Biomedical subjects

M Fiala

Publications and source records attributed to M Fiala.

At least 37 records · Page 2Linked to original sources

PubMed2001

Partnership, sexuality, and sexual disorders in morbidly obese women: consequences of weight loss after gastric banding.

BACKGROUND: A study was performed to determine what consequences surgery for morbid obesity has on sexual attitudes and partnership in obese female patients. METHOD: Semi-structured interviews concerning sociodemographic data, sexuality and relationship were conducted on 82 female patients preoperatively and at least 1 year postoperatively. RESULTS: Physical appearance played the main role in the decision to undergo weight reduction surgery in only 17% of the study patients. Postoperatively, half of the patients were satisfied with their physical appearance 1 year after surgery, the other half not. Preoperatively, 44% of the patients stated that sexuality with their partners was satisfying and the frequency of sexual intercourse was regular. Postoperatively, 63% of the patients stated that they enjoyed sex more, compared with 12% of the patients who enjoyed sex less than before surgery. Postoperatively, 20% of the patients reported that partnership had changed positively, 10% negatively. CONCLUSIONS: The results indicate that many of the sexual problems in obese individuals are the result of an underlying lack of self-esteem, unsatisfactory relationships, or collective stigmatization of obese individuals. Binge eating, often found in morbidly obese patients, seems to be less the result of or compensation for sexual problems but is more likely to stem from other psychosocial or psychological problems.

Adult↗

PubMed2001

HIV-1 penetrates coronary artery endothelial cells by transcytosis.

BACKGROUND: The pathogenesis of HIV-1-related cardiomyopathy is poorly understood, but HIV-1 has been detected in cardiomyocytes. Whether HIV-1 penetrates into the myocardium by infection of coronary artery endothelial cells (CAEC) or using transcellular or paracellular routes across CAEC has not been resolved. MATERIALS AND METHODS: A model of the CAEC barrier was constructed with primary CAEC (derived from human coronary vessels). Polymerase chain reaction (PCR) assay, infectious assay, and immunofluorescence were employed to show abortive nature of HIV-1 infection of CAEC. Tight junction (TJ) and cell adhesion proteins were visualized by immunofluorescence. The time course of HIV-1 invasion was measured by HIV-1 RNA assay. Inulin permeability assay determined paracellular leakage. Transmission electron microscopy demonstrated virus-induced endothelial vacuolization. RESULTS: Despite a strong display on CAEC of CXCR4 and a lesser expression of CCR3 and CCR5, HIV-1 did not productively replicate in CAEC, as shown by infectious assay, immunofluorescence, and electron microscopy. HIV-1 infection of CAEC was abortive with minimal reverse transcription of strong stop DNA and pol but not full-length or two LTR DNA circles. Upon infection of the model with 1 million RNA copies of HIV-1JR-FL, virus penetration 2 hr postinfection (PI) was negligible but increased by 1,750% 24 hr PI. The paracellular permeability increased during this period by only 25%. Neither AOP-RANTES nor v-MIPII significantly reduced HIV-1JR-FL invasion. Virus infection did not alter the integral TJ protein occludin and the TJ-associated protein ZO-1. HIV-1 exposed CAEC and brain microvascular endothelial cells (BMVEC) developed extensive cytoplasmic vacuolization with retroviral-like particles in the vacuoles. CONCLUSIONS: The endothelium is not an impenetrable barrier to HIV-1. The virus opens a transcellular route across coronary and brain endothelia in cytoplasmic vacuoles.

Arteries↗

PubMed2001

[Electrophysiologic parameters determining the success of radiofrequency ablation of atrioventricular reentry tachycardia].

The main objective was to assess electrophysiological parameters which may be important for effective radiofrequency ablation of accessory atrioventricular pathways. In a group of 66 patients a total of 490 applications of radiofrequency current were made, incl. 68 which led to successful severing of the accessory pathways. The ablations were successful in 65 patients (98.5%). The potential of the accessory pathways was present in effective ablations in 19 cases of 68 applications (28%), while in ineffective ablations it was present in 13 cases of 421 applications (3%, p < 0.001). Stability of the electrogram was found in all 68 effective ablations (100%), while in ineffective ablations a stable electrogram was found in 248 cases of 323 applications (77%, p < 0.001). In unstable electrograms the ablation was not effective in any of the patients. The V-delta interval was significantly longer in successful ablations (16 +/- 14.2 ms) than in unsuccessful ones (3 +/- 19.4 ms, p < 0.001). The ventriculoatrial interval was in successful ablations significantly shorter (57.5 +/- 22.5 ms) than in unsuccessful ones (74.5 +/- 20.9 ms, p < 0.001). In 90% applications the ventriculoatrial interval was less than 70 ms. Of 10 evaluated parameters the potential of the accessory pathway, stability of the electrogram, V-delta interval (equal or < or = 0) and short ventriculoatrial intervals (equal to or < or = 70 ms) proved important parameters for successful ablation of accessory pathways.

Adolescent↗

PubMed2001

[Ventricular tachyarrhythmias in patients without structural heart disease. Clinical and electrophysiologic characteristics of the tachyarrhythmias and long-term results of catheter ablation].

PURPOSE OF THE STUDY: Ventricular tachyarrhythmias without structural heart disease (SHD) form a heterogeneous group of unknown mechanism and different clinical and electrophysiological behavior. Purpose of the study was to analyze clinical and electrophysiological characteristics of the arrhythmias, and immediate and long-term results of catheter ablation. PATIENTS: Nineteen consecutive patients without SHD (7 F) aged 44.5 +/- 14.1 (18-66) years had 23 ablation procedures. Documented arrhythmias varied from incessant ventricular premature beats (1 patient) through paroxysmal nonsustained ventricular tachycardia (5 patients), incessant "repetitive" (non)sustained ventricular tachycardia (4 patients) to paroxysmal sustained ventricular tachycardia (9 patients). METHOD: Patients underwent standard electrophysiological examination. Mapping of focal arrhythmias was guided by earliest endocardial and epicardial activation, pace-mapping or both. In 1 patient with reentry tachycardia, mapping was guided by late potential during sinus rhythm and low-voltage fractionated diastolic potential during the tachycardia. RESULTS: Catheter ablation was performed in 19 patients and 23 ablation procedures. Mean fluoroscopy time per procedure was 25.4 +/- 16.0 (7-65) minutes. The arrhythmia was targeted in the right ventricle in 13 patients, and in the left ventricle in 6 patients. All clinically significant ectopic activity was eliminated in 14 patients and significantly reduced in other 2 patients. Ablation procedure failed in 2 patients. In 1 patient sustained monomorphic ventricular tachycardia originating in the epicardial aspect of outflow tract close to the left anterior descending artery was not ablated. During the long-term follow-up 19.2 +/- 10.9 (2-42) months 14 (73.7%) patients are free of targeted ectopic activity, symptoms, and antiarrhythmic drugs. Other 2 patients experienced significant reduction of ectopic activity and previously ineffective antiarrhythmic therapy could be reduced. Thus, the clinical benefit was enhanced to 16 (84.2%) patients. CONCLUSION: Ventricular tachyarrhythmias in patients without SHD form a heterogeneous group of different clinical and electrophysiological behavior and different pathophysiological mechanisms. Majority of the arrhythmias can be eliminated by focal catheter ablation with high efficacy and safety. Deep intramural and epicardial origin of the arrhythmic substrate is common reason for catheter ablation failure.

Adolescent↗

PubMed2000

Chronic cocaine alters hemodynamics and leukocyte-endothelial interactions in rat mesenteric venules.

We investigated the effects of chronic cocaine exposure on the microcirculation in the rat mesenteric venules under both non-inflammatory and FMLP-induced inflammatory conditions. Chronic cocaine significantly increased WBC rolling flux in both conditions, and potentiated FMLP-induced leukocyte-endothelial cell adhesion (LEA). In cocaine-treated animals, total WBC number increased by 91%, and the ratio of white blood cell to red blood cell velocity was significantly lower, while vessel diameter was unchanged. Chronic cocaine decreased serum levels of tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6), but had no effect on interleukin-1 beta (IL-1beta). Expression of intercellular adhesion molecule-1 (ICAM-1) was increased in mesenteric venules following chronic cocaine exposure, and may be one of the mechanisms underlying enhancement of FMLP-induced LEA. The increase in WBC count, WBC flux and LEA, and the change in cell velocity seen in the cocaine-treated animals could cause a decrease in effective vessel diameter and a change in intravascular resistance, and may underlie the progressive vascular damage seen in chronic cocaine-abusing individuals.

Animals↗

PubMed2000

[Radiofrequency catheter ablation of left-sided atrioventricular accessory pathways. Immediate and long-term results using the trans-aortic approach].

UNLABELLED: Catheter mapping and ablation of left accessory pathways may be difficult if the pathway fibre orientation is oblique across the mitral annulus. This is particularly true in case of concealed accessory pathway that conducts only in ventriculoatrial direction. The purpose of the study was to compare catheter ablation safety, efficacy, procedure and fluoroscopy times and number of radiofrequency energy deliveries for manifest and concealed left accessory pathways using retrograde transaortic approach. 56 patients (26 females) aged 41.6 +/- 15.1 years underwent 59 ablation procedures for 59 left accessory pathways. 25 (44.6%) patients with 27 concealed accessory pathways and additional 2 patients with a manifest pathway mappable only during retrograde conduction formed group I and were compared to 29 patients with a manifest accessory pathway mappable during ventricular preexcitation (group II). Ablation was acutely successful in all patients. Reablation was necessary for the pathway recurrence in 2 patients and for a different pathway in 1 patient. Deep femoral venous thrombosis complicated ablation in 1 patient. During the 14.9 +/- 8.2 (3-30) month follow-up period all the patients remain free of a pathway related tachyarrhythmia. Both the groups (I vs II) did not differ in procedure (180 +/- 76.7 vs. 187 +/- 75.8; p = 0.36) and fluoroscopy (25.3 +/- 18.6 vs. 33.5 +/- 24.7; p = 0.08) times (min) and number of radiofrequency energy deliveries (10.0 +/- 9.2 vs. 10.2 +/- 9.8; p = 0.46). CONCLUSION: Transaortic approach to the left concealed accessory pathways is safe and effective in virtually 100% of patients and, compared to manifest pathways, does not prolong procedure and fluoroscopy times nor the number of radiofrequency energy deliveries.

Adolescent↗

PubMed1999

Cocaine enhances brain endothelial adhesion molecules and leukocyte migration.

Leukocyte infiltration of cerebral vessels in cocaine-associated vasculopathy suggests that cocaine may enhance leukocyte migration. We have investigated cocaine's effects on leukocyte adhesion in human brain microvascular endothelial cell (BMVEC) cultures and monocyte migration in an in vitro blood-brain barrier (BBB) model constructed with BMVEC and astrocytes. Cocaine (10(-5) to 10(-9) M) enhanced adhesion of monocytes and neutrophils to BMVEC. In the BBB model, cocaine (10(-4) to 10(-8) M) enhanced monocyte transmigration. Cocaine increased expression of endothelial adhesion molecules, intercellular adhesion molecule-1 (ICAM-1, CD54), vascular cell adhesion molecule-1 (VCAM-1), and endothelial leukocyte adhesion molecule-1 (ELAM-1) on BMVEC. The peak effect on ICAM-1 expression was between 6 and 18 h after treatment. ICAM-1 was increased by cocaine in BMVEC, but not in human umbilical vein endothelial cells, and the enhancement was greater in a coculture of BMVEC with monocytes. ICAM-1 expression was enhanced by a transcriptional mechanism. Polymyxin B inhibited up-regulation of adhesion molecules by LPS but not by cocaine. In LPS-activated BMVEC/monocyte coculture, cocaine increased secretion of tumor necrosis factor-alpha and interleukin-6. Taken together, these findings indicate that cocaine enhances leukocyte migration across the cerebral vessel wall, in particular under inflammatory conditions, but the effects are variable in different individuals. Cocaine's effects are exerted through a cascade of augmented expression of inflammatory cytokines and endothelial adhesion molecules. These could underlie the cerebrovascular complications of cocaine abuse.

Astrocytes↗

PubMed1999

Microglial and astrocyte chemokines regulate monocyte migration through the blood-brain barrier in human immunodeficiency virus-1 encephalitis.

The numbers of immune-activated brain mononuclear phagocytes (MPs) affect the progression of human immunodeficiency virus (HIV)-1-associated dementia (HAD). Such MPs originate, in measure, from a pool of circulating monocytes. To address the mechanism(s) for monocyte penetration across the blood-brain barrier (BBB), we performed cross-validating laboratory, animal model, and human brain tissue investigations into HAD pathogenesis. First, an artificial BBB was constructed in which human brain microvascular endothelial and glial cells-astrocytes, microglia, and/or monocyte-derived macrophages (MDM)-were placed on opposite sides of a matrix-coated porous membrane. Second, a SCID mouse model of HIV-1 encephalitis (HIVE) was used to determine in vivo monocyte blood-to-brain migration. Third, immunohistochemical analyses of human HIVE tissue defined the relationships between astrogliosis, activation of microglia, virus infection, monocyte brain infiltration, and beta-chemokine expression. The results, taken together, showed that HIV-1-infected microglia increased monocyte migration through an artificial BBB 2 to 3.5 times more than replicate numbers of MDM. In the HIVE SCID mice, a marked accumulation of murine MDM was found in areas surrounding virus-infected human microglia but not MDM. For human HIVE, microglial activation and virus infection correlated with astrogliosis, monocyte transendothelial migration, and beta-chemokine expression. Pure cultures of virus-infected and activated microglia or astrocytes exposed to microglial conditioned media produced significant quantities of beta-chemokines. We conclude that microglial activation alone and/or through its interactions with astrocytes induces beta-chemokine-mediated monocyte migration in HAD.

AIDS Dementia Complex↗

PubMed1999

CXC and CC chemokine receptors on coronary and brain endothelia.

BACKGROUND: Chemokine receptors on leukocytes play a key role in inflammation and HIV-1 infection. Chemokine receptors on endothelia may serve an important role in HIV-1 tissue invasion and angiogenesis. MATERIALS AND METHODS: The expression of chemokine receptors in human brain microvascular endothelial cells (BMVEC) and coronary artery endothelial cells (CAEC) in vitro and cryostat sections of the heart tissue was determined by light and confocal microscopy and flow cytometry with monoclonal antibodies. Chemotaxis of endothelia by CC chemokines was evaluated in a transmigration assay. RESULTS: In BMVEC, the chemokine receptors CCR3 and CXCR4 showed the strongest expression. CXCR4 was localized by confocal microscopy to both the cytoplasm and the plasma membrane of BMVEC. In CAEC, CXCR4 demonstrated a strong expression with predominantly periplasmic localization. CCR5 expression was detected both in BMVEC and CAEC but at a lower level. Human umbilical cord endothelial cells (HUVEC) expressed strongly CXCR4 but only weakly CCR3 and CCR5. Two additional CC chemokines, CCR2A and CCR4, were detected in BMVEC and CAEC by immunostaining. Immunocytochemistry of the heart tissues with monoclonal antibodies revealed a high expression of CXCR4 and CCR2A and a low expression of CCR3 and CCR5 on coronary vessel endothelia. Coronary endothelia showed in vitro a strong chemotactic response to the CC chemokines RANTES, MIP-1alpha, and MIP-1beta. CONCLUSIONS: The endothelia isolated from the brain display strongly both the CCR3 and CXCR4 HIV-1 coreceptors, whereas the coronary endothelia express strongly only the CXCR4 coreceptor. CCR5 is expressed at a lower level in both endothelia. The differential display of CCR3 on the brain and coronary endothelia could be significant with respect to the differential susceptibility of the heart and the brain to HIV-1 invasion. In addition, CCR2A is strongly expressed in the heart endothelium. All of the above chemokine receptors could play a role in endothelial migration and repair.

Adult↗

PubMed1998

Cocaine infusion increases interferon-gamma and decreases interleukin-10 in cocaine-dependent subjects.

The effects of cocaine infusion (40 mg) on interferon-gamma (IFN-gamma) and interleukin-10 (IL-10) cytokine secretion were examined in 15 cocaine-dependent subjects. Pre- and postcocaine infusion peripheral blood mononuclear cells (PBMC), stimulated with phytohemagglutinin A, were cultured for 48 h and the cytokines in the supernatant measured by enzyme-linked immunosorbent assay. Cocaine infusion, but not saline infusion, increased IFN-gamma secretion and decreased IL-10 secretion, while, in PBMC collected simultaneously from control subjects, secretion of these cytokines was unaltered. Baseline IFN-gamma levels were lower and IL-10 levels higher in addicted subjects compared to those in control subjects. White blood cell and lymphocyte number and CD4(+) and CD8(+) counts were all increased following cocaine infusion. In vitro cocaine treatment of PBMC from addicted subjects suppressed both IL-10 and IFN-gamma secretion. These data suggest that acute cocaine administration, via both central and peripheral effects, may enhance Th1-type immune responses and inhibit Th2-type responses.

Adult↗

PubMed1998

Cocaine enhances monocyte migration across the blood-brain barrier. Cocaine's connection to AIDS dementia and vasculitis?

Cocaine has wide-ranging effects on the immune and neuroendocrine systems (Fiala et al., 1996) resembling an inflammatory "stress" response with upregulation of pro-inflammatory cytokines and stimulation of the HPA axis (Gan et al., 1997). Cocaine abuse has also been associated with vascular pathology, including vasculitis, vasospasm and hemorrhage. These effects suggest that cocaine could perturb the function of endothelial cells, including the blood-brain barrier, and influence the progression to AIDS in HIV-infected individuals (Shapshak et al., 1997; Goodkin et al., 1997). In order to understand clinical consequences of cocaine abuse, it is important to gain insight into molecular and cellular basis of cocaine's effects on immune and endothelial cells. Cocaine's in vitro effects on (a) permeability, (b) immune cell migration, (c) adhesion molecules, and (d) cytokine expression were investigated in a blood-brain barrier model constructed with brain microvascular endothelial cells and fetal astrocytes with the following results: (a) cocaine and tumor necrosis factor-alpha (TNF-alpha) increased the model's permeability to inulin similarly in a dose-responsive fashion; (b) cocaine (10(-4) to 10(-8_ M) enhanced monocyte migration across the barrier with the maximum increase, approximately 100%, by 10(-5) M cocaine; (c) cocaine treatment also increased the expression of endothelial adhesion molecules, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecules-1 (VCAM-1) and platelet/endothelial cell adhesion molecule-1 (PECAM-1); (d) although the cocaine in vitro effects on cytokine production by mononuclear cells have been difficult to assess due to a heterogeneity in the degree of responsiveness between individuals, the data suggest that mononuclear cells from cocaine addicts are sensitized to in vitro cocaine challenge with hypersecretion of inflammatory cytokines. Cocaine's in vivo manifestations are compatible with these in vitro effects: (A) chronic cocaine treatment of rats significantly increased rolling white blood cell flux, leukocyte-endothelium adhesion, and ICAM-1 expression in the mesentery (House et al., 1996); (B) cocaine injection to cocaine-dependent subjects tipped the balance of cytokine secretion by mononuclear cells to Th1-type (Gan et al., 1997), and (C) cocaine injection stimulated the hypothalamic-pituitary axis (HPA) to increase both anti- and pro-inflammatory hormonal secretion. Collectively, these results suggest that the immune effects of cocaine on endothelial, immune and neuroendocrine cells impair the function of the blood-brain, barrier, increase cell emigration from the blood vessels, in particular into the brain, and may cause vasculitis. These effects could also increase importation of HIV-1 into the brain.

AIDS Dementia Complex↗

PubMed1998

The effects of interaction between morphine and interleukin-1 on the immune response.

The findings presented here clearly indicate an association between opioid- and cytokine-dependent systems. Exposure to exogenous opioids can produce profound effects on IL-1-mediated immune responses. Chronic exposure to morphine appears to disrupt the brain-immune axis by desensitizing the IL-1 activation of the HPA axis, and consequently potentiate the LEA response to IL-1. On the other hand, endogeneous IL-1, secreted in response to disease or stress, may alter the endogenous opioid pathway by inducing the expression of opioid receptors in endothelial cells. Clinically, the potential impact on the body's defense mechanisms resulting from the interaction between opioids, such as morphine, and cytokines, such as IL-1, can be substantial. Further investigation of this interaction is essential to understanding the extent of damage in human body caused by drugs of abuse, such as morphine.

Animals↗

PubMed1998

Interleukin-1 induces the expression of mu opioid receptors in endothelial cells.

Immunocytokines, such as interleukin-1 (IL-1), have been shown to be involved in the activation and/or induction of a variety of transcription factors which may modulate the expression of genes possessing DNA binding sites on which these transcription factors act. The promoter DNA sequence of the mu opioid receptor gene contains IL-1 response elements such as NF-IL6, and, therefore, the receptor gene may be responsive to IL-1. To investigate the effect of IL-1 on the opioid receptor gene, the in vitro expression of mu opioid receptor mRNA in neural microvascular endothelial cells (NMVEC) was determined before and after IL-1 treatment. PCR analysis revealed that there was virtually no mu opioid receptor expression at basal levels and no increase after either IL-1alpha or IL-1beta treatment. However, simultaneous treatment with both IL-1alpha and IL-1beta increased mu opioid receptor expression. This upregulation of mu opioid receptor expression provides direct evidence of a relationship between opioid and cytokine actions, and suggests that opioid-dependent pathways may be modulated in the disease state.

Cells, Cultured↗

PubMed1998

Cocaine opens the blood-brain barrier to HIV-1 invasion.

Cocaine abuse has been associated with vasculitis and stroke, and is suspected to influence the progression of AIDS dementia. Cocaine may enhance HIV-1 neuroinvasion by actions directed at the blood-brain barrier. HIV-1 appears to penetrate the human brain microvascular endothelial cell barrier by a paracellular route breached by tumor necrosis factor-alpha (TNF-alpha). Cocaine's effects on the blood-brain barrier were investigated using human brain microvascular endothelial cells and peripheral blood monocytes. Cocaine (10(-5) M and 10(-6) M) increased molecular permeability of the barrier and viral invasion by the macrophage-tropic HIV-1(JR-FL) into the brain chamber. Cocaine also augmented apoptosis of brain endothelial cells and monocytes, increased secretion of four chemokines (interleukin-8, interferon-inducible protein-10, macrophage inflammatory protein-1alpha, and monocyte chemoattractant protein-1) and the cytokine, TNF-alpha, by human monocytes. TNF-alpha enhanced invasion of the brain compartment by macrophage-tropic, lymphotropic, and bitropic HIV-1 strains. These data indicate that HIV-1 neuroinvasion can be increased by (a) cocaine's direct effects on brain microvascular endothelial cells and (b) paracrine effects of cocaine-induced pro-inflammatory cytokines and chemokines on the blood-brain barrier.

Apoptosis↗

PubMed1998

Amyloid-beta induces chemokine secretion and monocyte migration across a human blood--brain barrier model.

BACKGROUND: Aside from numerous parenchymal and vascular deposits of amyloid beta (A beta) peptide, neurofibrillary tangles, and neuronal and synaptic loss, the neuropathology of Alzheimer's disease is accompanied by a subtle and chronic inflammatory reaction that manifests itself as microglial activation. However, in Alzheimer's disease, alterations in the permeability of the blood-brain barrier and chemotaxis, in part mediated by chemokines and cytokines, may permit the recruitment and transendothelial passage of peripheral cells into the brain parenchyma. MATERIALS AND METHODS: Human monocytes from different donors were tested for their capacity to differentiate into macrophages and their ability to secrete cytokines and chemokines in the presence of A beta 1-42. A paradigm of the blood-brain barrier was constructed utilizing human brain endothelial and astroglial cells with the anatomical and physiological characteristics observed in vivo. This model was used to test the ability of monocytes/macrophages to transmigrate when challenged by A beta 1-42 on the brain side of the blood-brain barrier model. RESULTS: In cultures of peripheral monocytes, A beta 1-42 induced the secretion of proinflammatory cytokines TNF-alpha, IL-6, IL-1 beta, and IL-12, as well as CC chemokines MCP-1, MIP-1 alpha, and MIP-1 beta, and CXC chemokine IL-8 in a dose-related fashion. In the blood-brain barrier model, A beta 1-42 and monocytes on the brain side potentiated monocyte transmigration from the blood side to the brain side. A beta 1-42 stimulated differentiation of monocytes into adherent macrophages in a dose-related fashion. The magnitude of these proinflammatory effects of A beta 1-42 varied dramatically with monocytes from different donors. CONCLUSION: In some individuals, circulating monocytes/macrophages, when recruited by chemokines produced by activated microglia and macrophages, could add to the inflammatory destruction of the brain in Alzheimer's disease.

Alzheimer Disease↗

PubMed1997

A model for monocyte migration through the blood-brain barrier during HIV-1 encephalitis.

HIV-1 invades the central nervous system early during viral infection, but neurologic impairment usually occurs years later. The strongest predictor for clinical dementia is the absolute numbers of immunocompetent brain macrophages. Thus, how monocytes penetrate the brain during disease remains critical for understanding the neuropathogenic mechanisms of HIV-1 encephalitis. To these ends, we constructed an artificial blood-brain barrier (BBB) consisting of a matrix-coated membrane with brain microvascular endothelial cells (BMVEC) on one side and astrocytes on the other. Astrocyte endfeet contacted the monolayer of BMVEC that formed tight junctions. To determine the role of viral and immune factors in monocyte penetration across the BBB, HIV-infected or uninfected monocytes with or without immune stimulation were placed onto the upper chamber of the BBB model system. Placement of immune-stimulated (LPS-treated) cells onto the BBB construct elicited gaps between BMVEC, with bulging of nuclear zones and increased numbers of vesicular Golgi complexes and endoplasmic reticulum. This correlated with a profound increase (up to 20-fold) in the number of migrating cells. Viral infection did not enhance monocyte migration. The activated monocytes showed increased numbers of philopodia, lysosomes, and vesicular Golgi complexes and expressed large levels of proinflammatory cytokines (TNF-alpha, IL-6, and IL-10). These data suggest that a major mechanism for the transendothelial migration of monocytes during HIV encephalitis is the immune activation that accompanies viral infection of the central nervous system.

AIDS Dementia Complex↗

PubMed1997

TNF-alpha opens a paracellular route for HIV-1 invasion across the blood-brain barrier.

BACKGROUND: HIV-1 invades the central nervous system early after infection when macrophage infiltration of the brain is low but myelin pallor is suggestive of blood-brain-barrier damage. High-level plasma viremia is a likely source of brain infection. To understand the invasion route, we investigated virus penetration across in vitro models with contrasting paracellular permeability subjected to TNF-alpha. MATERIALS AND METHODS: Blood-brain-barrier models constructed with human brain microvascular endothelial cells, fetal astrocytes, and collagen I or fibronectin matrix responded in a dose-related fashion to cytokines and ligands modulating paracellular permeability and cell migration. Virus penetration was measured by infectious and quantitative HIV-1 RNA assays. Barrier permeability was determined using inulin or dextran. RESULTS: Cell-free HIV-1 was retained by the blood-brain barrier with close to 100% efficiency. TNF-alpha increased virus penetration by a paracellular route in a dose-dependent manner proportionately to basal permeability. Brain endothelial cells were the main barrier to HIV-1. HIV-1 with monocytes attracted monocyte migration into the brain chamber. CONCLUSIONS: Early after the infection, the blood-brain barrier protects the brain from HIV-1. Immune mediators, such as TNF-alpha, open a paracellular route for the virus into the brain. The virus and viral proteins stimulate brain microglia and macrophages to attract monocytes into the brain. Infiltrating macrophages cause progression of HIV-1 encephalitis.

Astrocytes↗

PubMed1997

Zidovudine therapy, CD4+ and CD8+ counts are associated with a longer survival following AIDS onset.

In 60 patients followed from the onset of acquired immunodeficiency syndrome (AIDS) to death, survival was determined by Cox Proportional Hazards Analysis in relationship to seven variables: time-dependent CD4+ and CD8+ peripheral lymphocyte counts, zidovudine treatment, cytomegalovirus (CMV) retinitis, time from AIDS onset, calendar year of AIDS onset (cohort effect), and age. Two significant prognostic variables were identified: zidovudine therapy and either CD4+ or CD8+ counts (the latter could not be distinguished due to concomitant high correlation). Treatment with zidovudine reduced the death rate by 75% compared to no treatment. When included in a proportional hazards regression with all covariates except for the other T lymphocyte count, every increase in CD4+ count of 10 cells was equivalent to a decline in the mortality rate by 13% (p = 0.046), and every increase in CD8+ count of 10 cells lowered the mortality by 1.4% (p = 0.0031). Patients treated with zidovudine and without CMV retinitis showed the slowest decline of both CD4+ and CD8+ counts. Both CD4+ and CD8+ levels are useful predictors of survival in patients with AIDS.

Acquired Immunodeficiency Syndrome↗