Morphological studies have shown that macrophages and microglia undergo
apoptosis in the central nervous system (CNS) in acute experimental
autoimmune encephalomyelitis (EAE) in the Lewis rat. To assess the relative
levels of macrophage and microglial apoptosis, and the molecular mechanisms
involved in this process, we used three-colour flow cytometry to identify
CD45lowCD11b/c+ microglial cells and CD45highCD11b/c+ macrophages in the
inflammatory cells isolated from the spinal cords of Lewis rats 13 days
after immunization with myelin basic protein (MBP) and complete Freund's
adjuvant. Simultaneously, we analyzed the DNA content of these cell
populations to assess the proportions of cells undergoing apoptosis and in
different stages of the cell cycle or examined their expression of three
apoptosis- regulating proteins, i.e. Fas (CD95), Fas ligand (FasL) and
Bcl-2. Microglia were highly vulnerable to apoptosis and were
over-represented in the apoptotic population. Macrophages were less
susceptible to apoptosis than microglia and underwent mitosis more
frequently than microglia. The different susceptibilities of microglia and
macrophages to apoptosis did not appear to be due to variations in Fas,
FasL or Bcl- 2 expression, as the proportions of microglia and macrophages
expressing these proteins were similar, and were relatively high.
Furthermore, in contrast to T cell apoptosis, apoptosis of
microglia/macrophages did not occur more frequently in cells expressing Fas
or FasL, or less frequently in cells expressing Bcl-2. These results
indicate that the apoptosis of microglia and CNS macrophages in EAE is not
mediated through the Fas pathway, and that Bcl-2 expression does not
protect them from apoptosis. Expression of FasL by macrophages and
microglia may contribute to the pathogenesis and immunoregulation of EAE
through interactions with Fas+ oligodendrocytes and Fas+ T cells. The high
level of microglial apoptosis in EAE indicates that microglial apoptosis
may be an important homeostatic mechanism for controlling the number of
microglia in the CNS following microglial activation and proliferation.
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A 67-year-old woman with lymphoma presented with a neuromyopathy following "laetrile" (amygdalin) treatment. She had significant elevation of blood and urinary thiocyanate and cyanide levels. Sural nerve biopsy specimen revealed a mixed pattern of demyelination and axonal degeneration, the latter being prominent. Gastrocnemius muscle biopsy specimen showed histochemically a mixed pattern of denervation and myopathy with Type II atrophy. It is concluded that cyanide toxicity secondary to laetrile therapy and nutritional deficiency caused the neuromyopathy, as the changes in peripheral nerve are similar to changes described in ataxic polyneuropathy occurring in Nigeria attributed to high cyanide content in the diet and nutritional deficiency. Although this patient received vincristine initially, the development of the neuromyopathy had no temporal relationship to its administration. The clinical profile, as well as peripheral nerve and muscle changes were not similar to either vincristine neuromyopathy or neuromyopathy due to paraneoplastic manifestation of lymphoma. Clinical improvement following discontinuation of "laetrile" by the patient further supports the toxic etiologic results for the neuromyopathy in this patient. 相似文献
OBJECTIVES: To study the efficacy of otoacoustic emissions (OAEs) as a screening test for hearing impairment in children with acute bacterial meningitis. Hearing tests were performed before discharge from the hospital in an attempt to improve coverage and avoid delays in the diagnosis of postmeningitic hearing loss. METHODS: Children with bacterial meningitis were recruited from 21 centers. In the 48 hours before discharge from the hospital, all patients underwent a thorough audiologic assessment consisting of transient evoked OAEs, auditory brainstem responses (ABRs), otoscopy, and tympanometry. Hearing loss was defined as ABR threshold >/=30 dB. The results of OAE screening were compared with the gold standard of ABR threshold. RESULTS: Of 124 children recruited, we were able to perform both OAEs and ABRs on 110 children. Seven (6.3%) of the 110 children had ABR threshold >/=30 dB; 2 had sensorineural hearing loss and 5 had conductive hearing loss. At follow-up, hearing loss persisted in both cases of sensorineural hearing loss and no new cases were identified. All 7 children with hearing loss failed the OAE screening test. Ninety-four children with normal hearing thresholds passed the test, and 9 failed. Thus, the screening test had a sensitivity of 1.00 (95% confidence interval, 0.59 to 1.00), a specificity of 0.91 (0.85 to 0.97), a positive predictive value of 0. 44 (0.20 to 0.70), and a negative predictive value of 1.00 (0.96 to 1.00). CONCLUSIONS: OAE screening in children recovering from meningitis was found to be feasible and effective. The test was highly sensitive and reasonably specific. Inpatient OAE screening should allow early diagnosis of postmeningitic hearing loss and prompt auditory rehabilitation. 相似文献
Iron-overload diseases frequently develop hepatocellular carcinoma. The
genotoxic mechanism whereby iron is involved in hepatocarcinogenesis might
involve an oxidative process via the intermediate production of reactive
oxygen species. This was presently investigated by examining kinetics of
formation and repair of DNA base lesions in primary rat hepatocyte cultures
supplemented with the iron chelate, ferric nitrilotriacetate Fe-NTA (10 and
100 microM). Seven DNA base oxidation products have been identified in DNA
extracts by gas chromatography- mass spectrometry, which showed a
predominance of oxidized-purines (8- oxo-guanine, xanthine, fapy-adenine,
2-oxo-adenine) above oxidized pyrimidines (5-OHMe-uracil, 5-OH-uracil,
5-OH-cytosine) in control cultures. All these DNA oxidation products
revealed a significant dose- dependent increase at 4 to 48 h after Fe-NTA
supplementation, among which fapy-adenine showed the highest increase and
5-OH-cytosine was the least prominent. Involvement of iron in this
oxidative process was established by a correlation between extent in DNA
oxidation and intracellular level of toxic low molecular weight iron. DNA
excision- repair activity was estimated by release of DNA oxidation
products in culture medium. All the seven DNA oxidation products were
detected in the medium of control cultures and showed basal repair
activity. This DNA repair activity was increased in a time- and
dose-dependent fashion with Fe-NTA. Oxidized-pyrimidines, among which was
5-OHMe-Uracil, were preferentially repaired, which explains the low levels
detected in oxidized DNA. Since oxidized bases substantially differed from
one another in terms of excision rates from cellular DNA, specific
excision- repair enzymes might be involved. Our findings, however,
demonstrate that even though DNA repair pathways were activated in
iron-loaded hepatocyte cultures, these processes were not stimulated enough
to prevent an accumulation of highly mutagenic DNA oxidative products in
genomic DNA. The resulting genotoxic effect of Fe-NTA might be relevant in
understanding the hepatocarcinogenic evolution of iron-overload diseases.
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The incidence of depressive symptoms increases during adolescence, from 10.0% to 24.5% at age 11 to 15, respectively. Experiencing
elevated levels of depressive symptoms increases the risk of a depressive disorder in adulthood. A universal school-based
depression prevention program Op Volle Kracht (OVK) was developed, based on the Penn Resiliency Program, aimed at preventing
the increase of depressive symptoms during adolescence and enhancing positive development. In this study the effectiveness
of OVK will be tested and possible mediators of program effects will be focus of study as well. 相似文献
We examined assembly and expression of the factor X activating complex on human and rabbit alveolar macrophages. Kinetic parameters of the factor X activating reaction were determined by functional titrations of factors VII and X with macrophage tissue factor (TF) added. We found rapid activation of factor X to Xa on alveolar macrophage surfaces. Detection of rapid factor Xa formation on macrophages required addition of exogenous factors VII and X. At plasma concentrations of the purified factors, factor Xa was formed on freshly isolated macrophages at approximately 5.4 pmol/min/10(6) cells. After macrophage maturation in culture for 20 hours with LPS (endotoxin) added, the factor X activation rate was increased two- to sixfold. The km' (apparent km) of TF-factor VII enzymatic complexes assembled on alveolar macrophages for factor X were (258 +/- 55 and 475 +/- 264 nmol/L for human and rabbit cells, respectively). The km' did not change during macrophage maturation in culture, but V'max (apparent Vmax) was consistently increased. The K1/2 of human factor VII (concentrations giving half maximal rates of factor X activation) for the interaction with human and rabbit alveolar macrophage TF were 0.191 +/- 0.096 and 1.7 +/- 0.7 etamol/L, respectively. The K1/2 were not significantly changed after maturation, whereas rates of Xa formation at saturation with factor VII were increased. The fast rates of factor X activation observed at physiologic concentrations of plasma-derived factors VII and X indicate that TF on alveolar macrophages is likely to provide sites for binding of factor VII and activation of factor X in vivo during clotting reactions associated with alveolar edema and inflammation. 相似文献
An amphotropic retroviral vector, LgAL(delta Mo + PyF101) containing a human adenosine deaminase (ADA) cDNA was used to optimize procedures for the lasting genetic modification of the hematopoietic system of mice. The highest number of retrovirally infected cells in the hematopoietic tissues of long-term reconstituted mice was observed after transplantation of bone marrow (BM) cells that had been cocultured in the presence of both interleukin-1 alpha (IL-1 alpha) and IL-3. A significantly lower number was detected when IL-1 alpha was omitted from such cocultures. The yield of cells that generate spleen colony-forming cells (CFU-S) in the BM of lethally irradiated recipients (MRA-CFU-S) significantly improved on inclusion of the adherent cell fraction of cocultures in the transplant. Retroviral integration patterns in MRA-CFU-S-derived spleen colonies showed that an MRA-CFU-S can produce many CFU-S during BM regeneration. Expression of hADA was detected in the circulating white blood cells of long-term reconstituted animals, demonstrating that the LgAL(delta Mo + PyF101) vector is capable of directing the sustained expression of hADA, and in approximately 35% of the transduced MRA-CFU-S-derived spleen colonies. These results should facilitate the development of gene therapy protocols for the treatment of severe combined immunodeficiency caused by a lack of functional ADA. 相似文献
Purpose: Multipurpose robots that can perform a range of useful tasks have the potential to increase the quality of life for many people living with disabilities. Owing to factors such as high system complexity, as-yet unresolved research questions and current technology limitations, there is a need for effective strategies to coordinate the development process.
Method: Integrating established methodologies based on human-centred design and universal design, a framework was formulated to coordinate the robot design process over successive iterations of prototype development.
Results: An account is given of how the framework was practically applied to the problem of developing a personal service robot. Application of the framework led to the formation of several design goals which addressed a wide range of identified user needs. The resultant prototype solution, which consisted of several component elements, succeeded in demonstrating the performance stipulated by all of the proposed metrics.
Conclusions: Application of the framework resulted in the development of a complex prototype that addressed many aspects of the functional and usability requirements of a personal service robot. Following the process led to several important insights which directly benefit the development of subsequent prototypes.
Implications for Rehabilitation
This research shows how universal design might be used to formulate usability requirements for assistive service robots.
A framework is presented that guides the process of designing service robots in a human-centred way.
Through practical application of the framework, a prototype robot system that addressed a range of identified user needs was developed.
Older patients commonly suffer from multimorbidites and take multiple medications. As a result, these patients are more vulnerable to potentially inappropriate prescribing (PIP). PIP in older patients may result in adverse drug events (ADEs) and hospitalizations. However, little has been done to identify why PIP occurs. The objectives of this study were (i) to identify hospital doctors'' perceptions as to why PIP occurs, (ii) to identify the barriers to addressing the issues identified and (iii) to determine which intervention types would be best suited to improving prescribing.
Methods
Semi-structured interviews based on the Theoretical Domains Framework (TDF), a tool used to apply behaviour change theories, were conducted with 22 hospital doctors. Content analysis was conducted to identify domains of the TDF that could be targeted to improve prescribing for older people. These domains were then mapped to the behaviour change wheel to identify possible intervention types.
Results
Content analysis identified five of the 12 domains in the TDF as relevant: (i) environmental context and resources, (ii) knowledge, (iii) skills, (iv) social influences and (v) memory/attention and decision processes. Using the behaviour change wheel, the types of interventions deemed suitable were those based on training and environmental restructuring.
Conclusion
This study shows that doctors feel there is insufficient emphasis on geriatric pharmacotherapy in their undergraduate/postgraduate training. An intervention providing supplementary training, with particular emphasis on decision processes and dealing with social influences would be justified. This study has, however, uncovered many areas for potential intervention in the future. 相似文献