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PubMedDate not supplied

Intercellular junctions in the organ of Corti.

The intercellular junctions between adjacent supporting cells and between apposed hair and supporting cells in the organ of Corti of cat and human were studied. At the endolymphatic surface, the intercellular space was closed by a series of tight junctions (zonula occludens), whereas there were no tight junctions at the basilar membrane surface of the neuroepithelium. Beneath the adlumenal zonula occludens between adjacent supporting cells, a zonula adherens (intermediate junction, "desmosone") was found. Many gap junctions joined apposed supporting cells both within apposed hair and supporting cells, membrane specialization sharing the morphological characterics of both the macula adherens and zonula adherens was found. Between cells, there were short areas of parallel limiting membranes separated by a 20A intercellular space. These areas were suggestive but not characteristic of gap junctional specialization. The functional significance of the junctional specialization between cells in the organ of Corti is discussed.

Animals↗

PubMed2001

Hyper-excretion of human immunodeficiency virus type 1 RNA in saliva.

Anatomical compartments (e.g., the reproductive tract) are reservoirs of human immunodeficiency virus type-1 (HIV-1) and potential sites of residual infection in patients receiving anti-retroviral therapy (ART). Viral hyper-excretion relative to blood is a hallmark of reservoirs. To determine whether hyper-excretion can occur in the oral cavity, we compared viral loads in blood plasma and saliva of 67 adults. Salivary viral hyperexcretion was defined as a four-fold or higher viral load in saliva than in plasma. HIV-1 RNA was detected in 79% of plasma samples, in 44% of unfiltered saliva samples, in 16% of filtered saliva samples, and in 59% of saliva-derived cell pellets. Compared with non-hyper-excretors (n = 62), hyper-excretors (n = 5) had elevated levels of viral RNA in unfiltered saliva and saliva-derived cells, HIV-associated periodontal disease, gingival inflammation, and no combination ART. Morphological characterization of cell pellets identified lymphocytes as a likely HIV-1 source. These collective findings are consistent with an oral HIV-1 reservoir in selected individuals.

Adult↗

PubMed1990

Characterization of N-nitrosourea-induced tumors of the nervous system; their prospective value for studies of neurocarcinogenesis and brain tumor therapy.

Two decades of research with resorptive neurocarcinogens firmly established the high potency of methyl and ethylnitrosourea (MNU and ENU) as neurocarcinogens, particularly in rats. There are significant differences in susceptibility to these agents among species. There are also differences among age groups. Fetuses are between 50 to 100 times more susceptible than adult rats. One single iv inoculation of 20-50 mg/kg ENU into pregnant rats may produce neurogenic tumors in 100% of the offspring. The tumors produced by these compounds have been well characterized morphologically, biologically, biochemically and histochemically. Tumors produced by both compounds are mostly gliomas and neurinomas (Schwannomas), however, clear differences exist between ENU and MNU produced neoplasms. Transplacental exposure to ENU generally results in a high number of anaplastic neurinomas and mostly differentiated gliomas (astrocytomas, oligodendrogliomas or mixed gliomas). In contrast, multiple exposures of adult rats to MNU result in a moderate number of mostly differentiated neurinomas and a high number of anaplastic gliomas. Tumors usually start out as well differentiated oligodendrogliomas or astrocytomas. As they grow larger, they become more mixed and anaplastic. In contrast to spontaneous gliomas in old rats, MNU and ENU-induced astrocytomas can be readily identified with well established biomarkers such as the S100 protein and particularly GFAP (glial fibrillary acidic protein). Neurinomas are also strongly positive for S100 protein. No reliable markers exist for oligodendrogliomas. Neurogenic tumors induced by MNU or ENU, as well as derived cell lines and clones from such tumors, have been successfully used as models for neurocarcinogenesis and therapeutic screening.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2006

The nootropic and neuroprotective proline-containing dipeptide noopept restores spatial memory and increases immunoreactivity to amyloid in an Alzheimer's disease model.

The effects of the novel proline-containing nootropic and neuroprotective dipeptide, noopept (GVS-111, N-phenylacetyl-L-prolylglycine ethyl ester) were investigated in NMRI mice following olfactory bulbectomy. We have shown previously that these animals developed Alzheimer's disease (AD)-like behaviour, morphology and biochemistry including impairment of spatial memory, regional neuronal degeneration and elevated Abeta peptide brain levels. In the current investigation, spatial memory was assessed using the Morris water maze and serum antibodies to in vitro morphologically characterized amyloid structures of both Abeta((25-35)) peptide and equine lysozyme, as well as to neurotrophic glial factor S100b, were analyzed by enzyme-linked immunosorbent assay (ELISA). Noopept (administered at a dose of 0.01 mg/kg for a period of 21 days and during a further 5 days training) restored spatial memory and increased serum antibody levels to oligomers of Abeta((25-35)) peptide but not to equine lysozyme amyloid or S100b protein in bulbectomized animals. The positive immunotropic effect of noopept to Abeta((25-35)) peptide prefibrillar aggregates was more marked in sham-operated compared to the bulbectomized subjects which were characterized by an overall suppression of immunoreactivity. Enhancement of the immune response to Abeta((25-35)) peptide prefibrils caused by noopept may attenuate the neurotoxic consequences of amyloid fibrillization and also be associated with an improvement in spatial memory in bulbectomized mice. These actions of noopept, combined with its previously reported neuroprotective and cholinomimetic properties, suggests that this dipeptide may well be useful for improving cognitive deficits induced by neurodegenerative diseases.

Alzheimer Disease↗

PubMed1982

Mammary tumors in BALB/cfC3H and BALB/cfRIII virgin female mice bearing hypophyseal isografts.

The behavior and morphology of mouse mammary tumors in high cancer strain mice are controlled by the causative murine mammary tumor viruses (MuMTV). However, relationships also exist between mammary tumors and other factors such as host genotype, other etiologic agents (chemicals, X-rays), and hormones. Among the latter, prolactin has been particularly studied. The aim of this investigation was to test whether the mammary tumor morphology controlled by C3H and RIII MuMTVs is in any way influenced by continuous prolactin secretion. A total of 28 BALB/cfC3H and 24 BALB/cfRIII virgin female mice was implanted with 2 hypophyseal isografts under the kidney capsule. Mice were of the same BALB/c genotype and carried respectively C3H and RIII MuMTV infection. The biologic and morphologic characterization of the tumors observed showed that several differences previously reported between mammary tumors in breeding female mice of the 2 strains persisted in virgins bearing hypophyseal isografts. These data confirm that the mammary tumor characters in high cancer strain mice are mainly carried out and controlled by the causative MuMTVs but also suggest that different MuMTVs may show different sensitivity to continuous prolactin secretion.

Animals↗

PubMed1982

Report of a case of non-Hodgkin's lymphoma of large multilobated cell type with B-cell origin.

Large multilobated nuclei lymphoma is a rare entity that is characterized morphologically by large neoplastic elements with prominent nuclear lobations and clinically by a predilection for extranodal sites and a favorable prognosis. According to the data collected to date, the neoplasia is thought to be of T-cell origin. The authors describe the clinical, morphologic and immunohistochemical findings of a case of non-Hodgkin's lymphoma with large multilobated nuclei that showed a definite B-lymphocyte origin.

Aged↗

PubMed2001

Biovularity and "coalescence of primary follicles" in ovaries with mature teratomas.

Several theories have been postulated regarding the origin of ovarian teratomas, including incomplete twinning, neoplastic proliferation of sequestered totipotent blastomeres or primordial cells, derepression of totipotent genetic information in the nuclei of somatic cells, and parthenogenetic development of germ cells. At present parthenogenetic development of ova is the most widely accepted theory, primarily because of the presence of a 46 XX karyotype in almost all mature teratomas. However, some authors have raised the possibility of fusion of ova in the mechanism of formation of ovarian teratomas. We report the results of a study on ovarian tissue adjacent to 31 teratomas to assess the frequency of biovularity, which could provide evidence favoring the last theory. On the whole we found biovularity in 26 ovaries of young patients (mean age, 27 years) with variable numbers of biovular follicles ranging from 1 in 4 cases to more than 10 in 2 cases; the number of biovular follicles depended on the quantity of ovarian tissue examined as well as on the total number of ova in the tissue. In multiple occasions 2 ova were included within a single follicle; in 24 ovaries the biovularity was correlated with coalescence of primary follicles characterized morphologically by an ovoid or hourglass-like shape that resulted from cohesion of 2 follicles. As control cases, 30 ovaries of patients with an average age of 28 years were examined (12 removed for endometriosis, 8 for serous cystadenoma, 7 for tubal pregnancy, and 3 for acute salpingo-oophoritis). Only 1 ovary with endometriosis contained a single biovular follicle. The results suggest that ovarian teratoma development may result from fusion of ova in ovaries containing biovularity and phenomena of coalescence of primary follicles.

Adolescent↗

PubMed2003

A novel mechanism for imatinib mesylate-induced cell death of BCR-ABL-positive human leukemic cells: caspase-independent, necrosis-like programmed cell death mediated by serine protease activity.

Caspase-independent programmed cell death can exhibit either an apoptosis-like or a necrosis-like morphology. The ABL kinase inhibitor, imatinib mesylate, has been reported to induce apoptosis of BCR-ABL-positive cells in a caspase-dependent fashion. We investigated whether caspases alone were the mediators of imatinib mesylate-induced cell death. In contrast to previous reports, we found that a broad caspase inhibitor, zVAD-fmk, failed to prevent the death of imatinib mesylate-treated BCR-ABL-positive human leukemic cells. Moreover, zVAD-fmk-preincubated, imatinib mesylate-treated cells exhibited a necrosis-like morphology characterized by cellular pyknosis, cytoplasmic vacuolization, and the absence of nuclear signs of apoptosis. These cells manifested a loss of the mitochondrial transmembrane potential, indicating the mitochondrial involvement in this caspase-independent necrosis. We excluded the participation of several mitochondrial factors possibly involved in caspase-independent cell death such as apoptosis-inducing factor, endonuclease G, and reactive oxygen species. However, we observed the mitochondrial release of the serine protease Omi/HtrA2 into the cytosol of the cells treated with imatinib mesylate or zVAD-fmk plus imatinib mesylate. Furthermore, serine protease inhibitors prevented the caspase-independent necrosis. Taken together, our results suggest that imatinib mesylate induces a caspase-independent, necrosis-like programmed cell death mediated by the serine protease activity of Omi/HtrA2.

Amino Acid Chloromethyl Ketones↗

PubMed2005

A refined in vitro model to study inflammatory responses in organotypic membrane culture of postnatal rat hippocampal slices.

BACKGROUND: Propagated tissue degeneration, especially during aging, has been shown to be enhanced through potentiation of innate immune responses. Neurodegenerative diseases and a wide variety of inflammatory conditions are linked together and several anti-inflammatory compounds considered as having therapeutic potential for example in Alzheimer's disease (AD). In vitro brain slice techniques have been widely used to unravel the complexity of neuroinflammation, but rarely, has the power of the model itself been reported. Our aim was to gain a more detailed insight and understanding of the behaviour of hippocampus tissue slices in serum-free, interface culture per se and after exposure to different pro- and anti-inflammatory compounds. METHODS: The responses of the slices to pro- and anti-inflammatory stimuli were monitored at various time points by measuring the leakage of lactate dehydrogenase (LDH) and the release of cytokines interleukin 6 (IL-6) and tumour necrosis factor alpha (TNF-alpha) and nitric oxide (NO) from the culture media. Histological methods were applied to reveal the morphological status after exposure to stimuli and during the time course of the culture period. Statistical power analysis were made with nQuery Advisor, version 5.0, (Statistical Solutions, Saugus, MA) computer program for Wilcoxon (Mann-Whitney) rank-sum test. RESULTS: By using the interface membrane culture technique, the hippocampal slices largely recover from the trauma caused by cutting after 4-5 days in vitro. Furthermore, the cultures remain stable and retain their responsiveness to inflammatory stimuli for at least 3 weeks. During this time period, cultures are susceptible to modification by inflammatory stimuli as assessed by quantitative biochemical assays and morphological characterizations. CONCLUSION: The present report outlines the techniques for studying immune responses using a serum-free slice culture model. Statistically powerful data under controlled culture conditions and with ethically justified use of animals can be obtained as soon as after 4-5 DIV. The model is most probably suitable also for studies of chronic inflammation.

Journal Article↗

PubMed2002

Class A scavenger receptors mediate cell adhesion via activation of G(i/o) and formation of focal adhesion complexes.

Class A macrophage scavenger receptors (SR-A) are multifunctional receptors with roles in modified lipoprotein uptake, innate immunity, and macrophage adhesion. Our previous studies conducted in mouse peritoneal macrophages demonstrated that pertussis toxin (PTX) mediated inhibition of G(i/o) attenuated SR-A-dependent uptake of modified lipoprotein. The finding that SR-A-mediated lipoprotein internalization was PTX-sensitive led us to hypothesize that SR-A-mediated cell adhesion might be similarly regulated by G(i/o)-dependent signaling pathways. To test this hypothesis, SR-A was expressed in HEK cells under inducible control. Relative to HEK cells that lack SR-A, SR-A expressing cells displayed enhanced adhesion to tissue culture dishes. SR-A-mediated adhesion was significantly reduced following PTX treatment and was insensitive to chelating divalent cations with EDTA. SR-A-expressing cells exhibited a distinct cell morphology characterized by fine filopodia-like projections. Both polymerized actin and vinculin were codistributed with SR-A in the filopodia-like projections indicating the formation of focal adhesion complexes. Overall, our results indicate that the ability of SR-A to enhance cell adhesion involves G(i/o) activation and formation of focal adhesion complexes.

Actins↗

PubMed2006

Methamphetamine induces autophagy and apoptosis in a mesencephalic dopaminergic neuronal culture model: role of cathepsin-D in methamphetamine-induced apoptotic cell death.

Autophagy is a phylogenetically conserved process that plays a critical role in the degradation of oxidatively damaged proteins and organelle turnover. The role of oxidative stress and apoptosis in methamphetamine (METH)-induced neurotoxicity is well known; however, the potential contribution of autophagy to METH-induced oxidative damage in dopaminergic neuronal systems remains unclear. The goals of the present article were twofold: (a) to develop an in vitro dopaminergic cell culture model to study cellular and molecular mechanisms underlying METH-induced autophagy and apoptosis, and (b) to determine whether lysosomal protease cathepsin-D activation, resulting from the loss of lysosomal membrane integrity, contributes to METH-induced apoptosis. To accomplish these goals, we characterized morphological and biochemical changes in an immortalized mesencephalic dopaminergic neuronal cell line (N27 cells) following treatment with METH. Exposure of METH (2 mM) to N27 cells resulted in the appearance of cytoplasmic vacuolar structures reminiscent of autophagic vacuoles within 3 h. In order to ascertain the identity of the vacuolar structures that are formed following METH exposure, immunohistochemical staining for markers of autophagy were performed. LAMP 2, a classical marker of autophagolysosomes, revealed an extensive punctuate pattern of distribution on the vacuolar membrane surface, with exclusive localization in the cytoplasm. Additionally, using DNA fragmentation analysis we showed a dose-dependent increase in fragmented DNA in METH treated N27 cells. Since METH-induced autophagy preceded DNA fragmentation, we tested whether dysfunction of the autophagolysosomal system contributes to nuclear damage. Immunofluorescence studies with cathepsin-d demonstrated a granular pattern of staining in untreated cells, whereas an increased cathepsin- D immunoreactivity with a globular pattern of staining was observed in METH-treated cells. Nevertheless, blockade of cathepsin-D activation by pepstatin-A, cathepsin-D inhibitor, failed to alter METH-induced DNA fragmentation. Collectively, these results demonstrate that N27 dopaminergic neuronal cell model may serve as an excellent in vitro model to study the mechanisms of METH-induced autophagy and apoptosis. Furthermore, it is less likely that cathepsin-D may serve as a trigger for the induction of apoptosis subsequent to exposure of N27 dopaminergic neuronal cells to METH.

Animals↗

PubMed2003

Management of simple nodular goiter: current status and future perspectives.

The simple nodular goiter, the etiology of which is multifactorial, encompasses the spectrum from the incidental asymptomatic small solitary nodule to the large intrathoracic goiter, causing pressure symptoms as well as cosmetic complaints. Its management is still the cause of considerable controversy. The mainstay in the diagnostic evaluation is related to functional and morphological characterization with serum TSH and (some kind of) imaging. Because malignancy is just as common in patients with a multinodular goiter as patients with a solitary nodule, we support the increasing use of fine-needle aspiration biopsy (cytology). Most patients need no treatment after malignancy is ruled out. In case of cosmetic or pressure symptoms, the choice in multinodular goiter stands between surgery, which is still the first choice, and radioiodine if uptake is adequate. In addition to surgery, the solitary nodule, whether hot or cold, can be treated with percutaneous ethanol injection therapy. If hot, radioiodine is the therapy of choice. Randomized studies are scarce, and the side effects of nonsurgical therapy are coming into focus. Therefore, the use of the optimum option in the individual patient cannot at present be based on evidence. However, we are of the view that levothyroxine, although widely used, should no longer be recommended routinely for this condition. Within a few years, the introduction of recombinant human TSH and laser therapy may profoundly alter the nonsurgical treatment of simple nodular goiter.

Biopsy, Needle↗

PubMed1995

Membrane-anchored expression of transforming growth factor-alpha in human pituitary adenoma cells.

Growth factors induce cell proliferation and are implicated in the multistep process of tumorigenesis. Transforming growth factor-alpha (TGF alpha), a peptide that binds to the epidermal growth factor receptor, is expressed by carcinomas and normal tissues. To investigate the possible role of TGF alpha in adenohypophysial tumorigenesis, we studied its expression in nontumorous human pituitary and different clinically and morphologically characterized human pituitary adenomas. Ribonucleic acid was reverse transcribed and amplified by polymerase chain reaction; transcript signals were identified with marked variation in 14 of 15 adenomas, and a weak signal was detected in nontumorous pituitary. Immunohistochemical positivity was found with variable intensity in all adenoma types, but not all tumors. Ultrastructural immunogold localized TGF alpha in endoplasmic reticulum, in Golgi apparatus, and on cell membranes; surface localization was confirmed by immunofluorescence. To assess possible secretion, the reverse hemolytic plaque assay was performed; small plaques were identified using an antibody that recognizes the extracellular domain of pro-TGF alpha; however, the plaques did not increase in size with time, suggesting that they detected membrane-anchored TGF alpha. Moreover, TGF alpha was undetectable by enzyme-linked immunosorbent assay in pituitary tumor-conditioned culture media. The marked variable expression of TGF alpha, the absence of secretion in measurable quantities, and the preferential membrane localization suggest a specific juxtacrine mechanism for TGF alpha in pituitary tumorigenesis.

Adenoma↗

PubMed1996

Epidermal growth factor and its receptor (EGF-R) in human pituitary adenomas: EGF-R correlates with tumor aggressiveness.

Epidermal growth factor (EGF) has been localized in several human neoplasms and has been shown to have a significant correlation to prognosis. We investigated the potential role of the EGF receptor (EGF-R) system in pituitary tumorigenesis by examining the expression of EGF and EGF-R in the different types of human pituitary adenomas. EGF was identified by immunohistochemistry in all cell types of the nontumorous adenohypophysis and in all types of morphologically characterized functional (n = 9) and nonfunctional (n = 17) adenomas. To confirm local EGF synthesis, ribonucleic acid (RNA) from human pituitary adenomas was reverse transcribed and PCR amplified. Transcript signals of the expected size were identified, with marked variation in 41 of 48 adenomas. To assess possible secretion in vitro, EGF was measured in pituitary tumor culture medium. No measurable quantities of EGF were present in conditioned culture medium from all 35 adenomas examined, consistent with the rapid uptake of EGF by unoccupied functional EGF-R sites. Using a specific monoclonal antibody that recognizes the extracellular ligand-binding domain of the human EGF-R, we found EGF-R in cells in the normal pituitary and in some functional and nonfunctional adenomas with extremely variable intensity. By RT-PCR, EGF-R messenger RNA (mRNA) expression was also identified, with marked variation in all 48 adenomas examined and in the nontumorous pituitary. The highest degrees of EGF-R mRNA expression were present in somatotroph adenomas and the aggressive silent subtype 3 adenomas. Tumors from patients with recurrent acromegaly demonstrated significantly higher levels of EGF-R mRNA than those from patients with nonrecurrent disease. In conclusion, EGF and EGF-R are expressed in a variable manner in all types of human pituitary adenomas. The overexpression of EGF-R in recurrent somatotroph adenomas and aggressive silent subtype 3 adenomas suggests a selective mechanism for the EGF/EGF-R family in the growth of aggressive pituitary tumors.

Adenoma↗

PubMed1998

The MEN-1 gene is rarely down-regulated in pituitary adenomas.

The gene for multiple endocrine neoplasia type 1 (MEN-1) has recently been cloned and encodes a putative tumor suppressor protein named menin. We have previously reported inactivating MEN-1 gene mutations associated with loss of heterozygosity (LOH) of the normal allele in tumors of patients with MEN-1 and in some sporadic pituitary tumors. These genetic alterations, however, are noted in no more than 10% of sporadic adenomas. To investigate whether other mechanisms may result in down-regulation of menin gene expression in pituitary adenomas, we examined menin gene expression by semiquantitative RT-PCR in 60 sporadic pituitary adenomas. Ribonucleic acid (RNA) was extracted from surgically resected, morphologically characterized tumors. Primers were designed to amplify a 257-bp fragment spanning exons 4-6 of the MEN-1 gene. A product of the predicted size was amplified from normal pituitary samples as well as from adenomas. Competitive PCR was performed with the housekeeping gene PGK-1 to quantitate menin gene expression. A comparable ratio of menin/PGK-1 messenger RNA was identified in all but three samples; in two tumors with LOH, menin expression was weak, and in one tumor, menin messenger RNA was undetectable, associated with LOH and mutation of the other allele. Reduced expression of menin in some sporadic adenomas is consistent with a putative tumor suppressor role for this gene product. However, lack of menin down-regulation in the majority of these tumors, which exhibit LOH at 11q13 in up to 20% of cases, provides compelling evidence for an additional tumor suppressor gene at this locus, which is more commonly involved in the pathogenesis of pituitary neoplasms.

Adenoma↗

PubMed2000

The muscle mitogen-activated protein kinase is altered in sporadic inclusion body myositis.

OBJECTIVE: To examine the origin of hyperphosphorylated proteins within the vacuolated myofibers in sporadic inclusion body myositis (s-IBM) and search for dysregulated intracellular protein phosphorylation. BACKGROUND: s-IBM is morphologically characterized by primary endomysial inflammation and vacuolated myofibers containing tubulofilaments that originate from cytoskeletal proteins. Mitogen-activated protein kinases (MAPKs) play a role in regulating phosphorylation and maintaining the stability of the cytoskeletal architecture. METHODS: Muscle biopsies from seven patients with s-IBM and 15 controls were examined for the expression of the active components of the various MAPKs, including p44/42MAPK, p38MAPK, p46JNK1, p54JNK2, and p54JNK3, using immunocytochemistry and Western blot analysis. The expression of selected phosphorylated components was also examined in the same specimens. RESULTS: In s-IBM, but not the disease controls, the vacuolated muscle fibers express active p42MAPK but not JNK or p38MAPK. Western blots of cell lysates confirmed the hyperexpression of p42MAPK and demonstrated a novel 35 kD phosphoprotein. Antibodies against phosphoepitopes of the 35 kD protein preferentially immunostained antigens within the vacuolated muscle fibers of s-IBM but not disease controls. CONCLUSION: In s-IBM, there is increased p42MAPK activation and abnormal intracellular protein phosphorylation with selective accumulation of a 35 kD phosphoprotein within the vacuolated fibers. Although the hyperexpression of 35kD protein may represent cytoskeletal by-products due to heightened p42MAPK activation, its abundant expression only in s-IBM implies that hyperphosphorylated myofibrillar proteins may be involved in the primary disease process.

Aged↗

PubMed1986

Inflammatory lesions of the basal ganglia and thalamus: review of twenty-one cases.

We report a series of 21 patients with basal ganglia and thalamic granulomas or abscesses treated over 7 years. Among them, 15 were tubercular, 5 were pyogenic, and 1 was fungal. Pyogenic abscesses, usually hematogenous, also occurred secondary to osteomyelitis of the skull and chronic otitis media. The fungal abscess developed in a nonimmunocompromised patient with no intercurrent malignancy. Evidence of tuberculosis elsewhere in the body was detected in only 7 patients with tuberculomas. The computed tomographic (CT) image morphology characterizing an abscess or a tuberculoma was present in all except 2 patients with tuberculomas. The fungal abscess resembled a malignant glioma. The only hospital mortality occurred in a deeply unconscious patient with a thalamic pyogenic abscess. A 12-month or longer follow-up in 16 patients showed that 3 continued to be handicapped neurologically, and 2 died 13 and 16 months later, respectively. We conclude that inflammatory lesions at these sites are not uncommon and that CT scans are diagnostic in the great majority. Doubtful diagnosis merits stereotactic aspiration or biopsy of the lesion. Satisfactory results follow adequate medical therapy.

Adolescent↗

PubMed2005

The apoptosis/autophagy paradox: autophagic vacuolization before apoptotic death.

Autophagic cell death is morphologically characterized by an accumulation of autophagic vacuoles. Here, we show that inactivation of LAMP2 by RNA interference or by homologous recombination leads to autophagic vacuolization in nutrient-depleted cells. Cells that lack LAMP2 expression showed an enhanced accumulation of vacuoles carrying the marker LC3, yet a decreased colocalization of LC3 and lysosomes, suggesting that the fusion between autophagic vacuoles and lysosomes was inhibited. While a fraction of mitochondria from starved LAMP2-expressing cells colocalized with lysosomal markers, within autophagolysosomes, no such colocalization was found on removal of LAMP2 from the experimental system. Of note, LAMP1 depletion had no such effects and did not aggravate the phenotype induced by LAMP2-specific small interfering RNA. Serum and amino acid-starved LAMP2-negative cells exhibited an accumulation of autophagic vacuoles and then succumbed to cell death with hallmarks of apoptosis such as loss of the mitochondrial transmembrane potential, caspase activation and chromatin condensation. While caspase inhibition retarded cell death, it had no protective effect on mitochondria. Stabilization of mitochondria by overexpression of Bcl-2 or the mitochondrion-targeted cytomegalovirus protein vMIA, however, blocked all signs of apoptosis. Neither caspase inhibition nor mitochondrial stabilization antagonized autophagic vacuolization in LAMP2-deficient cells. Altogether, these data indicate that accumulation of autophagic vacuoles can precede apoptotic cell death. These findings argue against the clear-cut distinction between type 1 (apoptotic) and type 2 (autophagic) cell death.

Apoptosis↗