Preclinical safety evaluation of human mesenchymal stem cell transplantation in cerebrum of nonhuman primates.

The efficacy of stem cell transplantation for promoting recovery of patients with neurological diseases, such as stroke, has been reported in several studies. However, the safety of the intracerebral transplantation of human mesenchymal stem cells (hMSCs) remains unclear. The aim of the study was to evaluate the safety of hMSCs transplanted in cerebrum of Macaca fascicularis and to provide evidence for clinical application. A total of 24 M fascicularis were assigned to 3 groups randomly: low dose (3.0 × 10(5) cells/kg), high dose (2.5 × 10(6) cells/kg), and the control (normal saline [NS]). Human mesenchymal stem cells or NS were injected into each monkey for 2 times, with an interval of 3 weeks. The injection point was located outside of the right putamen, according to a stereotactic map and preoperative magnetic resonance imaging of the monkeys. Animal health, behavior, biophysical and biochemical parameters, and brain neurological function were routinely monitored over a 6-month period posttransplantation, and the histopathologic examinations were also performed. The results showed that local pathologic damage including local tissue necrosis and inflammation was induced after the injection. The damage of low-dose and high-dose groups was greater than that of the control group, yet over time, the damage could be repaired gradually. No major hMSCs-associated changes were induced from other indicators, and the transplantation of hMSCs in monkeys did not affect total immunoglobulin (Ig) M, total IgG, CD3, CD4, or CD8 values. We therefore conclude that transplantation of hMSCs to the cerebrum represents a safe alternative for clinical application of neurological disorders.

Toxocara encephalitis presenting with autonomous nervous system involvement.

Human toxocariasis has been reported to cause a broad spectrum of neurological syndromes, including encephalitis, meningitis and meningo-radiculitis. Nevertheless, cerebral infection by Toxocara may go undiagnosed due to its rarity, elusive symptoms and lack of availability of appropriate testing. We report the case of a 54-year-old man who presented with abdominal pain and paralytic ileus approximately 3 weeks after having eaten raw snails (a folk remedy for peptic ulcer). Three weeks later, marked eosinophilia ensued, associated with mental clouding, nystagmus, diplopia, peripheral limbs ataxia, urinary retention, slackened deep tendon reflexes, arthralgias and myalgias. Cerebrospinal fluid (CSF) examination demonstrated an eosinophilic meningitis, and Toxocara canis cerebral infection was diagnosed by positive serology and by the detection of T. canis DNA in the CSF. The patient made a full recovery following treatment with albendazole and corticosteroids. Physicians should be aware of this rare presentation of toxocariasis, whose diagnosis is, today, facilitated by molecular biology techniques. A history of ingestion of raw snails may alert the clinician to consider the possibility of such an uncommon condition.

Neoplastic meningitis.

Neoplastic meningitis occurs in approximately 5%-10% of all patients with cancer, and aggressive supportive measures are a critical component of comprehensive care. A literature review of the current diagnostic methods, randomized controlled trials, and available treatments was undertaken; and a comprehensive discussion of best-practice supportive care measures is provided. Although the prognosis for those diagnosed with neoplastic meningitis is poor, treatment and supportive care may allow stabilization of neurologic symptoms and afford protection from further neurologic deterioration, allowing patients to maximize their function and independence and adjust their expectations of treatment from cure to palliation.

MR imaging and quantification of the movement of the lamina terminalis depending on the CSF dynamics.

BACKGROUND AND PURPOSE: Brain pulsation is a well-known observation in neurosurgery, but methods for its visualization on MR imaging, like phase imaging, do not provide a detailed structural view. We prospectively investigated electrocardiographic (ECG)-gated cine true fast imaging with steady-state precession (FISP) sequence on volunteers to test a sequence for demonstrating brain pulsation and movements of intracranial structures related to CSF dynamics. MATERIALS AND METHODS: Eleven healthy volunteers were investigated with prospectively ECG-gated cine true-FISP in the midsagittal plane. A total of 50 phases were recorded per cardiac cycle and per volunteer. The lamina terminalis was chosen to study the pulsatility of the brain, and the optic recess diameter was chosen for means of objective quantification of the degree of pulsatility. RESULTS: Pulsatile motion of the lamina terminalis was apparent in all volunteers on the cine mode. The mean diameter of the optic recess was 2.5 mm. The greatest change in diameter in 1 volunteer was 1.5 mm. The mean change in diameter was 40% during 1 cardiac cycle. CONCLUSIONS: Cine true-FISP sequence is a well-suited method for investigations of passive movements of the ventricular system. It shows pulsations of the brain as well as passive changes caused by CSF dynamics with high temporal and spatial resolution.

Comparative efficacies of terbinafine and fluconazole in treatment of experimental coccidioidal meningitis in a rabbit model.

A rabbit model of coccidioidal meningitis was used to compare the therapeutic efficacies of terbinafine (TBF) and fluconazole (FCZ). Hydrocortisone acetate-treated New Zealand White male rabbits were infected intracisternally with either 2.2 x 10(4) or 6.4 x 10(4) Coccidioides immitis arthroconidia. Oral treatment with polyethylene glycol 200 (PEG) twice daily (n = 8), TBF twice daily (n = 9; 200 mg/kg of body weight/day), or FCZ once daily (n = 8; 80 mg/kg/day) began on day 5 and continued for 21 days. Mean survival times were 20, 24, and 32 days for rabbits treated with PEG, TBF, and FCZ, respectively. All of the FCZ-treated animals (100%; P = 0.003), 56% of the TBF-treated animals (P = 0.4), and 25% of the PEG-treated animals survived the length of the study. Both FCZ and TBF were effective at reducing the incidence of paresis. Only FCZ was effective at reducing most neurological and systemic signs. FCZ treatments resulted in lower cerebrospinal fluid (CSF) protein concentrations and leukocyte counts and faster clearing of CSF fungal cultures compared with those for PEG-treated controls, but TBF treatments had no significant effect on these parameters. Neither drug affected CSF glucose levels. Mean serum TBF levels by bioassay were within the range of 3.5 to 6.2 microgram/ml at 1, 2, and 4 h postdosing and 0.35 to 7.0 microgram/ml at 14 h postdosing. No TBF was detected in CSF. Mean FCZ levels (24 to 25.5 h postdosing) by bioassay were 16.4 to 19.2 and 13.5 to 19.2 microgram/ml in serum and CSF, respectively. The reduction in the numbers of CFU in the spinal cord and brain was over 100-fold (P = 0.0005) in FCZ-treated animals and 2-fold (P

Cerebrospinal fluid constituents collected at the atlanto-occipital site of xylazine hydrochloride sedated, healthy 8-week-old Holstein calves.

Cerebrospinal fluid (CSF) collected at the atlanto-occipital site and serum were obtained from 10 male, 8-week-old, Holstein calves after sedation with xylazine hydrochloride. Glucose, creatine kinase, alkaline phosphatase, urea nitrogen, creatinine, sodium, potassium, chloride, calcium, phosphorus, total protein, and albumin were determined in serum and CSF. Optical characteristics, specific gravity, total red blood cell and nucleated cell counts and differentials were also evaluated in the CSF. Additionally, CSF protein electrophoresis and immunoglobulin concentrations were determined. Then, albumin quotients (AQ) were derived. Erythrocytes were observed in 9 of 10 CSF samples. Total nucleated cell counts ranged from 0-10 cells x 10(6)/L with a mean of 3 cells x 10(6)/L. Differential nucleated cell count in the CSF consisted primarily of lymphocytes/small mononuclear cells (57%), fewer monocytes/ large mononuclear cells (38%), and scant neutrophils (4%) and eosinophils (0.05%). The concentration of sodium (134 to 139 mEq/L) was similar to that of serum, but the concentration of potassium (2.8 to 3 mEq/L) was lower than that of serum. Creatine kinase activity (0 to 4 U/L) of CSF was markedly lower than serum activity. The CSF glucose concentration was approximately 80% of the serum value. Cerebrospinal fluid total protein concentration determined by electrophoresis ranged from 110 to 330 mg/L with a mean of 159 mg/L. Cerebrospinal fluid albumin ranged from 48 to 209 mg/L with a mean of 86 mg/L. In all CSF samples, radial immunodiffusion of unaltered CSF and concentrated CSF (four-fold concentration) revealed quantities undetectable by the present techniques in which the lowest standard values for IgG1, IgG, and IgM determinations was 70 mg/L and IgG2 was 30 mg/L. The albumin quotient ranged from 0.15 to 0.65 with a mean of 0.25. Based on the results of this study, CSF may be collected at the atlanto-occipital site safely and efficiently in calves, and reported values for CSF from adult cattle may not be suitable for evaluation of CSF collected from immature cattle.

Failure of thiamphenicol in a penicillin-allergic patient with Listeria meningoencephalitis--delayed cure following penicillin desensitization.

A 27-year-old woman, without compromised immunodefenses, experienced a Listeria meningoencephalitis, with brainstem symptoms. The identified agent exhibited poor susceptibility to usual effective antibiotics, except for penicillins. Knowledge of past history of an allergic reaction to beta-lactam antibiotics lead to appropriate therapy after acute intravenous desensitization of the patient to amoxicillin. Treatment resulted in therapeutic administration rate over 24 h, and in rapid regression of clinical and biological disorders.

The system of cerebrospinal fluid-contacting neurons.

Cerebrospinal fluid (CSF)-contacting neurons are located periventricularly or inside the brain ventricles; they contact the CSF via their dendrites, perikarya or axons. Most of the CSF-contacting nerve cells send dendritic processes into the ventricular cavity where they form ciliated terminals. These ciliated dendritic endings resemble those of known sensory cells, yet their role is still unknown. There are two types of CSF-contacting dendritic terminals. One bears solitary 9 X 2 + 0 cilia; it is present in different hypothalamic regions such as the paraventricular organ and the vascular sac. The magnocellular neurosecretory nuclei also contain CSF-contacting neurons, which probably furnish information about the parameters of the CSF for the regulatory function of the hypothalamo-hypophyseal system. CSF-contacting nerve cells of the parvocellular hypothalamic nuclei are suspected to participate in hypothalamo-adenohypophyseal regulation. A second type of CSF-contacting dendritic terminal bears many stereocilia and is found in the central canal of the spinal cord. This type of terminal is also supplied with a 9 X 2 + 2 kinocilium that may contact Reissner's fiber, the secretory material of the subcommissural organ. Resembling mainly mechanoreceptors, these spinal CSF-contacting neurons appear to form axon terminals of the neurosecretory type at the external circumference of the spinal cord. Developing and/or regressing photoreceptor cells of the retina and pineal complex may display a similar dendritic structure characteristic of hypothalamic CSF-contacting neurons. Axons penetrating into the ventricles innervate the apical surface of the ependyma and/or the CSF-contacting dendritic terminals. Some bipolar neurons of the retina form so-called Landolt's clubs; these may be considered as the retinal component of the CSF-contacting neuronal system. Since in the lancelet nearly all nerve cells contact the CSF, the CSF-contacting neurons represent a specialized, but phylogenetically old cell type, a "protoneuron" in the vertebrate brain. They may be derived phylogenetically by inversion of the ciliated neurons found in the plate-like nervous system of more primitive deuterostomians.

Subpopulations of T lymphocytes in human extravascular fluids.

Surface markers of lymphocytes from various human extravascular fluids (cerebrospinal fluid, aqueous humour, colostrum, breast and ovary cyst fluids, peritoneal and pleural transudates) are compared with those of lymphocytes from peripheral blood. Significantly higher percentages of T cells are found in all extravascular fluids: the great majority of extravascular T lymphocytes show high E rosette-forming ability and bear IgG Fc receptors (T Fc+ cells). Functional implications of the shown high predominance of T Fc+ cells in extravascular fluids are discussed on the basis of presently available information on the immunological role of such cells (cytotoxic? suppressor? amplifier?).

Anticonvulsant prolongation of survival in adult murine lymphocytic choriomeningitis. II. Ultrastructural observations of pathogenetic events.

Because previous ultrastructural studies of murine lymphocytic choriomeningitis (LCM) had revealed only mononuclear cell infiltration with no cytopathology of target cells in the choroid plexus, ependyma, and leptomeninges, diazepam treatment was used to prolong survival for characterization of late pathogenetic events. Mice which were treated with diazepam and sacrificed 8, 9, and 10 days after intracerebral inoculation with LCM virus showed an increasing amount of inflammatory infiltration into choroid plexuses, leptomeninges, Virchow-Robin spaces, and ependyma. Mononuclear cells, lymphocytes, and polymorphonuclear (PMN) leukocytes increased in number as compared with terminally infected mice sacrificed 7 days after inoculation. Ultrastructurally, choroidal epithelial cells showed cytopathological changes varying from dilated endoplasmic reticulum through necrosis. Greater numbers of PMN leukocytes, macrophages, and activated macrophages and fewer undifferentiated mononuclear cells were seen in choroid plexuses of the drug-treated survivors. Virions and larger, more numerous arenavirus inclusions were present in choroid plexus and ependyma. Ultrastructurally the leptomeningitis was characterized by large numbers of activated macrophages. Choroidal epithelial necrosis appears to be the in vivo correlate of T-cell-mediated cytotoxicity in vitro.

Fine-structural and functional aspects of the cerebrospinal fluid-contacting subependymal cells in the anuran hypothalamus.

Cytological characteristics of the cerebrospinal fluid (CSF)-contacting subependymal cells in the frog hypothalamus were investigated to decide whether they should be classified as neurons, sensory cells or secretory (endocrine) cells. The CSF-contacting subependymal cells exhibited morphological characteristics similar to neurons or sensory cells, which are usually supplied with axo-somatic and -dendoritic synapses from other neurons and possess somato-dendritic synapses to other neurons. Furthermore, they were provided with so-called sensory cilia. The CSF-contacting subependymal cells also exhibited several cytological secretory cell characteristics: the presence of numerous secretory granules, well-developed granular endoplasmic reticulum and Golgi apparatus in the perikaryon as well as intraventricular processes, and some figures which may be regarded as microapocrine or diacrine secretions of the secretory granules. Furthermore, the CSF-contacting subependymal cells probably sent basal cell processes to the area around the blood vessels in the neurohypophysis and, perhaps, in the infundibulum. It seemed likely that CSF-contacting subependymal cells had two or three functions of a paraneuronic nature. They were sensory to chemical or physical stimuli frmones just as endocrine cells do.

Characterization of an unusual catecholamine-containing cell type in the toad hypothalamus. A correlated ultrastructural and fluorescence histochemical study.

A nucleus of catecholamine-containing cells bordering the preoptic recess of the toad hypothalamus has been studied by both fluorescence histochemical and electron microscopic methods. The perikarya of these cells form one to three rows immediately subjacent to the ependyma. They send brightly fluorescent apical processes between the ependymal cells to the ventricular surface, and also give rise to long basal processes, the proximal portions of which are also fluorescent. These cells contain two distinctive constitutents: juxtanuclear bundles of tightly packed filaments, the members of which are separated from one another by only approximately 100 A, and large numbers of dense-cored vesicles (400-2200 A in diameter), which appear to arise from an agranular tubular reticulum distinct from the Golgi apparatus. Axons containing either clear vesicles alone or clear and dense-cored vesicles form synapses on the subependymal cells, but no evidence has been found that the subependymal cells themselves form presynaptic contacts, or that axons originate from them. The cytological characteristics of these catecholamine-containing cells, plus the fact that they border directly on the cerebrospinal fluid, suggest that they may be more closely related to peripheral chromaffin cells than to the other cell types intrinsic to the central nervous system, and the name "encephalo-chromaffin cells" is therefore proposed for them. The possible functions of such cells in the central nervous system are discussed.