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PubMed2005

Alsin is partially associated with centrosome in human cells.

Mutations in the ALS2 gene has recently been linked to cases of juvenile amyotrophic lateral sclerosis, juvenile primary lateral sclerosis and ascending hereditary spastic paralysis. All reported mutations predict the production of truncated forms of Alsin suggesting a loss of function mechanism for these motor neuron disorders. Here we used the tetracycline-regulated expression system to overexpress the full-length and truncated forms of Alsin in different cell lines. Alsin overexpression caused severe phenotypic changes in monkey COS-7 cells including the enlargement and accumulation of early endosomes, impairment of mitochondria trafficking and fragmentation of the Golgi apparatus. Our results further demonstrate the requirement of the Alsin VPS9 domain for occurrence of the vacuolation process and the role of Alsin as a guanine nucleotide exchange factor for Rab5. Transfected human SW13 cells exhibited an unexpected centrosomal localization for Alsin that was linked to the presence of the c-terminal part of the protein. Immunofluorescence staining revealed a colocalization of Alsin with the centrosomal markers gamma-tubulin and A kinase anchoring protein (AKAP-450). Similar results were obtained with human LA-N-2 and SK-N-SH neuronal cells. Moreover endogenous Alsin was detected in a centrosome preparation purified from human cortical brain. Considering the crucial role of centrosome in the production of microtubules required for intracellular transport, these findings are of potential relevance for unravelling the disease mechanisms linked to Alsin mutations.

Animals↗
PubMed2002

Paradigm shifts in vaccine development: lessons learned about antigenicity, pathogenicity and virulence of Brucellae.

As part of a program to support the USDA Animal Plant Health Inspection Service Bovine Brucellosis Eradication Program, the Brucellosis Research Unit of the National Animal Disease Center (NADC) sought to develop a bovine brucellosis vaccine that would allow vaccinated animals to be distinguished from virulent field infected animals. In order to meet that goal, several avenues of research were undertaken to construct and test candidate vaccines, including Brucella abortus RB51. In early vaccine development studies, a subunit preparation obtained by extracting B. abortus with salts was studied as a candidate subunit vaccine. Later, molecular biological techniques were used both to clone genes encoding products found in the salt extract (BCSP31 and Cu-Zn SOD) and genes encoding proteins of B. abortus that were antigenic (HtrA) or possibly essential (two-component systems) for full virulence of B. abortus. In vitro systems using mammalian cells lines such as HeLa and macrophage-related were used along with the mouse model and host animal models. Results obtained at NADC and in other Brucellosis research laboratories, using survival in mammalian cell lines and the mouse model to access pathogenicity and virulence of genetically engineered strains, do not necessarily identify loci that are essential for full virulence or pathogenicity in the natural host, the bovine. Studies at NADC and other brucellosis laboratories showed that antigenicity was not a predictor of the effectiveness of a protein as a subunit vaccine.

Animals↗
PubMed2006

A large adolescent idiopathic scoliosis curve in a skeletally immature patient: is early surgery the correct approach? Overview of available evidence.

The goal of this study was to determine whether the available studies provide enough evidence that, in a borderline case of adolescent idiopathic scoliosis with a large (35 to 50 degrees) curve in a skeletally immature patient (Risser 0 to 2) with significant growth potential left, a conservative line of management in the form of bracing can be considered, rather than to rush into a potentially unnecessary major spinal surgery. We reviewed the literature spanning the last 20 years for the results of bracing in this specific group of patients. From the 9 studies selected, a group-specific data extraction was carried out. Three hundred and five patients with a 36 to 50 degrees scoliosis curve and Risser stages 0 to 2 were treated by bracing and the treatment was termed successful in 160 patients. Thus, more than half (52.5%) of the patients were successfully managed with a brace and were spared surgery. The current trend for management of these curves is early surgical intervention, the rationale being the ineffectiveness of bracing in preventing the progression of such a large curve and the difficulty in obtaining satisfactory correction by postponing surgery to a later date. On the basis of our results, we propose a conservative line of management for these curves, in contrast with current views, rather than to rush into a major spine surgery, expecting a favorable outcome with a well-supervised bracing program. If the curve progresses, surgery can always be considered later, keeping in mind the excellent correction obtained with the pedicle screw systems even for large curves of 70 to 100 degrees.

Adolescent↗
PubMed1992

Organic structures of the hypercalcified peritubular matrix in horse dentine.

EDTA-insoluble organic structures of the hypercalcified peritubular matrix (PM) in horse dentine were observed by scanning electron microscopy. The PM was enveloped in double cylindrical structures composed of fibrillar sheaths in the inner and outer peripheries. Between the outer fibrillar sheath and intrinsic fibrils of the intertubular matrix, a calcified cementing membrane existed. Within the PM, warped cone-shaped structures of fibrillar sheaths, overlapping at intervals of 4-6 microns and semiconcentrically surrounding the dentinal tubule, extended from the inner fibrillar towards the outer fibrillar sheath. The cone-shaped fibrillar sheaths following the inner and outer fibrillar sheaths were identified as the incremental lines of the PM. Most of these fibrils may be collagen although it could not be confirmed, whereas non-collagenous organic materials in the lateral branches of the dentinal tubule are radially arranged in the PM. These EDTA-insoluble structures were three-dimensionally illustrated using an image-analysing system.

Acid Etching, Dental↗
PubMed1998

Finding food: senses involved in foraging for insect larvae in the electric fish gnathonemus petersii

The weakly electric fish Gnathonemus petersii searches at night for insect larvae in tropical African streams. The aim of this study was to determine the contributions of different sensory modalities to foraging. The time that fish needed to find two randomly placed chironomid larvae was measured. The influence of various senses on search time was investigated by blocking the use of one or more senses. Active electrolocation was used by most fish for prey detection in the dark. In addition, passive electrolocation played a role in some individuals. If light was available, vision could become the dominant sense in some individuals, replacing active electrolocation. The presence of chemical cues decreased prey detection time in most fish. Prey movements also shortened search times when active electrolocation and vision were not possible, indicating that the mechanosensory lateral line also plays a role in the detection of moving prey. The results show that G. petersii uses several senses simultaneously during foraging. Each individual favours a specific combination of the available sensory inputs. If one sensory modality is eliminated, fish can switch to other modalities, indicating that the food detection system is flexible and plastic.

Journal Article↗
PubMedDate not supplied

Distribution of the carbohydrate epitope 3-fucosyl-N-acetyl-lactosamine (FAL) in the adult human brain.

The distribution of the carbohydrate epitope 3-fucosyl-N-acetyl-lactosamine was investigated on paraffin sections of the normal adult human central nervous system by means of immunohistochemistry, using the mouse monoclonal antibody anti-Leu-M1. This antibody is one among many others recognizing this epitope, which is also known as stage specific embryonic antigen I or X-hapten. We found this epitope predominantly localized on astrocytes especially along their numerous cell processes. There was a striking association of immunoreactive astrocytes with intracortical blood vessels and with distinct brain areas. Leu-M1-positive oligodendrocytes were present in the white matter with highest densities in the centrum semiovale and lateral pontine regions. Most cells of the ependymal lining, including tanycytes, showed Leu-M1 immunoreactivity but there was some topographical variability. Double-labelling experiments revealed that Leu-M1-positive glial cells may or may not be immunoreactive to glial fibrillary acidic protein or S-100 protein. The Leu-M1 antibody also stained a large number of different sets of neurons from cerebral cortex to spinal cord. Groups of immunostained cells were found in the hypothalamus, dorsal thalamus, ventral and mesial mesencephalic tegmentum, and several lower brainstem regions such as the lateral reticular formation, the raphe nuclei and the pons. Leu-M1 immunoreactivity appeared associated to neurochemically specified neuronal cell groups such as the mesencephalic dopaminergic system and the hypothalamic neurophysin system. In summary, our study demonstrates a distinct topographical distribution of the Leu-M1 epitope in the adult human central nervous system. Its exact functions, however, have not yet been elucidated, but there is evidence for the involvement of this epitope in cell-cell-adhesion and -interaction processes.

Adolescent↗
PubMed2006

Reconstruction of liver organoid using a bioreactor.

AIM: To develop the effective technology for reconstruction of a liver organ in vitro using a bio-artificial liver. METHODS: We previously reported that a radial-flow bioreactor (RFB) could provide a three-dimensional high-density culture system. We presently reconstructed the liver organoid using a functional human hepatocellular carcinoma cell line (FLC-5) as hepatocytes together with mouse immortalized sinusoidal endothelial cell (SEC) line M1 and mouse immortalized hepatic stellate cell (HSC) line A7 as non parenchymal cells in the RFB. Two x 10(7) FLC-5 cells were incubated in the RFB. After 5 d, 2 x 10(7) A7 cells were added in a similar manner followed by another addition of 10(7) M1 cells 5 d later. After three days of perfusion, some cellulose beads with the adherent cells were harvested. The last incubation period included perfusion with 200 nmol/L swinholide A for 2 h and then the remaining cellulose beads along with adherent cells were harvested from the RFB. The cell morphology was observed by transmission electron microscopy (TEM) and scanning electron microscopy (SEM). To assess hepatocyte function, we compared mRNA expression for urea cycle enzymes as well as albumin synthesis by FLC-5 in monolayer cultures compared to those of single-type cultures and cocultures in the RFB. RESULTS: By transmission electron microscopy, FLC-5, M1, and A7 were arranged in relation to the perfusion side in a liver-like organization. Structures resembling bile canaliculi were seen between FCL-5 cells. Scanning electron microscopy demonstrated fenestrae on SEC surfaces. The number of vesiculo-vacuolar organelles (VVO) and fenestrae increased when we introduced the actin-binding agent swinholide-A in the RFB for 2h. With respect to liver function, urea was found in the medium, and expression of mRNAs encoding arginosuccinate synthetase and arginase increased when the three cell types were cocultured in the RFB. However, albumin synthesis decreased. CONCLUSION: Co-culture in the RFB system can dramatically change the structure and function of all cell types, including the functional characteristics of hepatocytes. Our system proves effective for reconstruction of a liver organoid using a bio-artificial liver.

Albumins↗
PubMed1996

Extended lateral segmentectomy using intraoperative ultrasound to obtain a partial liver graft.

The important features of extended lateral segmentectomy to obtain a partial liver graft comprising the left lateral segment and the left half of the medial segment are described with special reference to anatomical variation of the hepatic venous system. Ramification patterns of the hepatic vein tributaries around the juncture of the major hepatic veins with the inferior vena cava are delineated before starting liver resection, using intraoperative ultrasound. The left medial vein draining the left part of the medial segment is recognized close to the confluence of the middle and left hepatic veins. This tributary flows into the left hepatic vein in the majority of cases, but sometimes into the middle hepatic vein. The liver transection line is established in order to obtain the graft, including the drainage area of the left medial vein. Intraoperative ultrasound is indispensable for identifying the left medial vein in extended lateral segmentectomy.

Adolescent↗
PubMed2002

A hybrid CT-free navigation system for total hip arthroplasty.

OBJECTIVE: To design and evaluate a novel CT-free image-guided surgical navigation system for assisting placement of both acetabular and femoral components in total hip arthroplasty (THA). MATERIALS AND METHODS: The methodology in this paper is conceptually based on our previous work on CT-free cup placement. For femoral component placement, two patient-specific reference coordinate systems are first defined: One for the pelvis, based on the so-called anterior pelvic plane (APP) concept, and one for the femur, using the center of the femoral head, the posterior condylar tangential line, and the medullary canal axis of the proximal femur. A hybrid method is used for the associated landmark acquisition, which involves percutaneous point-based digitization and bi-planar landmark reconstruction using multiple registered fluoroscopy images. The following clinical parameters are computed in real time: cup inclination and anteversion, antetorsion and varus/valgus of the stem, lateralization, and change in leg length for complete THA. In addition, instrument actions such as reaming, impaction, and rasping are visualized for the surgeon by superimposing virtual instrument representations onto the fluoroscopic images. RESULTS: A laboratory study of computer-assisted measurement of antetorsion and varus/valgus, change in leg length, and lateralization for femoral stem placement demonstrated the high precision of the proposed navigation system. Compared with CT-based measurement, mean deviations of 1.0 degrees, 0.6 degrees, 0.7 mm, and 1.7 mm were found for antetorsion, varus/valgus, change in leg length, and lateralization, respectively, with standard deviations of 0.5 degrees, 0.5 degrees, 0.6 mm, and 0.7 mm, respectively. A pilot clinical evaluation showed that THA could benefit from this newly developed CT-free hybrid system. CONCLUSIONS: The proposed CT-free hybrid system promises to increase the accuracy and reliability of THA surgery.

Aged↗
PubMed1995

3-D eye movement measurements on four Comex's divers using video CCD cameras, during high pressure diving.

Previous studies have shown the vulnerability of the vestibular system regarding barotraumatism (1) and deep diving may induce immediate neurological changes (2). These extreme conditions (high pressure, limited examination time, restricted space, hydrogen-oxygen mixture, communication difficulties etc.) require adapted technology and associated fast experimental procedure. We were able to solve these problems by developing a new system of 3-D ocular movements on line analysis by means of a video camera. This analyser uses image processing and forms recognition software which allows non-invasive video frequency calculation of eye movements including torsional component. As this system is immediately ready for use, we were able to realize the subsequent examinations in a maximum time of 8 min for each diver: oculomotor tests including saccadic, slow and optokinetic traditional automatic measurements; vestibular tests regarding spontaneous and positional nystagmus, and reactional nystagmus to the pendular test. For pendular induced nystagmus we used appropriate head positions to stimulate separately the lateral and the posterior semicircular canal, and we measured the gain by operating successively in visible light and complete darkness. Recordings were done during a simulated onshore dive to an ambient pressure corresponding to a depth of 350 m. The above examinations were completed on the first and last days by caloric tests with the same video system analyser. The results of the investigations demonstrated perfect tolerance of the oculomotor and vestibular systems of these 4 divers thus fulfilling the preventive conditions defined by Comex Co. We were able to overcome the limitations due to low cost PC computer operation and cameras (necessity of adaptation to pressure, focus difficulties and direct light exposure eye reflexions). We still have on line accurate measurements even on the torsional component of the eye movement. Due to this technological efficiency we also present some mathematical aspects of the software.

Adult↗
PubMed1984

Absorption of the cerebrospinal fluid and intracranial compliance in an amphibian, Rana pipiens.

Experiments have been carried out to investigate the absorption of the cerebrospinal fluid (c.s.f.) and the intracranial compliance in an amphibian, Rana pipiens, using infusions into the c.s.f. system through glass micropipettes. Resistance to absorption of the c.s.f. was estimated by the constant rate infusion technique. Mean absorption resistance for infusions of artificial c.s.f. into the lateral ventricles and into the cerebral subarachnoid space were 15.48 and 16.52 mmH2O min microliter-1 respectively. This difference was not significant and it is concluded that the pores in the posterior tela situated in the roof of the fourth ventricle do not offer any resistance to the flow of c.s.f. out of the ventricles. The resistance to drainage of the c.s.f. in this amphibian is higher than that found for mammals. Mean resting c.s.f. pressure, estimated from the intercept of the regression line with the pressure axis at zero infusion rate was 18.0 mmH2O. Absorption resistance was measured from the cerebral subarachnoid space before and after injection of 4 microliter Indian ink solution. There was a 3-fold increase in resistance following ink injection. Two-way analysis of variance showed the difference to be significant (P less than 0.01) suggesting that the outflow sites can become partially blocked by particulate matter. During a continuous 3 h infusion of artificial c.s.f. containing [14C]dextran or [125I]-labelled human serum albumin (RISA) into the lateral ventricles, the mean percentage uptakes into the systemic circulation after the first 0.5 h of a 3 h period were 74.1 and 61.9% respectively. The difference is not significant. The rapid and high uptake into blood suggests there is a direct communication between c.s.f. and blood in amphibians. During continuous infusion of RISA into the lateral ventricles, simultaneous blood samples were taken from the femoral artery and the internal dorsal vertebral vein. Radioactivity was found to be 13.2% higher in venous samples. This suggests that at least some c.s.f. drainage takes place directly into the spinal venous system. Intracranial compliance was investigated by recording the peak pressure in response to a series of bolus injections of artificial c.s.f. into one lateral ventricle. Compliance was estimated to be 0.11, 0.10 and 0.09 microliter mmH2O-1 for injection rates of 12.74, 16.62 and 25.10 microliters min-1 respectively. The difference between these values is not significant. The results suggest that for injection volumes over 5 microliters the c.s.f. system behaves elastically.

Absorption↗
PubMed1981

Overdistention of the neural tube causes congenital heart disease.

Congenital heart disease consists of cardiac anomalies that originated before or during the truncus arteriosus stage. The central nervous system, serving all organs, is the first to develop. It is the only organ possessing a third circulation. Immediately after the neural tube closes at the fourth week, its lining of immature ependymal cells secretes a proteinaceous neural tube fluid (NTF) at a pressure higher than the amniotic pressure. The resulting distention helps to shape not only the embryonic brain and spinal cord but also the bordering mesodermal cells that later will form vertebrae. The choroid plexus does not begin to secrete true cerebrospinal fluid until two weeks later. Should hypersecretion occur during this critical two week interval, the neural tube will overdistend and allow NTF to infiltrate into mesoderm (Fig. 1). Here, this fluid with its extraneous protein, may damage cells that are destined to form the anlagen of mesodermal organs such as the heart. It may also damage the primitive gut resulting in pulmonary, gastrointestinal and genitourinary anomalies. The most convincing evidence that the neural tube had been overdistended is the combination of anterior and posterior spina bifida that constitutes bilateral hemivertebrae. Vertebral anomalies are present in congenital heart disease though scarcely recognizable on the chest film of the newborn.

Animals↗
PubMed1980

Lymphocyte antigens in systemic lupus erythematosus: studies with heterologous antisera.

Rabbit antisera were produced against pooled living lymphocytes from 25 patients with active systemic lupus erythematosus (SLE). Lymphocytes collected at plasmapheresis or venipuncture were frozen in liquid nitrogen and later coated with rabbit antibody to normal human tonsils and normal thymocytes immediately before intravenous immunization of rabbits. Antisera were subsequently extensively absorbed with normal human tonsillar cells, thymocytes, peripheral blood lymphocytes, erythrocytes, and leukocytes from patients with myelogeneous and lymphatic leukemia until residual base-line immunofluorescent staining of normal human lymphocytes using F(ab)2' of whole antisera averaged less than 5%. Absorbed pepsin-digested antisera detected membrane antigens which were markedly increased (mean 32%) on lymphocytes from patients with active SLE (P less than 0.05). Membrane antigens reacting with absorbed, pepsin-digested antisera were present on both T and B cells but, in most instances, predominated on T cells. Control observations using absorbed pepsin-digested antisera to normal human lymphocytes or peripheral blood lymphocytes from patients with rheumatoid arthritis showed no similar specificity. SLE patients treated with moderate or high dose corticosteroids or immunosuppressive agents (cytoxan or azathioprine) appeared to lose lymphocyte antigens detected by these reagents. Control studies with other connective tissue disease patients, miscellaneous hospitalized subjects, or normal controls showed low levels of reactivity (2-5%). SLE lymphocyte membrane antigens uniquely increased during active disease; this may represent neoantigens or alterations associated with the disease itself.

Adult↗
PubMed1999

IgG anti-endothelial cell autoantibodies from patients with systemic lupus erythematosus or systemic vasculitis stimulate the release of two endothelial cell-derived mediators, which enhance adhesion molecule expression and leukocyte adhesion in an autocrine manner.

OBJECTIVE: To investigate the ability of anti-endothelial cell antibodies (AECA) to modulate endothelial cell function. METHODS: The effects of purified IgG from 11 patients with systemic lupus erythematosus (SLE) and 4 patients with systemic vasculitis on the expression of adhesion molecules (intercellular adhesion molecule 1, vascular cell adhesion molecule 1, E-selectin) by human umbilical vein endothelial cells and on the adhesion of the human promyelocytic cell line U937 were examined in vitro. RESULTS: IgG from 6 of 8 AECA-positive SLE patients and 3 of 3 AECA-positive systemic vasculitis patients up-regulated adhesion molecule expression and leukocyte adhesion to endothelial cells. The 4 AECA-negative samples had no effect. Transfer experiments demonstrated that at later time points (2-8 hours) after AECA addition, endothelium-derived interleukin-1 (IL-1) accounted for the ability of AECA to increase leukocyte adhesion. However, even within very short times after addition of AECA (<30 minutes), endothelial cells released a distinct transferable mediator with similar effects. CONCLUSION: AECA in patients with SLE or systemic vasculitis may contribute to pathogenesis by increasing leukocyte adhesion to endothelial cells. AECA act by inducing the release of at least two endothelium-derived mediators, one (as-yet-unidentified) rapidly and another (IL-1) more slowly, both of which stimulate endothelial cells in an autocrine manner.

Antibodies, Blocking↗
PubMed2004

Current pharmacologic approaches to treating neuropathic pain.

Most neuropathic analgesic medications have been introduced initially for other medical conditions. Anticonvulsants, local anesthetics, and antidepressants later were found to be effective in the treatment of neuropathic pain. Carbamazepine and the newer anticonvulsants such as gabapentin, lamotrigine, topiramate, and oxcarbazepine are being used as first-line or adjunctive therapy. The newer agents have less potential for drug interactions and a more favorable side-effect profile. Lidocaine administered systemically or topically is useful for some peripheral and central neuropathic pain conditions. The tricyclic antidepressants amitriptyline, nortriptyline, and desipramine have been shown to be effective for the management of neuropathic pain, independent of their antidepressant property. All of the available analgesics have considerable side effects, which necessitate careful titration. Future drug research may focus on developing medications specifically for neuropathic pain. These designer agents may have more desirable action without the unwanted side effects.

Analgesics↗
PubMed1990

A triangulation method for the quantitative measurement of arterial blood velocity magnitude and direction in humans.

A triangulation method has been applied to a duplex ultrasound scanner to quantify blood flow velocities in two dimensions. A position locating system (PLS) connected to the scanhead locates the sample volume (SV) in 3-D space to a precision of 1 mm. The PLS is used to obtain flow velocity data from two independent lines of sight in the human femoral artery. Data are gathered from anatomic sites of interest along one line of sight. Later the computer directs the SV to interrogate the same points in space from a second line of sight. Water tank studies using both constant velocity and pulsatile string targets were used to validate the method. Velocity magnitudes could be calculated to within 5% error for Doppler angles below 75 degrees for various string depths and speeds; the error in Doppler angle calculation was usually less than 3 degrees. Results from the superficial femoral artery show flow velocity vectors are nearly parallel to the vessel walls. Peak systolic velocity magnitudes range from 63-66 cm/s in three presumed normal individuals. Following the validation studies addressed in this paper, this triangulation approach is intended in future work to document the complex nonaxial character of blood flow that occurs normally at branch points and in regions of intraluminal disease.

Blood Flow Velocity↗
PubMed1996

Locomotion coincides with c-Fos expression in related areas of inferior olive and cerebellar nuclei in the rat.

Rats that had been walking on a rotating drum for a period of 75 min, demonstrated expression of the immediate early gene c-Fos in specific areas of the inferior olive and cerebellar nuclei. Non-walking control rats did not show consistent Fos-like immunoreactive labelling in these nuclei. Fos-like immunoreactive olivary neurons were consistently found in the caudolateral parts of the dorsal accessory olive and in its dorsal fold, and within specific areas of the medial accessory and principal olives. In the cerebellar nuclei, immunoreactive cells were found in the medial part of the anterior interposed nucleus, in the interstitial cell groups, and within specific parts of the medial, posterior interposed, and lateral nuclei. The lateral vestibular nucleus as well as the ventral part of the magnocellular red nucleus also displayed positive neurons. Most of these positive areas are known (1) to be related to the spinal cord and (2) to be anatomically linked. These results are in line with a presumptive role of the olivo-cerebellar system in ongoing movement control.

Animals↗
PubMed2006

Early brain development disruption from NMDA receptor hypofunction: relevance to schizophrenia.

Disruption to brain development at an early stage can potentially alter chemically coded neural networks and can affect behavior in later life. During early brain development antagonism of glutamate NMDA receptors, which play an important role in neuronal outgrowth and survival, leads to neuronal damage in several brain regions and causes behavioral alterations in rodents that mimic schizophrenia symptoms and endophenotypes. There are several lines of evidence implicating involvement of a dysfunctional glutamate system in schizophrenia. In normal subjects, NMDA receptor antagonists produce behavioral and neurochemical changes that mimic schizophrenia symptoms better than any other psychotomimetic drug. Moreover, these drugs worsen symptoms in schizophrenia patients and can trigger a recrudescence of the acute psychotic state in patients with stable chronic schizophrenia. In addition, genes consistently reported as being altered in schizophrenia play roles in development, neuroplasticity and glutamate/GABAergic neurotransmission. Perinatal NMDA receptor antagonist treatment is a useful model for studying the neurodevelopmental and NMDA receptor hypofunction hypotheses of schizophrenia because neurochemical and behavioral changes, reminiscent of those seen in schizophrenia, are present long after cessation of drug administration, which suggests that a permanent change in brain structure and organization has occurred during brain development.

Animals↗