Multiple oral and cerebral relapses of a Granular cell tumor (Abrikossoff Tumor) in a young girl affected by congenital dyserythropoietic anemia type II.

CASE REPORT: A 14-year-old girl presented with 1 cm large whitened lesion on the ventral surface of the tongue, appeared from 1 month. Past history showed congenital dyserythropoietic anemia type II. The lesion was excised and microscopic and immunohistochemical analyses were compatible with benign Abrikossoff tumor. Total body MRI was negative. After six months the patient presented a second tongue lesion and four months later another large painful lesion in the soft palate, with the same istological diagnosis. In addition, she had other multiple lesions: two apperead at pharyngeal level (not biopsied) that remain stable over time, and one at the pituitary gland. CONCLUSION: Granular cell tumors, with or without multiple lesions, are rare in children. About 50% of cases involve the head and neck region, with the tongue being the most affected site. Therapy is based on the surgical excision of the lesions; however some tumor forms, although their histological aspect of benignity, often have an important infiltrative power, making the therapeutic approach difficult, as in our case.

CREB decreases astrocytic excitability by modifying subcellular calcium fluxes via the sigma-1 receptor.

Astrocytic excitability relies on cytosolic calcium increases as a key mechanism, whereby astrocytes contribute to synaptic transmission and hence learning and memory. While it is a cornerstone of neurosciences that experiences are remembered, because transmitters activate gene expression in neurons, long-term adaptive astrocyte plasticity has not been described. Here, we investigated whether the transcription factor CREB mediates adaptive plasticity-like phenomena in astrocytes. We found that activation of CREB-dependent transcription reduced the calcium responses induced by ATP, noradrenaline, or endothelin-1. As to the mechanism, expression of VP16-CREB, a constitutively active CREB mutant, had no effect on basal cytosolic calcium levels, extracellular calcium entry, or calcium mobilization from lysosomal-related acidic stores. Rather, VP16-CREB upregulated sigma-1 receptor expression thereby increasing the release of calcium from the endoplasmic reticulum and its uptake by mitochondria. Sigma-1 receptor was also upregulated in vivo upon VP16-CREB expression in astrocytes. We conclude that CREB decreases astrocyte responsiveness by increasing calcium signalling at the endoplasmic reticulum-mitochondria interface, which might be an astrocyte-based form of long-term depression.

Molecular targets of non-steroidal anti-inflammatory drugs in neurodegenerative diseases.

During the last decade, interest has grown in the beneficial effects of non-steroidal anti-inflammatory drugs (NSAIDs) in neurodegeneration, particularly in pathologies such as Alzheimer's (AD) and Parkinson's (PD) disease. Evidence from epidemiological studies has indicated a decreased risk for AD and PD in patients with a history of chronic NSAID use. However, clinical trials with NSAIDs in AD patients have yielded conflicting results, suggesting that these drugs may be beneficial only when used as preventive therapy or in early stages of the disease. NSAIDs may also have salutary effects in other neurodegenerative diseases with an inflammatory component, such as multiple sclerosis and amyotrophic lateral sclerosis. In this review we analyze the molecular (cyclooxygenases, secretases, NF-kappaB, PPAR, or Rho-GTPasas) and cellular (neurons, microglia, astrocytes or endothelial cells) targets of NSAIDs that may mediate the therapeutic function of these drugs in neurodegeneration.

Pioglitazone does not increase cerebral glucose utilisation in a murine model of Alzheimer's disease and decreases it in wild-type mice.

AIMS/HYPOTHESIS: Clinical trials are in progress to test thiazolidinediones in neurodegenerative diseases such as Alzheimer's disease that involve deficiencies in brain glucose metabolism. While thiazolidinediones enhance glucose uptake in non-cerebral tissues, their impact on brain energy metabolism has not been investigated in vivo. We thus determined whether the thiazolidinedione pioglitazone reverses the decrease in cerebral glucose utilisation (CGU) in a model of brain metabolic deficiency related to Alzheimer's disease. Results are relevant to diabetes because millions of diabetic patients take pioglitazone as an insulin-sensitising drug, and diabetes increases the risk of developing Alzheimer's disease. MATERIALS AND METHODS: The regional pattern of CGU was measured with the 2-deoxy [(14)C] glucose autoradiographic technique in adult awake mice overexpressing transforming growth factor beta1 (TGFbeta1), and in wild-type littermates. Mice were treated with pioglitazone for 2 months. RESULTS: Measurement of CGU in 27 brain regions confirmed that TGFbeta1 overexpression induced hypometabolism across the brain. Pioglitazone did not reverse the effect of TGFbeta1 overexpression and decreased regional CGU in control animals by up to 23%. The extent of the regional CGU decrease induced by pioglitazone, but not that induced by TGFbeta1, correlated strongly with basal CGU, suggesting that the higher the local metabolic rate the greater the reduction of CGU effected by pioglitazone. CONCLUSIONS/INTERPRETATION: In contrast to its stimulatory effect in non-cerebral tissues, chronic treatment with pioglitazone decreases CGU in vivo. This evidence does not support the hypothesis that pioglitazone could act as a metabolic enhancer in Alzheimer's disease, and raises the question of how thiazolidinediones could be beneficial in neurodegenerative diseases.

Zoledronic acid induces antiproliferative and apoptotic effects in human pancreatic cancer cells in vitro.

Bisphosphonates (BPs) are an emerging class of drugs mostly used in the palliative care of cancer patients. We investigated the in vitro activity of the most potent antiresorptive BP, zoledronic acid (ZOL), on the growth and survival of three human pancreatic cancer (PC) cell lines (BxPC-3, CFPAC-1 and PANC-1). Pancreatic cancer frequently has a dysregulated p21(ras) pathway and therefore appears to be a suitable target for BPs that interfere with the prenylation of small GTP-binding proteins such as p21(ras). We found that ZOL induces growth inhibition (IC(50):10-50 micro M) and apoptotic death of PC cells. The proapoptotic effect was correlated to cleavage/activation of caspase-9 and poly(ADP)-ribose polymerase, but not of caspase-3. Moreover, we studied the p21(ras) signalling in cells exposed to ZOL and detected a reduction of p21(ras) and Raf-1 content and functional downregulation of the terminal enzyme ERK/MAPkinase and of the pKB/Akt survival pathway. Finally, we observed that ZOL induces significant cytoskeletal rearrangements. In conclusion, we demonstrated that ZOL induces growth inhibition and apoptosis on PC cells and interferes with growth and survival pathways downstream to p21(ras). These findings might be relevant for expanding application of BPs in cancer treatment.

Oxaliplatin (L-OHP) treatment of human myeloma cells induces in vitro growth inhibition and apoptotic cell death.

Oxaliplatin (L-OHP), a diaminocyclohexane platinum derivative, is an active and well tolerated anticancer drug which is presently used in the treatment of gastrointestinal tumours. Since the efficacy of L-OHP in the treatment of multiple myeloma (MM) has not yet been evaluated, we studied the antiproliferative activity of this compound in vitro in a panel of MM cell lines (XG1, XG1a, U266 and IM-9). We found that L-OHP inhibited the growth of MM cells at therapeutically achievable concentrations (IC(50): 5-10 microM after 24 h of exposure) and was more active than Cisplatin (CDDP) or Carboplatin (CBDCA). The activity of L-OHP was apparently not affected by interleukin-6 (IL-6), the major growth and survival factor of MM cells. We also found that L-OHP induced apoptotic cell death. We demonstrated that the combination of L-OHP with Dexamethasone (Dex) resulted in the enhancement of the anti-myeloma effects. L-OHP and Dex both induced poly adenosine diphosphate (ADP)-ribose polymerase (PARP) cleavage and this induction was enhanced by the combined treatment. L-OHP-induced apoptosis correlated with caspase-3 cleavage, but this correlation could not be demonstrated in Dex-treated cells. Taken together, these in vitro results provide a rationale for the experimental use of L-OHP in the treatment of MM patients and suggest therapeutic combinations of potential value.

The key role of caveolin-1 in estrogen-mediated regulation of endothelial nitric oxide synthase function in cerebral arterioles in vivo.

The marked impairment in cerebrovascular endothelial nitric oxide synthase (eNOS) function that develops after ovariectomy may relate to the observation that the abundance of cerebral vascular eNOS and its endogenous inhibitor, caveolin-1, vary in opposite directions with chronic changes in estrogen status. The authors endeavored, therefore, to establish a link between these correlative findings by independently manipulating, in ovariectomized female rats, eNOS and caveolin-1 expression, while monitoring agonist (acetylcholine)-stimulated eNOS functional activity. In the current study, the authors showed that individually neither the up-regulation of eNOS (through simvastatin treatment), nor the down-regulation of caveolin-1 (through antisense oligonucleotide administration) is capable of restoring eNOS function in pial arterioles in vivo in these estrogen-depleted rats. Only when eNOS up-regulation and caveolin-1 down-regulation are combined is activity normalized. These results establish a mechanistic link between the estrogen-associated divergent changes in the abundance of caveolin-1 and eNOS protein and eNOS functional activity in cerebral arterioles.

Estrogen and cerebrovascular physiology and pathophysiology.

Numerous studies have uncovered a wide variety of estrogen effects with apparent cardiovascular benefits, the most recognized ones being vasodilation, anti-atherogenesis, diminished post-ischemic inflammation and anti-oxidant effects. This article provides an overview of the influence of estrogen on the cerebral vasculature, under physiologic and pathophysiologic conditions, and covers both acute and chronic effects. The discussion is primarily focused on the vasodilatory and anti-inflammatory actions of estrogen, since those particular estrogen influences have received the greatest attention in studies published to date. With respect to vasodilation, although some consideration is given to the role of other vasodilating mechanisms and factors, the emphasis is mostly placed on the endothelial isoform of nitric oxide synthase, eNOS, which has emerged as a clear target of estrogen. Some consideration is given to recent findings that suggest that estrogen can stimulate eNOS activity by decreasing the expression of the eNOS inhibitor caveolin-1. With regard to the ability of estrogen to counteract inflammation, potential mechanisms by which estrogen limits the post-ischemic leukocyte adhesion, and the expression of the inducible NOS, are discussed.

Local anesthetics potentiate nitric oxide synthase type 2 expression in rat glial cells.

Expression of the calcium-independent nitric oxide synthase (NOS2) contributes to damage in neurologic disease and trauma. The effects of local anesthetics on NOS2 expression have not been examined. The authors tested the effects of four local anesthetics on the expression of NOS2 in immunostimulated rat C6 glioma cells. Incubation with local anesthetics alone did not induce nitrite accumulation; however, the nitrite production induced by stimulation with bacterial endotoxin lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma) was increased in a dose-dependent manner by bupivacaine (maximal 3-fold at 360 microM), tetracaine (maximal 7-fold at 360 microM), and lidocaine at higher doses (5-fold increase at 3.3 mM). Significant increases in nitrite production were observed in concentrations of bupivacaine or tetracaine as low as 120 microM, which correspond to 30 microg/mL (.003% weight/volume). In contrast, ropivacaine had little effect on nitrite production (160% of control values) and only at the highest concentration (3.3 mM, corresponding to 890 microg/mL or 0.089% w/v) tested. Increased nitrite production was not caused by cytotoxic effects of the drugs used, as assessed by release of intracellular lactate dehydrogenase. Increased nitrite production was accompanied by increased NOS2 catalytic activity, steady state mRNA levels, and promoter activation. These results demonstrate that submillimolar doses of two commonly used local anesthetics can increase glial NOS2 expression.

Growth inhibition and synergistic induction of apoptosis by zoledronate and dexamethasone in human myeloma cell lines.

Bisphosphonates (BPs) are commonly used in the treatment of myeloma-associated osteolytic lesions. Recent reports have suggested that BPs may also exert direct antitumor effects on myeloma cells. Here, we show that the treatment of myeloma cell lines with the combination of the potent BP zoledronate and dexamethasone inhibits cell growth and synergistically induces apoptotic cell death, providing a rationale for potential applications in vivo.

Cyclic adenosine monophosphate regulates the expression of the intercellular adhesion molecule and the inducible nitric oxide synthase in brain endothelial cells.

The authors studied whether cyclic AMP (cAMP), a widespread regulator of inflammation, modulates the cytokine-mediated expression of the intercellular adhesion molecule, intercellular adhesion molecule-1 (ICAM-1), and the inflammatory nitric oxide synthase 2 (NOS-2), in primary and immortalized brain endothelial cell cultures (GP8.3 cell line). When measured by enzyme-linked immunosorbent assay (ELISA), ICAM-1 was constitutively expressed and was up-regulated twofold by interleukin-1beta, with no effect of interferon-gamma. The NOS-2 activity, assessed by nitrite accumulation, was absent from untreated cultures but was induced by interleukin-1beta and interferon-gamma acting synergistically. Stimulation of cAMP-dependent pathways with forskolin or dibutyryl cAMP decreased ICAM-1 protein expression, whereas it increased NOS-2 protein expression. For both ICAM-1 and NOS-2, mRNA expression correlated with protein expression. Blockade of NOS activity with L-N-monomethylargiuine (L-NMMA) did not alter ICAM-1 expression, indicating that the nitric oxide released by NOS-2 did not cause the down-regulation of ICAM-1. Analysis of NFKB activation indicated that cAMP acted through a mechanism other than inhibition of nuclear translocation of NFKB. The authors conclude that cAMP modulates the expression of proinflammatory molecules in brain endothelium. This suggests that inflammatory processes at the blood-brain barrier in vivo may be regulated by perivascular neurotransmitters via cAMP.

Regulation of the expression of the inflammatory nitric oxide synthase (NOS2) by cyclic AMP.

The enzyme nitric oxide synthase 2 (NOS2), often called inducible NOS, plays a central role in the inflammatory reactions that follow infection or tissue damage. NOS2 has been detected in virtually every cell type, and the NO it produces can perform both beneficial and detrimental actions. It is thus conceivable that regulatory mechanisms exist which control the timing and intensity of NO production by NOS2 in order to outweigh protective effects against detrimental ones. Since cyclic AMP inhibits numerous immunological reactions, studies have been carried out to determine whether cAMP-dependent pathways could inhibit NOS2 expression as well. Pharmacological studies in cultured cells show that, depending on the cell type examined, increased cAMP can exert opposite effects on the endotoxin- or cytokine-induced expression of NOS2, being either stimulatory or inhibitory in macrophages, stimulatory in adipocytes, smooth muscle, skeletal muscle, and brain endothelial cells, and inhibitory in pancreatic, liver, and brain glial cells. Regulation of NOS2 gene transcription appears to be the primary mechanism of action of cAMP, and whether it is stimulatory or inhibitory hinges on the cell-specific regulation of transcription factors including CREB, NF-kappaB, and C/EBP. Cyclic AMP must therefore be considered a modulator rather than a suppressor of NOS2 expression. This review summarizes evidence derived from in vitro studies, considers regulation of NOS2 by cAMP in vivo, and discusses possible therapeutic applications of cAMP treatment.-Galea, E., Feinstein, D. L. Regulation of the expression of the inflammatory nitric oxide synthase (NOS2) by cyclic AMP.

Peroxisome proliferator-activated receptor gamma agonists protect cerebellar granule cells from cytokine-induced apoptotic cell death by inhibition of inducible nitric oxide synthase.

Cerebellar granule cells (CGCs) can express the inducible isoform of nitric oxide synthase (iNOS) in response to inflammatory stimuli. We demonstrate that induction of iNOS in CGCs by bacterial lipopolysaccharide and pro-inflammatory cytokines results in cell death that was potentiated by excess L-arginine and inhibited by the selective iNOS inhibitor, 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine. The NO-mediated cell death was accompanied by increased caspase-3-like activity, DNA fragmentation and positive terminal transferase dUTP nick end labeling (TUNEL), suggesting that apoptosis mediates CGC cell death. Incubation of CGCs with the non-steroidal anti-inflammatory drugs (NSAIDs), ibuprofen or indomethacin, or with 15-deoxy-delta12,14 prostaglandin J2 (PGJ2) downregulates iNOS expression and reduces subsequent cell death. Since in other cell types, both NSAIDs and PGJ2 can activate the peroxisome proliferator-activated receptor-gamma (PPARgamma) and downregulate cytokine levels and iNOS expression, and since CGCs express PPARgamma in vivo and in vitro, our data suggest that activation of CGC PPARgamma mediates iNOS suppression and reduced cell death. Because PPARgamma is expressed in brains of Alzheimer's Disease (AD) patients, in which neuronal iNOS expression and apoptotic cell death have been described, these results may help explain the basis for the beneficial effects of NSAIDs in AD.

Stimulation of cerebellar fastigial nucleus inhibits interleukin-1beta-induced cerebrovascular inflammation.

Electrical stimulation of the cerebellar fastigial nucleus (FN) in rat protects the brain against ischemia. We studied whether FN could reduce the cerebrovascular inflammation as a mechanism of protection. FN or dentate nucleus (sham controls) was electrically stimulated for 1 h, and 72 h later rats were either injected with interleukin (IL)-1beta into the striata or processed to analyze inflammatory responses in isolated brain microvessels. In striata, IL-1beta induced a recruitment of leukocytes that was reduced by 50% by FN stimulation. In isolated microvessels, IL-1beta induced the transient and dose-dependent upregulation of the mRNAs encoding for the inducible nitric oxide synthase (NOS-2), intercellular adhesion molecule 1 (ICAM-1), and inhibitory kappaB-alpha (IkappaB-alpha), an inhibitor of nuclear factor-kappaB. FN stimulation decreased the upregulation of NOS-2 and ICAM-1 mRNAs, whereas it increased IkappaB-alpha mRNA expression. Dentate nucleus stimulation did not mimic the FN actions. These findings suggest that FN stimulation may render brain microvessels refractory to IL-1beta by overproduction of IkappaB-alpha and support the hypothesis that alteration of microvascular inflammation may contribute to the central neurogenic neuroprotection elicited from the FN.

Cerebellar stimulation reduces inducible nitric oxide synthase expression and protects brain from ischemia.

A focal infarction produced by occlusion of the middle cerebral artery (MCAO) in spontaneously hypertensive rats induced expression of inducible nitric oxide synthase (iNOS) mRNA, measured by competitive reverse transcription-polymerase chain reaction. The mRNA appeared simultaneously in the ischemic core and penumbra at 8 h, peaked between 14 and 24 h, and disappeared by 48 h. At 24 h, inducible nitric oxide synthase (iNOS)-like immunoreactivity was present in the endothelium of cerebral microvessels and in scattered cells, probably representing leukocytes or activated microglia. Electrical stimulation of the cerebellar fastigial nucleus (FN) for 1 h, 48 h before MCAO, reduced infarct volumes by 45% by decreasing cellular death in the ischemic penumbra. It also reduced by >90% the expression of iNOS mRNA and protein in the penumbra, but not core, and decreased by 44% the iNOS enzyme activity. We conclude that excitation of neuronal networks represented in the cerebellum elicits a conditioned central neurogenic neuroprotection associated with the downregulation of iNOS mRNA and protein. This neuroimmune interaction may, by blocking the expression of iNOS, contribute to neuroprotection.

Metabolism of agmatine in macrophages: modulation by lipopolysaccharide and inhibitory cytokines.

Agmatine is an amine derived from the decarboxylation of arginine by arginine decarboxylase (ADC) and metabolized to putrescine by agmatinase. While prevalent in bacteria and plants, agmatine and its metabolic enzymes have been recently identified in mammalian tissues. In the present study we sought to determine: (a) whether macrophages (cell line RAW 264.7) express ADC and agmatinase, and (b) if the enzymes are regulated by lipopolysaccharide (LPS), and/or by the inhibitory cytokines transforming growth factor-beta (TGF-beta), interleukin-10 (IL-10) and interleukin-4 (IL-4). LPS induced a dose-dependent stimulation of agmatinase, while it decreased ADC, the effect in both cases being maximum at 20 h. As expected, LPS dose-dependently stimulated the inducible nitric oxide synthase activity (iNOS). A strong correlation was observed between the effects of LPS on the agmatine-related enzymes and iNOS. By contrast, exposure to IL-10 and TGF-beta caused a reduction in ADC and agmatinase, whereas IL-4 was ineffective on ADC, but reverted the LPS-induced increase of agmatinase. We conclude that the agmatine pathway may be an alternative metabolic route for arginine in macrophages, suggesting a regulatory role of agmatine during inflammation.

Suppression of glial nitric oxide synthase induction by heat shock: effects on proteolytic degradation of IkappaB-alpha.

Rat C6 glioma cells were stably transfected with a human cDNA encoding heat shock protein (HSP)70. Immunostaining revealed the presence of largely cytosolic HSP70 in C6-hsp70 cells, but not in control (vector transfected) C6-pTK cells. Induction of nitric oxide synthase (NOS-2) expression in C6-hsp70 cells, assessed by nitrite accumulation, was significantly reduced compared to control C6-pTK cells (25+/-8% of control cell induction, P < 0.005), when induced with a maximally stimulatory combination of bacterial endotoxin lipopolysaccharide (LPS) plus a mixture of three cytokines ("CM:" TNF-alpha, IL1-beta, and IFN-gamma). Immunostaining for the transcription factor NFkappaB p65 subunit revealed decreased cytokine-dependent nuclear uptake in HSP70 expressing cells compared to control cells. Activation of C6 cell NFkappaB by LPS plus CM required IkappaB degradation by the 20S proteasome, since NOS-2 expression was blocked by a selective proteasome inhibitor. In parental C6 cells, the presence of LPS plus CM caused a rapid (within 30 min) decrease in inhibitory IkappaB-alpha protein levels, and this loss was abolished by prior heat shock of the cells. In contrast, IkappaB-alpha levels in transfected cells were not modified by the expression of HSP70. These results demonstrate that constitutive HSP70 expression in glial cells can reduce NOS-2 induction, presumably due to inhibition of NFkappaB nuclear uptake. Furthermore, whereas prevention of decreases in IkappaB-alpha can account for the suppressive effects of heat shock, the results suggest that HSP70 blocks NOS-2 induction by interfering at a later step in the NFkappaB activation pathway.

Central neurogenic neuroprotection: central neural systems that protect the brain from hypoxia and ischemia.

The brain can protect itself from ischemia and/or hypoxia by two distinct mechanisms which probably involve two separate systems of neurons in the CNS. One, which mediates a reflexive neurogenic neuroprotection, emanates from oxygen-sensitive sympathoexcitatory reticulospinal neurons of the RVLM. These cells, excited within seconds by reduction in blood flow or oxygen, initiate the systemic vascular components of the oxygen conserving (diving) reflex. They profoundly increase rCBF without changing rCGU and, hence, rapidly and efficiently provide the brain with oxygen. Upon cessation of the stimulus the systemic and cerebrovascular adjustments return to normal. The system mediating reflex protection projects via as-yet-undefined projections from RVLM to upper brainstem and/or thalamus to engage a small population of neurons in the cortex which appear to be dedicated to transducing a neuronal signal into vasodilation. It also appears to relay the central neurogenic vasodilation elicited from other brain regions, including excitation of axons innervating the FN. This mode of protection would be initiated under conditions of global ischemia and/or hypoxemia because the signal is detected by medullary neurons. The second neuroprotective system is represented in intrinsic neurons of the cerebellar FN and mediates a conditioned central neurogenic neuroprotection. The response can be initiated by excitation of intrinsic neurons of the FN and does not appear dependent upon RVLM. The pathways and transmitters that mediate the effect are unknown. The neuroprotection afforded by this network is long-lasting, persisting for almost two weeks, and is associated with reduced excitability of cortical neurons and reduced immunoreactivity of cerebral microvessels. This mode of neuroprotection, moreover, is not restricted to focal ischemia, as we have demonstrated that it also protects the brain against global ischemia and excitotoxic cell death. That the brain may have neuronal systems dedicated to protecting itself from injury, at first appearing to be a novel concept, is, upon reflection, not surprising since the brain is not injured in naturalistic behaviors characterized by very low levels of rCBF, diving and hibernation. An understanding of the pathways, transmitters, and molecules engaged in such protection may provide new insights into novel therapies for a range of disorders characterized by neuronal death.

Computer modelling of human behaviour in aircraft fire accidents.

The mathematical simulation of the evacuation process has a wide and largely untapped scope of application within the aircraft industry. The function of the mathematical model is to provide insight into complex behaviour by allowing designers, legislators, and investigators to ask 'what if' questions. Such a model, EXODUS, is currently under development, and this paper describes its evolution and potential applications. EXODUS is an egress model designed to simulate the evacuation of large numbers of individuals from an enclosure, such as an aircraft. The model tracks the trajectory of each individual as they make their way out of the enclosure or are overcome by fire hazards, such as heat and toxic gases. The software is expert system-based, the progressive motion and behaviour of each individual being determined by a set of heuristics or rules. EXODUS comprises five core interacting components: (i) the Movement Submodel -- controls the physical movement of individual passengers from their current position to the most suitable neighbouring location; (ii) the Behaviour Submodel -- determines an individual's response to the current prevailing situation; (iii) the Passenger Submodel -- describes an individual as a collection of 22 defining attributes and variables; (iv) the Hazard Submodel -- controls the atmospheric and physical environment; and (v) the Toxicity Submodel -- determines the effects on an individual exposed to the fire products, heat, and narcotic gases through the Fractional Effective Dose calculations. These components are briefly described and their capabilities and limitations are demonstrated through comparison with experimental data and several hypothetical evacuation scenarios.