Development of microglia in the prenatal rat hippocampus

The distribution and appearance of microglial cell precursors in the prenatal hippocampus were examined in embryonic day 14 (E14) to E21 rats by nucleoside diphosphatase histochemistry. For comparison, the differentiation of astroglial cells was analyzed from E17 by vimentin and glial fibrillary acidic protein immunohistochemistry. Based on morphologic features, nucleoside diphosphatase-positive microglial cell precursors were classified as ameboid microglial cells and primitive ramified microglial cells. Ameboid microglia were present in the hippocampal primordium on E14. As the hippocampus developed, however, ameboid microglia gradually transformed into primitive ramified microglia, first recognized at E19. Microglial cell precursors, often related to nucleoside diphosphatase-labeled blood vessels, were particularly observed next to the pial surface on days E14 and E17 and in the highly vascularized area around the hippocampal fissure from E19. Within the brain parenchyma, the microglial cell precursors tended to be located within the differentiating cell and neuropil layers rather than in the germinative zones. The late developing dentate gyrus remained almost devoid of microglial cell precursors before birth. Vimentin-positive astroglial processes with radial orientation were observed throughout the hippocampal subregions from E17. In contrast, glial fibrillary acidic protein-positive, radial processes were barely discernible in the fimbria and the dentate gyrus before E19. The results are discussed in relation to the possible interactive role of microglial cells in central nervous tissue development and histogenesis. Regarding the origin of hippocampal microglial cell precursors, the present observations support the view that these cells may well originate from different mesodermal sources depending on time and localization. J. Comp. Neurol. 377:70-84, 1997. © 1997 Wiley-Liss, Inc.     

Differential Responses of Human Mononuclear Phagocytes to Mycobacterial Lipoarabinomannans: Role of CD14 and the Mannose Receptor

CD14 is a signaling receptor for both gram-negative bacterial lipopolysaccharide (LPS) and mycobacterial lipoarabinomannan (LAM) that lacks terminal mannosyl units (AraLAM). In contrast, terminally mannosylated LAM (ManLAM) binds the macrophage mannose receptor (MMRc), although the ability of the MMRc to serve as a signaling receptor has not been previously reported. We compared the abilities of AraLAM and ManLAM to induce distinct responses in two monocytic cell populations, freshly isolated human peripheral blood monocytes (PBM) and monocyte-derived macrophages (MDM). The responses examined were chemotaxis and transient changes in free cytosolic calcium ([Ca²⁺]_in). We found that AraLAM but not ManLAM was chemotactic for both PBM and MDM. Migration of these cells in vitro to AraLAM was specifically blocked by an anti-CD14 monoclonal antibody, suggesting that CD14 mediates the chemotactic response to AraLAM. Subsequently, we found that AraLAM induced a transient rise in [Ca²⁺]_in levels within a subpopulation of PBM but not MDM. This response was blocked by anti-CD14 antibodies. In contrast, ManLAM induced a transient rise in [Ca²⁺]_in levels within a subpopulation of MDM but not PBM. This response was blocked by either anti-CD14 or anti-MMRc antibodies. These data suggest that the MMRc can serve as a signaling receptor and that coligation of both CD14 and the MMRc is required to elicit a specific response. Thus, one response to LAM (chemotaxis) can be elicited solely by engaging CD14, whereas a different response (changes in [Ca²⁺]_in levels) depends on both the differentiation state of the cells and concomitant engagement of CD14 and the MMRc.Uptake of Mycobacterium tuberculosis by mononuclear phagocytes is the first step leading to the development of tuberculosis infection. Following ingestion of the bacilli, the innate immune response against tuberculosis is predominantly directed by activated macrophages (reviewed in reference 17). The cell wall glycolipid lipoarabinomannan (LAM) is one of many mycobacterial products that can affect these immune responses. Vesicles containing LAM are released from phagosomes following macrophage ingestion of M. tuberculosis (36, 38), suggesting that transport of mycobacterial products out of infected macrophages is possible. Furthermore, the presence of anti-LAM antibodies in the sera of tuberculosis patients suggests that LAM is released from infected macrophages in vivo (29). LAM is comprised of a mannose-rich core polysaccharide, containing highly branched arabinofuranosyl side chains, linked via a phosphatidylinositol moiety at the reducing terminus to acyl groups consisting of palmitic and tuberculostearic acids. LAM isolated from pathogenic M. tuberculosis and M. bovis BCG is capped with mannose residues at the nonreducing arabinofuranosyl termini (ManLAM), whereas LAM isolated from rapidly growing avirulent mycobacteria lacks mannose caps at the arabinofuranosyl ends (AraLAM [10, 26]). The presence or absence of terminal mannose residues has been shown to affect the biological activity of LAM. For example, tumor necrosis factor (TNF) production can be induced in macrophages by purified LAM, although AraLAM is 100-fold more potent in this respect than ManLAM (11, 13). Similar results have been observed for interleukin-1 (IL-1) (41), IL-6 (13), chemokines (28, 40), and nitric oxide (28) production. In contrast, both AraLAM and ManLAM induce similar amounts of transforming growth factor β (TGF-β) production in human monocytes (13).Two potential LAM receptors have been identified on monocytic cells. Zhang and colleagues first showed that the release of IL-1β and TNF by LAM-stimulated human blood mononuclear cells could be blocked by an anti-CD14 monoclonal antibody (MAb) (40). CD14 is a 55-kDa glycosylphosphatidylinositol-linked protein expressed on the surface of monocytes, macrophages, microglial cells, and polymorphonuclear leukocytes which serves as a receptor for gram-negative bacterial lipopolysaccharide (LPS) (reviewed in reference 42). Evidence that LAM can bind directly to CD14 was provided by the demonstration that AraLAM could compete for the binding of LPS to soluble CD14 in vitro (27). A role for CD14 in the receptor-mediated uptake of nonopsonized M. tuberculosis was suggested by studies which showed that both anti-CD14 MAbs and soluble CD14 could significantly block the uptake of M. tuberculosis by human microglial cells (25). In contrast, ManLAM has been shown to function as the ligand which is most likely to mediate uptake of M. tuberculosis via the macrophage mannose receptor (MMRc) on human blood monocyte-derived macrophages (MDM) (31, 32). The MMRc is a 162-kDa glycoprotein expressed in abundance on MDM and tissue macrophages but not on freshly isolated peripheral blood monocytes (PBM) (reviewed in reference 33). A role for ManLAM in the MMRc-mediated adherence of M. tuberculosis to MDM was suggested by the finding that an anti-LAM MAb blocked the binding of M. tuberculosis to MDM by up to 49% (31). A subsequent study revealed that differences in the ability of LAM from different strains of M. tuberculosis to mediate adherence to macrophages and to serve as ligands for the MMRc are not solely determined by the presence of terminal mannosyl units (32).In this study, we compared the capacity of AraLAM and ManLAM to regulate different monocytic cell functions in vitro. We found that purified AraLAM, but not ManLAM, could induce a chemotactic response in human PBM and MDM. Antibody blocking and inhibitor data suggest that CD14 serves as a signaling receptor for AraLAM. This chemotactic response is distinct from the abilities of ManLAM and AraLAM to differentially induce a transient rise in free cytosolic calcium levels in the two cell populations. The capacity of PBM to generate a calcium response upon exposure to AraLAM appears to involve CD14, whereas the capacity of MDM to generate a calcium response following exposure to ManLAM requires engagement of both CD14 and the MMRc. Lastly, exposure of MDM to either AraLAM or ManLAM resulted in the selective down-regulation of the function of complement receptor CR3, although LAM treatment did not affect the level of surface CR3 expression.     

Self-assessment of tuberculosis infection risk by urban adolescents

OBJECTIVE: To examine self-reported risks for tuberculosis (TB) infection relative to recalled receipt of TB risk assessments and skin testing in a cohort of urban adolescents. DESIGN, SETTING, AND PARTICIPANTS: Survey of ninth graders and their parents from 3 inner-city public high schools. Students and parents were asked about TB infection risk factors, frequency of routine health maintenance visits, TB risk assessments, and TB skin testing. Students were surveyed in schools and asked to take home surveys for their parents to complete. RESULTS: Of 578 students (95.4% response rate), 436 (75.4%) claimed at least 1 TB infection risk factor. Although 468 (81.0%) of the students reported having a regular checkup within the past year, only 128 (22.1%) recalled being asked TB risk assessment questions and only 231 (40.0%) recalled undergoing skin testing during the previous year. Parent response rates were low (n = 207; 34.2% response rate), and parents of students attending bilingual classes were overrepresented among responders. There were no significant relationships between self-indicating a risk for TB infection and self-recollection of having undergone TB screening, having had a tuberculin skin test placed, or having had a regular checkup, with the exception that students who responded that they lived with a tuberculin skin test-positive person were 38% less likely to recall having had a tuberculin skin test themselves (n = 21; 95% confidence interval, 24%-50%). The level of agreement between student and parent responses in the 207 survey pairs available for analysis ranged from poor to good (kappa = 0.07-0.61) on individual questions. CONCLUSIONS: These observations suggest that most at-risk adolescents in this city are not being adequately screened for TB infection. Programs to improve health care provider acceptance of targeted testing principles or to reengage in school-based screening of students with certain risk factors seem necessary.     

Dyskinesia associated with hyperglycemia and basal ganglia hyperintensity: report of a rare diabetic complication

The syndrome of dyskinesia associated with hyperglycemia and basal ganglia hyperintensity on T1 – weighted MR images is rare and most often affects elderly patients with type 2 diabetes. We report a case of a 79 year-old female patient who presented to the ED with a 12 h history of a left sided hemichoreoathetosis. Laboratory results revealed pronounced nonketotic hyperglycemia [27 mmol/L (486 mg/dL); HbA1c 140 mmol/mol (15 %)] and brain MRI showed bilateral T1 hyperintensity in the basal ganglia, more noticeable on the right side. One week before she had been admitted with a diagnosis of transient ischemic attack consisting in left hemiparesthesia, also with nonketotic hyperglycemia [38.9 mmol/L (700 mg/dL)] and was discharged home with partial correction of her metabolic disturbance. The movement disorder did not improve with adequate glycemic control so haloperidol was started. Six weeks later she was seen on an outpatient basis. She still had minimal residual involuntary movements of the left arm and leg. Laboratory exams revealed a well controlled diabetes mellitus [glycemia 6.0 mmol/L (109 mg/dL), HbA1c 57 mmol/mol (7.4 %)]. In conclusion, the syndrome of dyskinesia associated to hyperglycemia and hyperintensity in the basal ganglia on T1 – weighted MR images is a rare, intriguing and yet incompletely understood complication of diabetes mellitus. The increasing number of reported cases may help to better understand its peculiarities such as the existence of a clear clinical radiological dissociation and to unveil pathophysiological aspects. We suggest the possibility that the metabolic disturbances unmask a previous established asymptomatic striatum vasculopathy.     

Adolescent Coping Across Time: Implications for Psychiatric Mental Health Nurses

This article compares rural adolescents' coping responses before and after the behavioral intervention Teaching Kids to Cope with Anger (TKC-A). A quasi-experimental design was used, that included 94 (intervention) and 85 (control) students who were enrolled in three high schools in rural southwestern Pennsylvania. Results showed no statistically significant differences between the intervention and control groups' coping responses following the TKC- A intervention. The majority of youth in this study demonstrated healthy coping skills. In the future, the TKC-A needs to be integrated into the high school curriculum as a health promotion effort that is tailored to adolescents.     

Plasmapheresis in Diffuse Alveolar Hemorrhage as Perinuclear Antineutrophil Cytoplasmic Antibody-Associated Vasculitis Relapse on Hemodialysis

Unlike Goodpasture's syndrome with diffuse alveolar hemorrhage (DAH), there are scarce reports on the use of plasmapheresis for patients with a recurrence of DAH associated with antineutrophil cytoplasmic antibody (ANCA)-associated small vessel vasculitis (AAV) on hemodialysis. We report a case of a relapse of perinuclear-AAV with DAH, five months after starting hemodialysis. The patient received apheresis and induction immunosuppressive therapy, added to a short course of daily hemodialysis treatments. The DAH resolved with seven apheresis procedures and there were no adverse effects. We suggest that patients on hemodialysis with a relapse of AAV and DAH would benefit from the prompt initiation of apheresis in combination with aggressive immunosuppressive therapy. Pulmonary hemorrhage is not included in the current guidelines for therapeutic apheresis; therefore, we report this case and, if warranted, propose this condition to be included in the guidelines.     

Relationship of the Asthma Control Test (ACT) with Lung Function,Levels of Exhaled Nitric Oxide and Control According to the Global Initiative for Asthma (GINA)

IntroductionThe current goal of asthma treatment is to achieve and maintain control. This study aimed to explore the relationship between the ACT (Asthma Control Test) questionnaire and the levels of control according to GINA (Global Initiative for Asthma) to establish the cut-off points for the ACT and evaluate its relationship with lung function and fractionated exhaled nitric oxide level (FeNO).Patients and methodsA multi-centre prospective study including 441 patients followed up in an outpatient Chest Clinic. A clinical protocol was followed, and FeNO, spirometry and ACT performed. Disease was classified according to levels of control using GINA. The study analysed sensitivity, specificity and area under the curve (ROC), and the ACT cut-off points. We studied the differences between the functional parameters and FeNO between levels of control.ResultsFor controlled asthma the cut-off obtained was ACT≥ 21 (area under the curve 0.791) and for uncontrolled ≤ 18 (AUC 0.774). We found significant differences in FeNO levels and pulmonary function among ACT≥ 21 and ACT ≤ 18, although only 26.3% of patients with ACT≤ 18 had a FEV1 <80% and 40% higher FeNO (≥ 35 ppb). We found a correlation between baseline FEV1 and ACT (r = 0.19, P < 0.01) and between ACT and FeNO (r = -0.16, P < 0.01).ConclusionsThe cut-off points would be, for controlled asthma ACT≥ 21, partly controlled asthma ACT = 19-20 and uncontrolled asthma ACT ≤ 18. A more complete assessment would require including monitoring operating parameters and FeNO.     

hCG-secreting pineal teratoma causing precocious puberty: report of two patients and review of the literature

Two boys are described with precocious puberty (PP) due to pineal immature teratoma associated with choriocarcinoma. Patient 1 was a 7 year-old boy with a 2-year history of PP. He had elevated CSF and plasma beta-hCG levels. Magnetic resonance imaging (MRI) showed a 3.0 cm pineal mass. He was initially submitted to a trial with radiotherapy, followed by radical surgical resection, stereotactic radiotherapy and chemotherapy. Long-term follow up included the appearance of acute hydrocephalus requiring CSF shunting, local hemorrhage and extensive radionecrosis. Death occurred 1.5 years after diagnosis. Patient 2 was a 7 year-old boy with an 8-month history of PP. He had elevated CSF and plasma beta-hCG and alpha-fetoprotein levels. MRI showed a 1.0 cm pineal mass. He was submitted to radical surgical resection (which caused normalization of levels of markers) and prophylactic chemotherapy. The boy is doing well 1.5 years after diagnosis. An extensive review of the literature corroborates the idea that this last treatment paradigm (surgery and chemotherapy) probably represents the best treatment regimen for these patients.