Biomedical subjects

K Warfvinge

Publications and source records attributed to K Warfvinge.

At least 19 recordsLinked to original sources

PubMed2001

Retinal integration of grafts of brain-derived precursor cell lines implanted subretinally into adult, normal rats.

The ability of in vitro-expanded neural precursor cells or cell lines to differentiate following transplantation has significant implications for current research on central nervous system repair. Recently, interest has been focussed on grafts of such neural precursors implanted also into the eye or retina. Here, we demonstrate with a non-traumatizing subretinal transplantation method, that grafts of the two immortalized brain-derived cell lines C 17-2 (from postnatal mouse cerebellum) and RN33B (from the embryonic rat medullary raphe) survive for at least up to four weeks, after implantation into the adult normal rat retina. For both cell lines, implanted cells gradually integrate into all major retinal cell layers, including the retinal pigment epithelium, and judged by the morphology differentiate into both glial- and neuron-like cells, as shown by thymidine autoradiography, mouse-specific in situ hybridization, and using immunohistochemistry to detect the reporter gene LacZ. Our results suggest that these and other similar neural cell lines could be very useful in the continuous experiments in models of retinal disorders to further assess both the cell replacement and ex vivo gene therapy approaches.

Animals↗

PubMed2000

Mercury distribution in the neonatal and adult cerebellum after mercury vapor exposure of pregnant squirrel monkeys.

The objectives of the study were (1) to map the detailed localization of mercury in the monkey cerebellum after mercury vapour exposure; (2) to investigate whether there is any difference in mercury distribution between neonatal and adult cerebellum after mercury vapor exposure; (3) to investigate the ability of mercury to accumulate in the cerebellum years after the end of exposure. Pregnant squirrel monkeys were exposed 5 days/week to mercury vapor at a concentration of 0.5 mg Hg/m(3) air 4 or 7 h/day or 1 mg Hg/m(3) air for 4 or 7 h/day. Mercury concentration in the offspring and maternal brains was examined by cold vapor, flameless atomic absorption spectrophotometry. Mercury distribution was examined by processing cerebellar sections for autometallographic (AMG) silver enhancement. Mercury concentration in the offspring cerebral occipital pole ranged between 0.20 and 0.70 microg Hg/g tissue, and in the maternal between 0.80 and 2.58 microg/Hg tissue in animals killed immediately after the end of exposure. AMG revealed that the external granule cell layer of offspring cerebellar tissue contained small amounts of mercury. The molecular layer contained mercury in some of the mercury-exposed monkeys. In the Purkinje cell layer, the Bergmann glial cells together with the Purkinje cells contained mercury. The granule cells and the Golgi cells contained small amounts of mercury. The astrocytes of the medullary layer, identified by immunohistochemistry, contained considerable amounts of mercury, but the cerebellar nuclei accumulated the highest amounts of mercury. No correlation was found between cellular accumulation and maturity of the brain; that is, the cellular localization of mercury did not differ between adult and neonatal brain, except for the amount of visualized mercury. This pattern corresponded well to the mercury concentrations found in the cerebral occipital pole. The differences found in mercury accumulation were instead considered to be dose-related. The results demonstrate that the distribution of mercury in the cerebellum after mercury vapor exposure is similar to the distribution pattern obtained after methyl mercury exposure and that mercury is trapped in the cerebellum over a long period of time.

Animals↗

PubMed2000

Mercury distribution in the squirrel monkey retina after in Utero exposure to mercury vapor.

Pregnant squirrel monkeys were exposed to mercury vapor during approximately 2/3 of a pregnancy, at a concentration of 0.5 or 1 mg Hg/m(3) air for 4 or 7 h a day, 5 days a week. The offspring were sacrificed at different ages (gestational week 16 to 5 years). The eyes were enucleated and horizontal sections of the retina, comprising the optic disc and the fovea, were processed for autometallographic (AMG) silver enhancement. The AMG mercury distribution was mapped using light and epipolarization microscopy. In young offspring (16-week-old fetus to 3 days old), mercury was detected mainly in the optic nerve, retinal pigment epithelium, inner plexiform layer, vessel walls, and ganglion cells. Three and a half months later, the amount of visualized mercury had decreased in all areas except for the retinal pigment epithelium. In adult monkeys that had survived for 2 to 5 years, only a faint AMG staining was seen in the retinal pigment epithelium, the optic nerve, and in some vessel walls. In conclusion, in offspring sacrificed in utero or shortly after birth, the structures accumulating mercury were the same as those which accumulate mercury following direct exposure through the lungs, as reported previously (K. Warfvinge and A. Bruun, 1996, Toxicology 107, 189-200), although the amount of AMG staining was less in transplacental animals. This demonstrates that inorganic mercury penetrates the blood-retina barrier. In monkeys that had survived 3 to 5 years, only tiny amounts of mercury were detected, which is in contrast to findings from direct exposure, in which large amounts were still found 3 years after exposure. This may suggest that the elimination process in the retina is more efficient in young animals, but a possible adverse effect of mercury on retinal development cannot be ruled out.

Animals↗

PubMed1996

Mercury accumulation in the squirrel monkey eye after mercury vapour exposure.

Squirrel monkeys were exposed to mercury vapour at different concentrations and for different numbers of days. The calculated total mercury absorption ranged between 1.4-2.9 mg (range of daily absorption 0.02-0.04 mg). The monkeys were killed at different intervals after the end of exposure (range 1 month - 3 years) and the eyes were enucleated. Eyes from four un-exposed monkeys were used as control material. Mapping of the mercury distribution in the eye revealed that the non-myelin-containing portion of the optic disc was densely loaded with mercury deposits, which are mostly confined to the capillary walls and the glial columns. The white matter of the brain does not accumulate mercury at these exposure levels, which might suggest that the myelinization process inhibits the accumulation of mercury. The pigmented epithelium of the pars plicata of the ciliary body and of the retina contained a considerable amount of mercury. This finding indicates that mercury is trapped within the melanocytes, which keeps potentially dangerous material from reaching the neural retina. In addition, the retinal capillary walls were densely loaded with mercury deposits, even 3 years after exposure. It was also found that the inner layers of the retina accumulated mercury during a 3-year period. It is known that the biological half-time of mercury in the brain may exceed years. This seems also to be the case for the ocular tissue.

Administration, Inhalation↗

PubMed1996

Histopathological and immunocytochemical demonstration of retinal degeneration in the squirrel monkey.

Here we describe the spontaneous appearance of a retinal degeneration in two squirrel monkeys (New World monkey). Since the retinal pathology sufficiently resembles that seen in human degenerative disorder, studies of degeneration in monkeys could contribute to the prevention and treatment of the human disorder. The histopathological examination of horizontal sections comprising the optic disc and the fovea revealed photoreceptor outer and inner segments only in the central fovea. The morphology of the photoreceptors and outer nuclear layer changed rapidly away from the central fovea. There was a loss of outer segments, a shortening of inner segments and disorganized and flattened cells were found in the outer nuclear layer. AO labelling not only detected opsin in the few areas where outer segments were present, but also in the inner segments and the outer nuclear layer. The OS-2 antibody failed to stain the outer segments of the blue sensitive cones. The COS-1 antibody stained many red/green sensitive cones in the fovea, but their density decreased quickly outside this region. Thus, we have detected retinal degeneration in two outbred squirrel monkeys who were being examined for other reasons unrelated to research in retinal degeneration. One was feral and the other was only two generations removed from the feral state. The identification of retinal degeneration in a non-human primate holds great promise for the development of a treatment for human retinitis pigmentosa because access to a primate model would be of invaluable importance for studying the biochemistry behind these disorders.

Animals↗

PubMed1996

Behavioral consequences of in utero exposure to mercury vapor: alterations in lever-press durations and learning in squirrel monkeys.

Exposure to mercury vapor in utero results in the accumulation of mercury in the cerebellum, hippocampus, and other regions of the nervous system associated with motor function and learning, but little is known about the functional consequences of prenatal exposure. The offspring of pregnant squirrel monkeys exposed to 0.5 or 1.0 mg/m3 of mercury vapor during the last 2/3 or more of gestation were studied. Median maternal blood levels ranged from 0.025 to 0.18 microgram/g and exposures were estimated to range from 20 to 62 micrograms/day, with cumulative doses of 1304 to 4305 micrograms. Unexposed monkeys born at about the same time served as controls. The monkeys' lever pressing was maintained under various Concurrent Random-Interval Random-Interval schedules of reinforcement. Time allocation on each lever was examined during behavioral transitions and in steady state. No difference in sensitivity to reinforcer ratios was identified in steady state, but there was much more variability in the steady-state performance of exposed monkeys, as indicated by the standard deviation of the regression, than in controls. Logistic regression was used to examine the transition to new schedule parameters. Exposed monkeys were found to produce smaller or slower transitions than controls. The magnitude and stability of lever-press durations for controls and exposed monkeys were indistinguishable early in the experiment, but at the end the exposed monkeys had longer lever-press durations and the session-to-session variability was much greater. One monkey's exposure began during the third week of gestation (earlier than any of the others) and the behavior of this monkey was so erratic that some of the analyses could not be accomplished. Long-term effects of prenatal mercury vapor exposure included instability in lever-press durations and steady-state performance under concurrent schedules of reinforcement as well as aberrant transitions. The levels used were close to those reported in occupational settings under conditions of poor hygiene, but were at least 10- to 50-fold greater than those more commonly reported.

Administration, Inhalation↗

PubMed1995

Mercury exposure of a female dentist before pregnancy.

A 30-year-old female dentist was exposed to mercury vapour from a leaking amalgamator for approximately one year. No toxic effect was noted. During and after the exposure urine samples were regularly taken for mercury analysis. The highest value during this period was 60 micrograms Hg/l urine (expressed in micrograms/g creatinine: 42; the normal value for unexposed persons is a few micrograms/g creatinine). The mercury concentration in air was at most 840 micrograms/m3 at the amalgamator (threshold limit for occupational exposure: 50 micrograms/m3). The dentist became pregnant and during pregnancy her average urine mercury concentration was 18 micrograms/g creatinine. Ultrasound examination of the fetus at 20 weeks of gestation showed a mild bilateral hydronephrosis. At 32 weeks of gestation the hydronephrosis had resolved. The dentist gave birth to a normal-weight baby boy, who, at the time of writing, is 2 years of age and appears clinically healthy.

Adult↗

PubMed1995

Systemic autoimmunity due to mercury vapor exposure in genetically susceptible mice: dose-response studies.

Six groups of genetically mercury-susceptible female SJL/N (H-2s) mice were exposed to mercury vapor at a concentration of 0.3-1.0 mg Hg/m3 air for 0.5-19 hr/day 5 days a week for 10 weeks. The absorbed doses were calculated to be between 75 and 2365 micrograms Hg/week/kg body wt (micrograms Hg/week/kg). The correlation between the dose and the concentration of Hg in kidney, spleen, and thymus was highly significant (p < 0.0001; Spearman's rank correlation test). The lowest observed adverse effect level (LOAEL) for serum IgG antinucleolar antibodies (ANoA) was 170 micrograms Hg/week/kg, corresponding to a renal mercury concentration of 4.0 +/- 0.76 micrograms Hg/g wet wt. The correlation between the absorbed dose and the ANoA titer was highly significant (p < 0.0001; Spearman's rank correlation test), and all mice were ANoA-positive at a dose of 480 micrograms Hg/week/kg. High-titer ANoA targeted the nucleolar 34-kDa protein fibrillarin. The LOAEL for B-cell stimulation, measured as an increase in serum IgG2a and IgG1 concentrations, was 360 micrograms Hg/week/kg, but the increase was fivefold higher and also included IgE at a dose of 690 and 2365 micrograms Hg/week/kg. The serum Ig concentrations peaked after 2-4 weeks and then slowly declined but, except for IgE, remained significantly increased during the entire exposure time. Glomerular, mesangial IgG immune complex (IC) deposits, accompanied by systemic vessel wall IC deposits, were first detected at a dose of 480 micrograms Hg/week/kg. The mesangium also showed increased titers of IgM IC deposits and complement factor C3c. The correlation between the absorbed dose, and the individual titer of IgG, IgM, and C3c, was highly significant (p < 0.0001; Spearman's rank correlation test). In conclusion, mercury vapor efficiently induced an autoimmune syndrome in genetically susceptible mice, and the LOAEL for the adverse effects varied in the order ANoA < B-cell stimulation < IC deposits. Comparing the body burden of mercury in mice at the LOAEL for autoantibodies with the body burden in populations of occupationally exposed humans suggests that the safety margin may be narrow for genetically susceptible individuals.

Administration, Inhalation↗

PubMed1995

Single cilia in human epidermis are susceptible to challenge.

Single cilia were found in melanocytes and basal keratinocytes in normal epidermis and in epidermis subjected to various types of exposure. Quantitative electron microscopy showed that about 31% of the melanocytes and 71% of the keratinocytes from normal skin possessed a ciliary apparatus, but there was a wide individual variation. A statistically significant decrease in the number of ciliated keratinocytes followed exposure to nickel, sodium lauryl sulphate, UVA and UVB irradiation. There was no statistically significant difference between controls and skin subjected to various exposures regarding the number of ciliated melanocytes. We have earlier reported that single cilia are frequently seen on epithelial cells capable of mitotic activity in human oral and vaginal epithelia. The present study showed that single cilia react to external exposures. The cilium might be a sensitive, easily damaged organelle, or the decrease in ciliated cells might reflect a change in normal mitotic activity as a result of exposure.

Cilia↗

PubMed1995

Mercury distribution in the mouse brain after mercury vapour exposure.

Female SJL/N mice were exposed to mercury vapour 5 days/week for 10 weeks, at a mercury concentration of approximately 0.5 mg/m3, 19 h/day; 1 mg/m3, 3 h/day; 0.3 mg/m3, 6 h/day or 1 mg/m3, 1.5 h/day. The total mercury concentrations in the brain were 6.4, 6.3, 1.6 and 0.64 micrograms/g tissue, respectively. The mercury distribution in the brains was examined. Mercury was found in almost the whole brain in the two groups with the highest exposure. In the third group, mercury was primarily found in the neocortical layer V, the white matter, thalamus, and the brain-stem. In the fourth group, the white matter and the brain-stem were the targets for mercury accumulation. Similarities and differences between rats and mice in the distribution pattern are discussed.

Animals↗

PubMed1994

Mercury distribution in cortical areas and fiber systems of the neonatal and maternal adult cerebrum after exposure of pregnant squirrel monkeys to mercury vapor.

Pregnant squirrel monkeys were exposed 5 days/week to mercury vapor at a concentration of 0.5 mg Hg/m3 air for 7 hr/day, or at 1 mg Hg/m3 air for 4 or 7 hr/day. The calculated total mercury absorption ranged between 0.8 and 5.4 mg (range of daily absorption 0.04-0.07 mg). The mercury concentration in the cerebral occipital lobe of the offspring ranged between 0.20 and 0.70 microgram/g tissue, and in the mothers between 0.8 and 2.58 micrograms/g tissue. Mapping of the distribution of mercury in the neocortical layers of the maternal brains revealed that the pyramidal cells contained more visualized mercury than the other neurons. In addition, the mapping disclosed that the deeper the pyramidal cells were situated the more mercury they contained. In the offspring brains, no laminar distribution pattern was found. In the hippocampal formation, the pyramidal cells again contained more mercury than the other neurons. By contrast, the stratum granulosa of the dentate gyrus was always devoid of visualized mercury. The claustrum and the amygdaloid complex always contained mercury. In the fiber systems, the offspring brains contained more mercury than the adult brains. Mercury was found in both glial cells and neurons both in the cortical areas and in the fiber systems.

Air Pollutants↗

PubMed1994

Histochemical visualization of mercury in the oral mucosa, salivary and lacrimal glands of BN rats with HgCl2-induced autoimmunity.

BN, but not LEW, rats treated with subcutaneous injections of mercuric chloride (HgCl2) develop an autoimmune syndrome with infiltration of mononuclear cells into various organs including the oral mucosa. In the present study, we have utilized autometallographic techniques to visualize mercury in the oral mucosa, salivary and lacrimal glands of mercury-sensitive BN and -non-sensitive LEW rats injected with HgCl2. Mercury was deposited intracellularly in dendritic cells that were scattered throughout the lamina propria and submucosal connective tissue of both rat strains. In addition, mercury was detected in dendritic cells appearing within small cell clusters in the juxtaepithelial connective tissue of BN oral mucosa. In salivary and lacrimal glands, mercury was found in dendritic cells scattered throughout the stroma as well as in mononuclear cell foci. Mercury was also found in ductal epithelium. No staining was seen in any of the non-mercury-treated controls. Phenotypic analysis revealed that most mercury-laden cells were ED2+ resident macrophages and that some, but not all, of these cells expressed MHC class II antigens (RT1B).

Animals↗

PubMed1992

Mercury distribution in the rat brain after mercury vapor exposure.

Brown Norwegian rats were exposed to mercury vapor at a concentration of approximately 1 mg/m3 for 5 weeks 24 hr/day 7 days a week and 6 hr/day 3 days a week, respectively. The total mercury absorption was calculated to 264 and 35 micrograms per week and 100 g body weight. The mean blood mercury concentration was 0.25 +/- 0.03 and 0.09 +/- 0.01 microgram/g, and the total concentration in the brain was 5.03 +/- 0.73 and 0.71 +/- 0.10 microgram/g tissue, respectively. The mercury distribution in the brains was examined using a method based on chemographic principles. Mercury was found primarily in the neocortex, in the basal nuclei, and in the cerebellar Purkinje cells. This distribution pattern corresponded to the pattern of inorganic mercury described after exposure to methyl mercury. Distribution of mercury after administration of different mercury compounds is discussed.

Administration, Inhalation↗

PubMed1991

Functionally different Langerhans' cells in human epidermis.

Experiments comparing the L-dopa histofluorescence method for the visualization of epidermal Langerhans' cells and immunocytochemical labelling with monoclonal anti-T6 antibodies have demonstrated the existence of two functionally different human Langerhans' cells: those that take up L-dopa by a mediated transport and those that lack the capacity to take up L-dopa.

Biological Transport↗

PubMed1990

Attachment and detachment of human epidermal melanocytes.

Human epidermal melanocytes can leave their basal position following topical application of sodium lauryl sulphate. They thereby undergo changes which strongly indicate that the dense plates along their cytomembrane constitute a mechanism for attachment to the basal lamina. These detached melanocytes move rapidly to, or are transported to, more superficial levels of the living epidermis. They are probably not desquamated, but disintegrate within the stratum spinosum. It was remarkable that one melanocyte was found that broke the basal lamina, showing that melanocytes are capable of migrating, under certain conditions. A special fixation method which exposes the cytomembranes and allows the demarcation of cells and their finest cytomembrane protrusions was used to demonstrate that keratinocytes often bulge into the innermost spinous layer and become attached to the basal lamina only via more or less thin cytoplasmic protrusions. This is in contrast to the routine textbook description of a basal layer that consists of a strict single row of cuboid or columnar keratinocytes.

Administration, Cutaneous↗

PubMed1989

The human gingival indeterminate cell revisited.

Electron microscopic examination of over 100 dendritic cells in human keratinized gingiva has shown that the indeterminate cells are not a separate cell type. This approach disclosed the sources of error which have led to the commonly held, but erroneous, view that there exist numerous indeterminate cells in this epithelium. Two interesting differences were found between gingival and epidermal Langerhans cells. The number of Birbeck granules in the former cells can be extremely low while they occur frequently in the epidermal cells, and granules in their formative stage are commonplace in the gingival cells but rare in the epidermal cells.

Cell Membrane↗

PubMed1989

Human epidermal Langerhans' cells are sensitive to rapid cooling by ethyl chloride.

Topical anesthesia with ethyl chloride spraying generates some remarkable reactive events in the human Langerhans' cell (LC) system. Many LC retract their dendrites and a considerable number move to the innermost layers of the epidermis within 15 minutes. This rapid motility supports the view that the interstices between cells in living epidermis are large. The LC cytomembrane is very susceptible to cold shock which causes the cytomembrane to superimpose upon itself forming abnormally shaped Birbeck granules. This process may consume too much of the cytomembrane to be compatible with cell survival.

Biopsy↗

PubMed1988

Single modified cilia displayed by cells of human internal stratified epithelia (oral cavity, vagina).

Serial sections of human vaginal and keratinized oral-gingival epithelia were investigated for ciliary structures. Most melanocytes of the gingival epithelium lacked cilia, whereas almost all basal keratinocytes of the deeper portion of the epithelial ridges possessed one cilium each. In the suprabasal layers of the ridges only a few keratinocytes exhibited a single cilium. In the basal layer, at the top of the connective tissue papillae, approximately every second keratinocyte displayed a single cilium. In the suprabasal layers above the ridges no ciliated keratinocytes were observed. The basal cells of the vaginal epithelium were endowed with cilia, while cilia were absent from the suprabasal cells. In the human forearm epidermis most melanocytes and keratinocytes are supplied with a single cilium; it has been suggested that they may play a role in light reception. However, the widespread occurrence of 9 + 0 cilia in epithelial cells of internal epithelia and their coincidence with the sites of renewal of keratinocytes suggests that a relationship may exist between solitary cilia and mitotic activity.

Adult↗