for delineation of reactive astrocytes, the examples presented here and previous work by others demonstrate that chronic fibrillary gliosis may be best detected by Holzer's method and not by GFAP immunocytochemistry. The authors' studies indicate that if, as in a recent study of gliosis in schizophrenia, computer-assisted densitometry is to be used to measure gliosis, the immunoperoxidase method may not be a sensitive technique to demonstrate glial changes in human postmortem material.
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A computer program in Fortran 77 was developed to analyse the isoenzyme patterns of trypanosomes isolated from African sleeping sickness patients, to allow biochemical relationships between populations of trypanosomes from different hosts and geographic areas to be elucidated. However, the generality of the design allows it to be used with presence/absence data from a variety of sources, including DNA fingerprints. The program reads in isoenzyme band patterns from an ASCII file and calculates a matrix of similarity coefficients. Four different similarity measures are offered, suitable for presence/absence data from a range of organisms and experimental procedures. The matrix of similarity values produced is suitable for analysis by ordination methods including principal coordinates analysis, and the production of dendrograms and icicle plots using SPSS/PC+.
Recently, several authors have claimed prominent abnormalities in the entorhinal cortex of both patients with Alzheimer's disease (AD) and schizophrenia. The entorhinal cortex is the origin of the perforant pathway, a major input to granule cells of the dentate gyrus of the hippocampus. The present study explored the possibility of a lesion in the entorhinal cortex of both AD and schizophrenic patients by quantitating astrocytic markers within the terminal fields of the perforant pathway. An increase in fibrillary astrocytes was found in half (3/6) of the AD patients while none of the schizophrenic (n = 6) or control (n = 7) brains exhibited gliosis. Since the redistribution and hyperplasia of astrocytes within the molecular layer of the partially deafferented dentate gyrus depend on the chronicity of the entorhinal lesion, the abnormalities observed in AD patients are consistent with the progressive course of the illness. Furthermore, the presence of gliosis in the subiculum of three out of six AD patients suggested pathology secondary to projections from the entorhinal region, amygdala, or prepyriform cortex. The absence of similar changes in schizophrenic patients does not disprove previous claims of entorhinal pathology but suggests that the lesion, if it exists, is either static in nature or occurred long before death.
Between 1958 and 1968, 14 patients from the epilepsy clinic at the University of Oregon Hospitals and Clinics with a diagnosis of temporal lobe epilepsy (TLE) had a temporal lobectomy for medically intractable seizures. Nine of the 14 patients operated on remained seizure-free over the 20-30-year period of follow-up. Between 6 months and one year following temporal lobectomy, two women, previously healthy from a psychiatric standpoint, developed psychoses, and the previous psychiatric problems of four other patients worsened. Two patients, one with incapacitating paranoid personality disorder and the other with explosive rage attacks preoperatively, had marked improvement in their psychiatric status following temporal lobectomy. The remaining six patients, all psychiatrically healthy prior to surgery, have had no change in psychiatric status following surgery. Development of psychosis or deterioration in psychiatric status after surgery was more common in patients with later age of onset, unreality or déjà vu rather than epigastric aura, pre-operative evidence of bilateral brain damage, and persistence of EEG or clinical seizure activity. Development of a chronic psychosis in psychiatrically healthy individuals many months after temporal lobectomy, even when seizures are arrested or ameliorated, suggests that anomalous synaptic regeneration may follow the surgery in these cases. Careful analysis of histories and outcomes may contribute to better understanding of the pathophysiology and anatomical substrates of psychoses.
Numerous immunologic abnormalities have been reported in patients with schizophrenia, suggesting that this disorder may in some cases represent a viral or immunologic disorder of the brain. To further examine this question, evidence for intrathecal production of immunoglobulin (IgG) and immunoglobulin oligoclonal bands (OCB) was sought in patients with acute or early schizophrenia. Using high resolution zone electrophoresis and immunofixation, there was no evidence for intrathecal IgG generation in 5 of 5 patients tested. One of 9 patients had OCBs in CSF. This man, although he had a typical history of schizophrenia, tested positive for human immunodeficiency virus antibody in serum.