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1.
J Autism Dev Disord ; 42(7): 1510-4, 2012 Jul.
Article in English | MEDLINE | ID: mdl-21979109

ABSTRACT

Possible explanations for the well-replicated platelet hyperserotonemia of autism include an alteration in the platelet's handling of serotonin (5-hydroxyserotonin, 5-HT) or an increased exposure of the platelet to 5-HT. Measurement of platelet-poor plasma (PPP) levels of 5-HT appears to provide the best available index of in vivo exposure of the platelet to 5-HT. Mean (± SD) concentrations of PPP 5-HT observed in the autism (N = 18), hyperserotonemic subgroup (N = 5) and control (N = 24) groups were 0.86 ± 0.53, 0.87 ± 0.43 and 0.86 ± 0.36 nM, respectively. The results suggest that the hyperserotonemia of autism is not due to increased exposure of the platelet to 5-HT and make it more likely that the factor(s) contributing to the hyperserotonemia of autism have to do with the platelet's handling of 5-HT.


Subject(s)
Blood Platelets/metabolism , Child Development Disorders, Pervasive/blood , Platelet Count , Serotonin/blood , Adolescent , Child , Child, Preschool , Female , Humans , Male , Reference Values , Young Adult
2.
J Virol ; 75(19): 9320-7, 2001 Oct.
Article in English | MEDLINE | ID: mdl-11533195

ABSTRACT

Although the ultimate target of infection is the central nervous system (CNS), there is evidence that the enteric nervous system (ENS) and the peripheral nervous system (PNS) are involved in the pathogenesis of orally communicated transmissible spongiform encephalopathies. In several peripherally challenged rodent models of scrapie, spread of infectious agent to the brain and spinal cord shows a pattern consistent with propagation along nerves supplying the viscera. We used immunocytochemistry (ICC) and paraffin-embedded tissue (PET) blotting to identify the location and temporal sequence of pathological accumulation of a host protein, PrP, in the CNS, PNS, and ENS of hamsters orally infected with the 263K scrapie strain. Enteric ganglia and components of splanchnic and vagus nerve circuitry were examined along with the brain and spinal cord. Bioassays were carried out with selected PNS constituents. Deposition of pathological PrP detected by ICC was consistent with immunostaining of a partially protease-resistant form of PrP (PrP(Sc)) in PET blots. PrP(Sc) could be observed from approximately one-third of the way through the incubation period in enteric ganglia and autonomic ganglia of splanchnic or vagus circuitry prior to sensory ganglia. PrP(Sc) accumulated, in a defined temporal sequence, in sites that accurately reflected known autonomic and sensory relays. Scrapie agent infectivity was present in the PNS at low or moderate levels. The data suggest that, in this scrapie model, the infectious agent primarily uses synaptically linked autonomic ganglia and efferent fibers of the vagus and splanchnic nerves to invade initial target sites in the brain and spinal cord.


Subject(s)
Autonomic Nervous System/physiopathology , Autonomic Nervous System/virology , Central Nervous System/physiopathology , Central Nervous System/virology , Digestive System/physiopathology , Digestive System/virology , Scrapie/physiopathology , Animals , Cricetinae , Immunohistochemistry
3.
Biol Psychiatry ; 48(11): 1045-52, 2000 Dec 01.
Article in English | MEDLINE | ID: mdl-11094137

ABSTRACT

BACKGROUND: Executive control of cognition, emotion, and behavior are disrupted in the manic state of bipolar disorder. Whereas frontal systems are implicated in such dysfunction, the localization of functional brain abnormalities in the manic state is not well understood. METHODS: We utilized a high-sensitivity H(2)(15)0 positron emission tomography technique to investigate regions of increased brain activity in mania, compared to euthymia, in bipolar disorder. RESULTS: The principal findings were manic state-related increased activity in left dorsal anterior cingulate, and left head of caudate. CONCLUSIONS: The findings suggest that the manic state of bipolar disorder may be associated with heightened activity in a frontal cortical-subcortical neural system that includes the anterior cingulate and caudate.


Subject(s)
Bipolar Disorder/diagnostic imaging , Bipolar Disorder/physiopathology , Caudate Nucleus/physiopathology , Cerebrovascular Circulation , Dominance, Cerebral , Gyrus Cinguli/physiopathology , Adult , Brain/blood supply , Brain/diagnostic imaging , Brain/physiopathology , Case-Control Studies , Caudate Nucleus/blood supply , Caudate Nucleus/diagnostic imaging , Cognition , Confounding Factors, Epidemiologic , Female , Gyrus Cinguli/blood supply , Gyrus Cinguli/diagnostic imaging , Humans , Male , Middle Aged , Psychiatric Status Rating Scales , Tomography, Emission-Computed
4.
Microsc Res Tech ; 50(1): 40-5, 2000 Jul 01.
Article in English | MEDLINE | ID: mdl-10871547

ABSTRACT

Transmissible spongiform encephalopathies (TSEs) or "prion diseases" are a group of unconventional fatal diseases. TSEs are characterised by the accumulation of a modified form of the normal host glycoprotein, PrP (PrP(c)). In the course of infection PrP(c) is converted to an abnormally protease resistant form, PrP(Sc). The exact nature of the infectious agent responsible for these diseases remains controversial. While there is compelling evidence that TSE agents contain an informational molecule, possibly a nucleic acid, some believe that the infectious agent or "prion" is solely composed of PrP(Sc). Nevertheless, PrP is required for TSE pathogenesis, as mice devoid of the PrP gene (PrP(-/-)) remain healthy when challenged with TSE isolates and are unable to replicate infectivity within the central nervous system (CNS) or in other tissues. In recent years immunocytochemistry has been used to pinpoint which cells are associated with abnormal accumulations of PrP, providing important information on the cellular targeting of TSE infection. In uninfected and scrapie-infected mice, PrP protein is found in the CNS and in extraneural tissues such as spleen and lymph nodes. In the peripheral lymphoid system, PrP is associated with follicular dendritic cells that are known to be important for replication of infectivity for at least one TSE strain. This review will focus on current methods for the immunocytochemical detection of PrP in murine extraneural tissues, mainly lymphoid tissues, and will discuss recent findings on the role of the peripheral lymphoid system in TSE pathogenesis.


Subject(s)
Lymphoid Tissue/metabolism , Prion Diseases/metabolism , Prions/analysis , Animals , Dendritic Cells, Follicular/metabolism , Dendritic Cells, Follicular/pathology , Disease Models, Animal , Immunohistochemistry/methods , Lymphoid Tissue/pathology , Mice , Microscopy, Confocal , Pancreas/metabolism , Paraffin Embedding , Prion Diseases/pathology , Salivary Glands/metabolism , Spleen/metabolism , Spleen/pathology
5.
Neurosci Lett ; 278(3): 181-4, 2000 Jan 14.
Article in English | MEDLINE | ID: mdl-10653023

ABSTRACT

Infection of the central nervous system (CNS) is a defining feature of scrapie. Several findings suggest that scrapie agent invades the CNS via the splanchnic and vagus nerve after ingestion of infectivity. Here we address the involvement of the enteric nervous system (ENS) and gut-associated lymphoid tissue (GALT) in this pathogenetic process. Immunocytochemistry was used for the detection of pathological PrP in the duodenum and ileum of hamsters fed with 263K scrapie and sacrificed at different stages of incubation. The experiments revealed early infection of various GALT components and of submucosal and myenteric ENS ganglia. These results provide evidence for an important role of the ENS in scrapie neuroinvasion and for centripetal vagal spread of infection from the gut to the brain after oral uptake of agent.


Subject(s)
Enteric Nervous System/metabolism , Intestinal Mucosa/metabolism , Lymphoid Tissue/metabolism , Prions/metabolism , Scrapie/metabolism , Administration, Oral , Animals , Cricetinae , Duodenum/metabolism , Ganglia, Sympathetic/metabolism , Ileum/metabolism , Mesocricetus , Myenteric Plexus/metabolism , Scrapie/transmission , Submucous Plexus/metabolism
6.
Acta Neuropathol ; 98(5): 453-7, 1999 Nov.
Article in English | MEDLINE | ID: mdl-10541866

ABSTRACT

There is some evidence that the peripheral nervous system (PNS) is involved in the pathogenesis of transmissible spongiform encephalopathies (TSEs). The TSE-specific abnormal prion protein (PrP(sc)) is considered as surrogate marker for infectivity. We traced the deposition of PrP(sc) by immunocytochemistry in sheep and hamsters inoculated intraperitoneally with scrapie. The trigeminal, dorsal root, celiac, thoracic, and nodose ganglia contained ganglion cells and fewer satellite cells with prominent granular PrP(sc) deposition. As a novel deposition pattern, punctate deposits in adaxonal location were seen along nerve fibers of peripheral nerve adjacent to ganglia. Such prominent involvement of the PNS in two different experimental scrapie models emphasizes the need to consider the PNS in natural scrapie and other TSEs including bovine spongiform encephalopathy as potential source of infectivity.


Subject(s)
Peripheral Nervous System/pathology , PrPSc Proteins/analysis , Scrapie/pathology , Spinal Cord/pathology , Animals , Cricetinae , Immunohistochemistry , Sheep
7.
Am J Psychiatry ; 156(12): 1986-8, 1999 Dec.
Article in English | MEDLINE | ID: mdl-10588416

ABSTRACT

OBJECTIVE: This study investigated prefrontal cortex function in the manic state of bipolar disorder. METHOD: High-sensitivity [15O]H2O positron emission tomography and a word generation activation paradigm were used to study regional cerebral blood flow in five manic and six euthymic individuals with bipolar disorder and in five healthy individuals. RESULTS: Decreased right rostral and orbital prefrontal cortex activation during word generation and decreased orbitofrontal activity during rest were associated with mania. CONCLUSIONS: The data support the presence of rostral and orbital prefrontal dysfunction in primary mania. These findings, when seen in the context of the human brain lesion and the behavioral neuroanatomic literatures, may help to explain some of the neurobehavioral abnormalities characteristic of the manic state.


Subject(s)
Bipolar Disorder/physiopathology , Neuropsychological Tests , Prefrontal Cortex/physiopathology , Tomography, Emission-Computed , Adult , Bipolar Disorder/diagnostic imaging , Female , Humans , Male , Oxygen Radioisotopes , Prefrontal Cortex/blood supply , Prefrontal Cortex/diagnostic imaging , Regional Blood Flow , Water
8.
Neurosci Lett ; 265(2): 135-8, 1999 Apr 16.
Article in English | MEDLINE | ID: mdl-10327187

ABSTRACT

Although the ultimate target of infection is the CNS, there is evidence that the peripheral nervous system (PNS) is involved in the pathogenesis of Transmissible Spongiform Encephalopathies (TSEs). We used immunocytochemistry to identify the presence of pathological accumulations of a host protein, PrP, in the CNS and PNS (sensory and autonomic ganglia) of hamsters orally infected with 263K scrapie. All hamsters showed pathological deposition of PrP in most brain areas, along the length of the spinal cord, in nodose (NG) and dorsal root (DRG) ganglia and in the coeliac mesenteric ganglion complex (CMGC). In one case, scant deposition was observed along a few axons of the vagus nerve. This finding suggests that, after oral challenge, TSE infectious agent uses neural pathways and ganglia of the peripheral nervous system to reach target sites in the CNS.


Subject(s)
Ganglia, Sensory/metabolism , Ganglia, Sympathetic/metabolism , Prions/metabolism , Scrapie/metabolism , Administration, Oral , Animals , Axons/metabolism , Brain/metabolism , Cricetinae , Ganglia, Spinal/metabolism , Immunohistochemistry/methods , Mesocricetus , Nerve Tissue , Nodose Ganglion/metabolism , Spinal Cord/metabolism , Staining and Labeling , Vagus Nerve/metabolism
9.
Biol Psychiatry ; 44(7): 568-77, 1998 Oct 01.
Article in English | MEDLINE | ID: mdl-9787881

ABSTRACT

BACKGROUND: This study reports relationships between suicidal behavior and its risk factors in prepubertal children and whole blood and platelet serotonin-related measures. METHODS: Seventy-five prepubertal psychiatric inpatients including 23 (30.7%) nonsuicidal, 32 (42.7%) with suicidal ideation, and 20 (26.6%) with a suicide attempt were compared to 35 normal prepubertal controls with regard to platelet serotonin content, serotonin-amplified platelet aggregation, and whole blood tryptophan. RESULTS: Mean whole blood tryptophan content was significantly lower among inpatient children with a recent suicide attempt than among normal controls or inpatients with suicidal ideation (F = 3.94, df = 3.54, p < or = .01). Inpatient children with a mood disorder had significantly higher platelet serotonin content than inpatients without a mood disorder (F = 3.86, df = 2.80, p < or = .03). Racial/ethnic differences were also observed for inpatients and normal controls, with whites having significantly lower levels of platelet serotonin (expressed as ng/mL blood or ng/10(9) platelets) than blacks or Latinos. Blacks had significantly higher levels of whole blood tryptophan than other racial/ethnic groups. CONCLUSIONS: The results suggest that whole blood tryptophan and platelet serotonin content should be studied for their predictive validity as risk factors for suicidal behavior in youth while controlling for racial/ethnic differences.


Subject(s)
Mental Disorders/metabolism , Serotonin/metabolism , Suicide/psychology , Attention Deficit and Disruptive Behavior Disorders/blood , Attention Deficit and Disruptive Behavior Disorders/psychology , Blood Platelets/metabolism , Child , Female , Humans , Inpatients , Male , Mental Disorders/blood , Mood Disorders/blood , Mood Disorders/psychology , Platelet Aggregation/drug effects , Psychiatric Status Rating Scales , Receptors, Serotonin/blood , Risk Factors , Serotonin/blood , Suicide, Attempted , Tryptophan/blood
10.
J Am Acad Child Adolesc Psychiatry ; 37(7): 767-76, 1998 Jul.
Article in English | MEDLINE | ID: mdl-9666633

ABSTRACT

OBJECTIVE: To reevaluate platelet serotonin (5-HT) levels in autism, measuring and controlling for effects of race and puberty. The specificity of hyperserotonemia for autism versus cognitive impairment is also assessed. METHOD: Platelet 5-HT levels were measured in 77 individuals, aged 2 through 37 years, with autistic disorder; 65 normal controls; and 22 mentally retarded or otherwise cognitively impaired (MR/CI) prepubertal children. Effects of diagnosis, race, and pubertal status were evaluated by analysis of variance in separate pre- and postpubertal groups. 5-HT levels were expressed as ng/mL blood and ng/microL platelet volume. RESULTS: Among prepubertal children, significant effects of diagnosis (ng/mL; F2,109 = 5.9, p = .004) and race (F2,109 = 14.7, p < .0005) were found. Autistic youngsters had significantly higher 5-HT concentrations than controls, although the elevation (25%) was less than typically reported; MR/CI children had levels very similar to those of controls. White children had significantly lower 5-HT levels than black or Latino youngsters, regardless of diagnosis. Diagnosis and race effects were nonsignificant in the postpubertal group. Postpubertal subjects had lower 5-HT concentrations than prepubertal subjects (ng/mL; F1,114 = 28.5, p < .0005). CONCLUSIONS: The data underscore the importance of matching for race and pubertal status in neuropsychiatric research and suggest that the prevalence of hyperserotonemia in autistic individuals may have been overestimated because of a failure to control for both variables. Hyperserotonemia was not found in MR/CI youngsters without autistic features.


Subject(s)
Autistic Disorder/blood , Intellectual Disability/blood , Puberty , Racial Groups , Serotonin/blood , Adolescent , Adult , Autistic Disorder/diagnosis , Biomarkers/blood , Blood Platelets/chemistry , Child , Child, Preschool , Female , Humans , Intellectual Disability/diagnosis , Male
11.
Vet Rec ; 142(20): 534-7, 1998 May 16.
Article in English | MEDLINE | ID: mdl-9637378

ABSTRACT

Brains from 17 histopathologically confirmed cases of scrapie, five of which had congophilic vascular amyloid, were stained immunohistochemically for prion protein (PrP) using a polyclonal antibody. Two clinically suspect but pathologically unconfirmed cases of natural sheep scrapie and the brains of four mice infected with the 111A murine scrapie strain were also examined. Selected sections containing amyloid were stained with each of two peptide antibodies which recognise the N-terminal amino acid residues which are lost following protease digestion of the disease-specific isoform of PrP. The mice infected with the 111A murine scrapie strain had large numbers of hypermature plaques. All the amyloid plaques from both natural sheep scrapie brains and experimental murine brains were heavily immunostained by the polyclonal and both peptide antibodies. In addition, disease-specific accumulations of PrP were detected in endothelial cells or in the intima of blood vessels of the cerebral cortex of sheep scrapie brains. The affected blood vessels were located in areas which otherwise lacked typical scrapie pathology. Vascular accumulations of PrP were also found in leptomeningeal and choroid plexus blood vessels. Vascular amyloid was found mainly in the neocortex. Vascular amyloid and disease-specific parenchymal accumulations of PrP were found in two sheep which showed clinical signs of scrapie but lacked its typical vacuolar pathology. These results show that the mature amyloid of scrapie is composed of, or contains a substantial proportion of, whole length PrP protein. Thus truncation of PrP is not essential for the aggregation of PrP into amyloid. The vascular amyloid of natural sheep scrapie originates from the accumulation and release of PrP from endothelial cells presumably following systemic scrapie infection. The topography of vascular amyloid distribution in Great Britain differs from that reported in the Netherlands. As amyloid deposition in mice is largely controlled by the strain of the infecting agent it is possible that the strain of the agent may influence vascular amyloid deposition.


Subject(s)
Amyloid/analysis , PrPSc Proteins/analysis , Scrapie/physiopathology , Amyloid/immunology , Animals , Antibody Specificity , Brain/immunology , Immunohistochemistry , Mice , Peptide Fragments , PrPSc Proteins/immunology , Scrapie/immunology , Sheep
12.
Exp Neurol ; 149(2): 447-54, 1998 Feb.
Article in English | MEDLINE | ID: mdl-9500966

ABSTRACT

Heparan sulfate proteoglycan (HSPG) has been found to be associated with amyloid deposits in a number of diseases including the cerebral amyloid plaques of Alzheimer's disease and the transmissible spongiform encephalopathies (TSEs). The role of HSPG in amyloid formation and the neurodegenerative pathology of these diseases have not been established. We have addressed these questions using a scrapie mouse model which exhibits both amyloid and nonamyloid deposition of abnormal PrP protein, the protein marker of TSE infection. The distribution of HSPG was examined throughout the course of the disease in the brains of experimentally infected mice and compared with the distribution of abnormal PrP. Abnormally high levels of HSPG were associated with most types of PrP pathology including all plaque types and diffuse neuroanatomically targeted forms. Scrapie-associated HSPG was present from 70 days after infection, the earliest time-point examined, in the same target areas as abnormal PrP. The association with amyloid plaques may indicate that HSPG is involved in amyloid plaque formation and/or persistence but involvement with early diffuse forms of PrP suggests a more fundamental role in scrapie pathogenesis.


Subject(s)
Amyloid/analysis , Brain/pathology , Heparan Sulfate Proteoglycans/analysis , Prions/analysis , Prions/pathogenicity , Scrapie/pathology , Alleles , Animals , Brain/cytology , Cerebrovascular Circulation , Endothelium, Vascular/pathology , Homozygote , Immunohistochemistry , Mice , Mice, Inbred Strains , Prions/genetics , Reference Values , Scrapie/genetics
13.
J Gen Virol ; 79 ( Pt 3): 601-7, 1998 Mar.
Article in English | MEDLINE | ID: mdl-9519840

ABSTRACT

The pathogenesis of scrapie and other transmissible spongiform encephalopathies (TSEs) following oral uptake of agent is still poorly understood and can best be studied in mice and hamsters. The experiments described here further extend the understanding of the pathways along which infection spreads from the periphery to the brain after an oral challenge with scrapie. Using TSE-specific amyloid protein (TSE-AP, also called PrP) as a marker for infectivity, immunohistochemical evidence suggested that the first target area in the brain of hamsters orally infected with scrapie is the dorsal motor nucleus of the vagus nerve (DMNV), rapidly followed by the commissural solitary tract nucleus (SN). The cervical spinal cord was affected only after TSE-AP had been deposited in the DMNV, SN and other medullary target areas. For the first time, these results demonstrate conclusively that, in our animal model, initial infection of the brain after oral ingestion of scrapie agent occurs via the vagus nerve, rather than by spread along the spinal cord.


Subject(s)
Brain/metabolism , Prions/pathogenicity , Scrapie/etiology , Vagus Nerve/metabolism , Administration, Oral , Animals , Biomarkers , Cricetinae , Immunohistochemistry , Prions/metabolism , Solitary Nucleus/metabolism , Spinal Cord/metabolism , Time Factors
14.
Nat Genet ; 18(2): 118-25, 1998 Feb.
Article in English | MEDLINE | ID: mdl-9462739

ABSTRACT

Classical genetic analysis has identified Sinc/Prni as the major gene controlling mouse scrapie incubation time. Sinc/Prni is linked to Prnp, the gene encoding the prion protein (PrP). Prnp alleles express distinct PrP protein variants, PrP A and PrP B, which arise from codon 108L/F and 189 T/V dimorphisms. Prnp genotype segregates with incubation time length which suggests, but does not prove, that incubation time is controlled by PrP dimorphisms, and that the Sinc/Prni and Prnp loci are congruent. We have used gene targetting to construct mice in which the endogenous Prnp allele has been modified to express PrP B instead of PrP A. Challenge with a mouse-adapted BSE strain results in dramatically shortened incubation times and demonstrates that PrP dimorphisms at codon 108 and/or 189 control incubation time, and that Sinc/Prni and Prnp are congruent.


Subject(s)
Prions/genetics , Alleles , Animals , Brain/metabolism , Brain/pathology , Codon , Genetic Variation , Mice , Mice, Mutant Strains , Mice, Transgenic , Molecular Sequence Data , Point Mutation , Prions/biosynthesis , Prions/chemistry , Scrapie/genetics , Scrapie/pathology , Species Specificity
15.
J Child Psychol Psychiatry ; 38(6): 705-15, 1997 Sep.
Article in English | MEDLINE | ID: mdl-9315980

ABSTRACT

Plasma levels of the hypothalamo-pituitary-adrenal axis hormones beta-endorphin (BE), adrenocorticotropin hormone (ACTH), and cortisol were measured in autistic (N = 48), mentally retarded/cognitively impaired (MR/CI, N = 16), and normal control (N = 26) individuals. Comparison of log transformed data from the three groups revealed that levels of BE and ACTH were significantly higher (p < .05) in the autistic individuals than in normal controls. The higher means in the autistic group were due to significantly higher plasma levels of BE and ACTH, indices of acute stress response, in the more severely affected individuals. The data support the idea that individuals with severe autism have a heightened response to acute stressors rather than chronic hyperarousal or elevated basal stress response system functioning.


Subject(s)
Adrenocorticotropic Hormone/blood , Hydrocortisone/blood , beta-Endorphin/blood , Adolescent , Arousal/physiology , Autistic Disorder/physiopathology , Child , Female , Humans , Hypothalamo-Hypophyseal System/physiopathology , Intellectual Disability/physiopathology , Intelligence/physiology , Male , Pituitary-Adrenal System/physiopathology , Reference Values
16.
Neuropathol Appl Neurobiol ; 23(2): 93-101, 1997 Apr.
Article in English | MEDLINE | ID: mdl-9160894

ABSTRACT

Prion protein (PrP) is a cell surface, host coded, sialoglycoprotein which accumulates in excess in scrapie, Creutzfeldt-Jakob disease, bovine spongiform encephalopathy and other transmissible spongiform encephalopathies. Infection of mice with the 87 V or ME7 scrapie strains results in distinctive and very different light microscopical patterns of vacuolation and disease specific PrP accumulation. In both of these scrapie strains immunogold electron microscopy was used to locate PrP to the plasmalemma of neurons from where it was released into the neuropil. Initial PrP accumulation around neurons and in early plaques lacking amyloid fibrils was generally not associated with morphological changes either of the neuron or dendrite releasing the PrP or in the adjacent neuropil in which excess PrP accumulated. However, accumulation of pre-amyloid PrP in some brain areas was associated with specific degeneration of dendritic spines and axon terminals. Initial PrP aggregation into fibrils was also associated with tissue damage with both ME7 and 87 V plaques and diffuse accumulations. Tissue damage associated with fibrillogenesis was localized and would not be expected to have clinical significance. We conclude that pre-amyloid PrP release and accumulation is not invariably toxic, either to the neuron releasing PrP or to the neuropil into which it is released. However, axon terminal degeneration and dendritic spine loss in some neuroanatomical areas may be indicative of specific PrP toxicity and may be the main cause of neurological dysfunction in murine scrapie.


Subject(s)
Brain/pathology , Brain/ultrastructure , Prions/toxicity , Scrapie/pathology , Animals , Cattle , Dendrites/ultrastructure , Hippocampus/pathology , Hippocampus/ultrastructure , Immunohistochemistry , Mice , Mice, Inbred C57BL , Mice, Inbred Strains , Microscopy, Electron , Nerve Degeneration , Presynaptic Terminals/ultrastructure , Thalamus/pathology , Thalamus/ultrastructure
17.
Am J Psychiatry ; 154(4): 556-8, 1997 Apr.
Article in English | MEDLINE | ID: mdl-9090347

ABSTRACT

OBJECTIVE: Indirect evidence suggests that abnormalities in serotonergic function may be involved in the pathogenesis of premenstrual dysphoric disorder. The goal of this study was to test the hypothesis of serotonergic deficiency in premenstrual dysphoric disorder by measuring the prolactin response to fenfluramine. METHOD: The authors administered the serotonin-releasing drug dl-fenfluramine in a placebo-controlled protocol to nine women with premenstrual dysphoric disorder and 11 healthy female volunteers in the luteal phase of the menstrual cycle. RESULTS: Compared to the normal subjects, the women with premenstrual dysphoric disorder had a significantly blunted prolactin response to fenfluramine. CONCLUSIONS: Premenstrual dysphoric disorder appears to be associated with serotonergic deficiency.


Subject(s)
Fenfluramine , Premenstrual Syndrome/diagnosis , Premenstrual Syndrome/physiopathology , Serotonin/physiology , Adult , Ambulatory Care , Female , Fenfluramine/pharmacology , Humans , Luteal Phase/physiology , Premenstrual Syndrome/blood , Prolactin/blood , Serotonin/blood
19.
Nature ; 380(6575): 639-42, 1996 Apr 18.
Article in English | MEDLINE | ID: mdl-8602267

ABSTRACT

There is a wealth of data supporting a central role for the prion protein (PrP) in the neurodegenerative prion diseases of both humans and other species, yet the normal function of PrP, which is expressed at the cell surface of neurons and glial cells, is unknown. It has been speculated that neuropathology may be due to loss of normal function of PrP. Here we show that in mice devoid of PrP there is an alteration in both circadian activity rhythms and patterns. To our knowledge, this is the first null mutation that has been shown to affect sleep regulation and our results indicate that at least one of the inherited prion diseases, fatal familial insomnia, where there is a profound alteration in sleep and the daily rhythms of many hormones, may be related to the normal function of the prion protein.


Subject(s)
Circadian Rhythm/physiology , Prions , Sleep/physiology , Animals , Circadian Rhythm/genetics , Mice , Mice, Inbred C57BL , Motor Activity , Mutation , Prion Diseases/genetics , Prion Diseases/physiopathology , Prions/genetics , Sleep/genetics
20.
Neurodegeneration ; 5(1): 101-9, 1996 Mar.
Article in English | MEDLINE | ID: mdl-8731389

ABSTRACT

Disease specific forms of a host encoded cell surface sialoglycoprotein called prion protein (PrP) accumulate during this incubation period of the transmissible spongiform encephalopathies. A 33-35 kDa disease specific form of PrP is partially resistant to protease digestion whereas the normal form of PrP can be completely digested. Proteinase K digestion of the murine disease specific form of PrP produces diverse forms of low molecular weight PrP, some of which are N-terminally truncated at amino acid residue 49 or 57 within the octapeptide repeat segment. Amyloid plaques are a pathological feature of many of the transmissible spongiform encephalopathies and are composed of PrP. Using synthetic peptide antibodies to the N-terminus of PrP (which is not present in truncated disease specific PrP) and antibodies to the protease resistant fraction of PrP we have immunostained plaques and pre-amyloid deposits in the brains of mice, experimentally infected with the 87V strain of scrapie, for examination by light and electron microscopy. Classical fibrillar amyloid deposits in plaques as well as pre-amyloid deposits were both immunostained by antibodies to the N-terminus of PrP and to the protease resistant core of the PrP molecule. This suggests that both N-terminal and core amino acid residues are present in disease specific PrP released from scrapie infected cells in vivo. The results also suggest that N-terminal truncation of PrP may not be essential for formation of amyloid fibrils.


Subject(s)
Brain/pathology , Prions/analysis , Scrapie/pathology , Amyloid/analysis , Animals , Antibodies , Brain/ultrastructure , Hippocampus/pathology , Hippocampus/ultrastructure , Hypothalamus/pathology , Hypothalamus/ultrastructure , Immunohistochemistry , Mice , Microscopy, Immunoelectron/methods , Organ Specificity , Peptide Fragments/chemical synthesis , Peptide Fragments/immunology , Pyramidal Cells/pathology , Pyramidal Cells/ultrastructure , Thalamus/pathology , Thalamus/ultrastructure
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