Stages Of Lesion Development Research Articles

New insights into neuropathology and pathogenesis of autoimmune glial fibrillary acidic protein meningoencephalomyelitis.

Anti-glial fibrillary acidic protein (GFAP) meningoencephalomyelitis (autoimmune GFAP astrocytopathy) is a new autoimmune central nervous system (CNS) disease diagnosable by the presence of anti-GFAP autoantibodies in the cerebrospinal fluid and presents as meningoencephalomyelitis in the majority of patients. Only few neuropathological reports are available and little is known about the pathogenic mechanisms. We performed a histopathological study of two autopsies and nine CNS biopsies of patients with anti-GFAP autoantibodies and found predominantly a lymphocytic and in one autopsy case a granulomatous inflammatory phenotype. Inflammatory infiltrates were composed of B and T cells, including tissue-resident memory T cells. Although obvious astrocytic damage was absent in the GFAP-staining, we found cytotoxic T cell-mediated reactions reflected by the presence of CD8+/perforin+/granzyme A/B+ cells, polarized towards astrocytes. MHC-class-I was upregulated in reactive astrocytes of all biopsies and two autopsies but not in healthy controls. Importantly, we observed a prominent immunoreactivity of astrocytes with the complement factor C4d. Finally, we provided insight into an early phase of GFAP autoimmunity in an autopsy of a pug dog encephalitis that was characterized by marked meningoencephalitis with selective astrocytic damage with loss of GFAP and AQP4 in the lesions.Our histopathological findings indicate that a cytotoxic T cell-mediated immune reaction is present in GFAP autoimmunity. Complement C4d deposition on astrocytes could either represent the cause or consequence of astrocytic reactivity. Selective astrocytic damage is prominent in the early phase of GFAP autoimmunity in a canine autopsy case, but mild or absent in subacute and chronic stages in human disease, probably due to the high regeneration potential of astrocytes. The lymphocytic and granulomatous phenotypes might reflect different stages of lesion development or patient-specific modifications of the immune response. Future studies will be necessary to investigate possible implications of pathological subtypes for clinical disease course and therapeutic strategies.

A Timing Effect of 17-β Estradiol on Atherosclerotic Lesion Development in Female ApoE-/- Mice.

Differences in size or composition of existing plaques at the initiation of estrogen (E2) therapy may underpin evidence of increased risk of atherosclerosis-associated clinical sequelae. We investigated whether E2 had divergent effects on actively-growing versus established-advanced atherosclerotic lesions. Eight weeks of subcutaneous bi-weekly injections of 3 µg/g 17β-estradiol (n = 18) or vehicle control (n = 22) were administered to female Apolipoprotein null-mice aged 25- or 45 weeks old. Histological assessment of lesion size within the brachiocephalic artery was conducted. Lesion composition was also assessed with acellular, calcification and fibrosis areas measured and other cellular features (intimal thickening, foam cells, lipid pools and cholesterol) scored (0–3) for severity. The comparison showed increased lesion size and calcified area with advancing age but no effect of E2. However, subtle changes in composition were observed following E2. Within the younger group, E2 increased intima thickening and acceleration of calcification. In the older group, E2 increased the thickness of the lesion cap. Therefore, this study shows different effects of E2 depending on the underlying stage of lesion development at the time of initiation of treatment. These divergent changes help explain the controversy of the adverse effects of E2 treatment in cardiovascular disease.

What Have We Learned from Perfusion MRI in Multiple Sclerosis?

Using MR imaging, perfusion can be assessed either by dynamic susceptibility contrast MR imaging or arterial spin-labeling. Alterations of cerebral perfusion have repeatedly been described in multiple sclerosis compared with healthy controls. Acute lesions exhibit relative hyperperfusion in comparison with normal-appearing white matter, a finding mostly attributed to inflammation in this stage of lesion development. In contrast, normal-appearing white and gray matter of patients with MS has been mostly found to be hypoperfused compared with controls, and correlations with cognitive impairment as well as fatigue in multiple sclerosis have been described. Mitochondrial failure, axonal degeneration, and vascular dysfunction have been hypothesized to underlie the perfusion MR imaging findings. Clinically, perfusion MR imaging could allow earlier detection of the acute focal inflammatory changes underlying relapses and new lesions, and could constitute a marker for cognitive dysfunction in MS. Nevertheless, the clinical relevance and pathogenesis of the brain perfusion changes in MS remain to be clarified.

Digital Dermatitis in Cattle: Current Bacterial and Immunological Findings.

Simple SummaryDigital dermatitis causes lameness in cattle. Numerous studies have identified multiple bacteria associated with these painful lesions. Several types of a spiral shaped bacteria, Treponema species, are thought to play a role in disease development. Little is known about the immune response to bacteria involved in digital dermatitis. Local inflammatory cells can contribute to the non-healing nature of the disease. Animal models of infection are required to develop effective vaccines and treatments.Globally; digital dermatitis is a leading form of lameness observed in production dairy cattle. While the precise etiology remains to be determined; the disease is clearly associated with infection by numerous species of treponemes; in addition to other anaerobic bacteria. The goal of this review article is to provide an overview of the current literature; focusing on discussion of the polybacterial nature of the digital dermatitis disease complex and host immune response. Several phylotypes of treponemes have been identified; some of which correlate with location in the lesion and some with stages of lesion development. Local innate immune responses may contribute to the proliferative, inflammatory conditions that perpetuate digital dermatitis lesions. While serum antibody is produced to bacterial antigens in the lesions, little is known about cellular-based immunity. Studies are still required to delineate the pathogenic traits of treponemes associated with digital dermatitis; and other host factors that mediate pathology and protection of digital dermatitis lesions.

Red mark syndrome in rainbow trout Oncorhynchus mykiss: Investigation of immune responses in lesions using histology, immunohistochemistry and analysis of immune gene expression

Red mark syndrome (RMS) is an economically significant disease which affects farmed rainbow trout in the United Kingdom, in the US and in mainland Europe. From the pattern of incidence, it appears to be transmissable, although no causative agent has yet been identified. RMS presents as a severe lymphocytic infiltration centred on the dermis and an alternative, host-focused approach was taken to understand the disease through investigating immune responses occurring in the lesion. Lesion and non-lesion skin at different stages of lesion development were examined using histochemistry and immunohistochemistry on paraffin sections. Expression of immune-related genes was compared between lesion and non-lesion skin. Investigation of early stage lesions suggested that the initial immune response is targeted at the region of the scale pocket, with lymphocyte infiltration and anti-tumour necrosis factor (TNF)-α staining of the stratum spongiosum, and increased numbers of major histocompatibility complex (MHC) II-positive cells immediately adjacent to the scale pocket. Gene expression analysis suggested a counterbalancing T helper (Th)1 and T regulatory (Treg) – type response is occurring in the lesion, with repression of Th2 and Th17-type responses.

Animal Models of Atherosclerosis

Atherosclerosis is a chronic inflammatory disorder that is the underlying cause of most cardiovascular disease. Both cells of the vessel wall and cells of the immune system participate in atherogenesis. This process is heavily influenced by plasma lipoproteins, genetics, and the hemodynamics of the blood flow in the artery. A variety of small and large animal models have been used to study the atherogenic process. No model is ideal as each has its own advantages and limitations with respect to manipulation of the atherogenic process and modeling human atherosclerosis or lipoprotein profile. Useful large animal models include pigs, rabbits, and nonhuman primates. Due in large part to the relative ease of genetic manipulation and the relatively short time frame for the development of atherosclerosis, murine models are currently the most extensively used. Although not all aspects of murine atherosclerosis are identical to humans, studies using murine models have suggested potential biological processes and interactions that underlie this process. As it becomes clear that different factors may influence different stages of lesion development, the use of mouse models with the ability to turn on or delete proteins or cells in tissue specific and temporal manner will be very valuable.

Proteinase inhibitor 9 is reduced in human atherosclerotic lesion development

Granzyme B, a proapoptotic serine protease, is abundant in advanced, unstable atherosclerotic plaques, and it is suggested to contribute to plaque instability by inducing vascular smooth muscle cells apoptosis and by degrading plaque extracellular matrix. Proteinase inhibitor 9, the only known endogenous inhibitor of granzyme B in humans, confers protection against granzyme-B-induced apoptosis. However, the role of proteinase inhibitor 9 in atherosclerotic lesion development has yet to be determined. We hypothesized that atherosclerotic lesions have lower proteinase inhibitor 9 expression levels that will increase their susceptibility to granzyme-B-induced apoptosis. Serial sections of human coronary arteries exhibiting different stages of lesion development were assessed by immunohistochemistry for proteinase inhibitor 9, α-smooth muscle cells actin, granzyme B, CD8, and active caspase-3. Frozen samples were analyzed by Western blot to evaluate total proteinase inhibitor 9 levels. Vascular smooth muscle cells express less proteinase inhibitor 9 as disease severity increases, and a significant difference in proteinase inhibitor 9 expression is observed between medial and intimal smooth muscle cells. High granzyme B levels colocalize with CD8+ cells and foam cells in the shoulder region and necrotic core area of advanced lesions. In advanced lesions, increased expression of activated caspase-3 in intimal SMC was associated with reduced proteinase inhibitor 9 expression in the presence of granzyme B. Reduced proteinase inhibitor 9 expression in human vascular smooth muscle cells is associated with atherosclerotic disease progression and is inversely related to the extent of apoptosis within the intima. Reduced proteinase inhibitor 9 expression may contribute to increased smooth muscle cell susceptibility to granzyme-B-induced apoptosis within the plaque.

Imaging and quantitative analysis of atherosclerotic lesions by CARS-based multimodal nonlinear optical microscopy.

The purpose of this study was to assess the ability of label-free multimodal nonlinear optical (NLO) microscopy to characterize, and thus enable quantitative in situ analyses of, different atherosclerotic lesion types, according to the original scheme suggested by the AHA Committee. Iliac arteries were taken from 24 male Ossabaw pigs divided into lean control and metabolic syndrome groups and were imaged by multimodal NLO microscopy where sum-frequency generation (SFG) and 2-photon excitation fluorescence (TPEF) were integrated on a coherent anti-Stokes Raman scattering (CARS) microscope platform. Foam cells, lipid deposits, matrices, and fibrous caps were visualized with submicron 3D resolution. Starting from the adaptive intimal thickening in the initial stage to the fibrous atheroma or mineralization in the advanced stages, lesions were visualized without labels. Histological staining of each lesion confirmed the lesion stages. Lipid and collagen contents were quantitatively analyzed based on the CARS and SFG signals. Lipid accumulation in thickened intima culminated in type IV whereas the highest collagen deposition was found in Type V lesions. Luminal CARS imaging showed the capability of viewing the location of superficial foam cells that indicate relatively active locus in a lesion artery. We have demonstrated the capability of CARS-based multimodal NLO microscopy to interrogate different stages of lesion development with subcellular detail to permit quantitative analysis of lipid and collagen contents.

Macrophages: Promising Targets for the Treatment of Atherosclerosis

Atherosclerosis is now recognised as a chronic inflammatory disease occurring within the artery wall and ultimately responsible for myocardial infarction, stroke and peripheral vascular disease. A crucial step in atherogenesis is the infiltration of monocytes into the subendothelial space of large arteries where they differentiate into macrophages and become functionally active. Macrophage accumulation within plaques is a hallmark of all stages of atherosclerosis, indeed recent studies have shown their presence has the potential to act as a non-invasive marker of disease activity and plaque stability. Activated macrophages are major players in all stages of lesion development. They not only accumulate lipids but also express effector molecules that are pro-inflammatory, cytotoxic and chemotactic. Furthermore, they secrete enzymes that degrade extracellular matrix leading to plaque destabilisation and increased risk of rupture. However, macrophages are heterogeneous and when appropriately activated they have the potential to drive tissue remodelling and ultimately vascular repair. Pharmacological modulation of macrophage activities therefore represents an important strategy for the prevention and treatment of atherosclerosis and other inflammatory diseases. The aim of this review is to give a brief overview of our current understanding of macrophage activation, distribution and function within inflamed tissue. This will provide the basis for highlighting already available and future methods to exploit specifically activated macrophages as diagnostic and therapeutic targets for atherosclerosis.

P1-379: Heparan sulphate proteoglycans affect the biological activity of Aβ

Amyloid beta (Aβ) deposits in Alzheimer's disease brains, i.e. senile plaques and vascular amyloid, also contain heparan sulphate proteoglycans (HSPGs). HSPGs consist of a protein core with sulphated glycosaminoglycans (GAGs) attached. The expression of HSPG in plaques suggests that these proteins play a role in the deposition of Aβ. It has been suggested that HSPGs may affect Aβ aggregation and clearance. However, the spatiotemporal association between HSPGs and Aβ has not yet been studied. Similarly, it is not known how HSPG/GAG expression relates to Aβ expression and biological activity. 1) to study in vitro (in human brain pericytes) the expression of HSPGs in response to Aβ; 2) to study in vitro (in human brain pericytes and smooth muscle cells) the role of GAGs in Aβ–mediated cellular toxicity; 3) to investigate the spatiotemporal association of HSPGs with Aβ. Protein expression of HSPGs was determined using Western blot analysis. RNA expression was measured using a quantitative RT–PCR (Taqman). The effect of GAGs on Aβ–mediated cellular toxicity was investigated using viability assays. In vitro, protein expression of the HSPGs agrin and glypican–1 and the degree of glycosylation of these HSPGs in pericytes was upregulated after treatment with Aβ. To confirm these findings at the mRNA level, quantitative PCR was performed. Finally, we demonstrated that several GAGs dose–dependently inhibited Aβ–mediated cellular degeneration in pericytes and smooth muscle cells. Moreover, we observed that the degree of inhibition was dependent on the degree of sulphation of the GAGs. In conclusion, GAGs may modulate the biological activity of Aβ and this capacity is related to the degree of negatively charged sulphate groups present in these GAGs. Furthermore, HSPG expression (both at the protein level and degree of glycosylation) is increased in response to Aβ. This suggests that HSPG expression in senile plaques and vascular amyloid follows the expression of Aβ. Currently, a study to confirm this association between Aβ and HSPGs, by investigating the expression of HSPGs in relation to Aβ expression in transgenic mice (APPSwe/PS–1 and SwDI Tg mice) during different stages of lesion development, is in progress.

Repopulation of Apolipoprotein E Knockout Mice With CCR2-Deficient Bone Marrow Progenitor Cells Does Not Inhibit Ongoing Atherosclerotic Lesion Development

Using bone marrow transplantation, we have previously demonstrated the critical role that hematopoietic CCR2 plays in early atherogenesis. Reconstitution of irradiated apolipoprotein (apo) E3-Leiden mice with CCR2-deficient bone marrow progenitor cells resulted in 86% reduction on overall atherosclerotic lesion development. However, no data on CCR2 in the cause of established atherosclerosis have been reported so far. To study the role of CCR2 in established atherosclerotic lesions, bone marrow progenitor cells harvested from apoE-/- and apoE-/-/CCR2-/- mice were transplanted into lethally irradiated 16-week-old apoE-/- mice with established atherosclerotic lesions. No significant differences were found in serum total cholesterol and triglycerides levels at different time points after transplantation. At age 16 weeks, lesion size in control apoE-/- mice was 3.28+/-1.06x10(5) microm2. At 9 weeks after transplantation, apoE-/---> apoE-/- and apoE-/-/CCR2-/---> apoE-/- mice had developed significantly larger atherosclerotic lesions (4.49+/-0.92x10(5) microm2, P<0.02 and 4.15+/-0.62x10(5) microm2, P<0.04 compared with controls, respectively). However, no significant effect of disruption of hematopoietic CCR2 was observed on the progression of lesions. Furthermore, the macrophage positive area (78+/-4% versus 72+/-9%) and collagen content (11+/-6% versus 15+/-3%) of the lesions were similar as well. In contrast to the critical role of CCR2 in the initiation of atherogenesis, bone marrow progenitor cell-derived CCR2 does not influence the progression of established atherosclerotic lesions, pointing to additional mechanisms for recruitment of monocytes at later stages of lesion development.

Serum Amyloid A and Lipoprotein Retention in Murine Models of Atherosclerosis

Elevated serum amyloid A (SAA) levels are associated with increased cardiovascular risk in humans. Because SAA associates primarily with lipoproteins in plasma and has proteoglycan binding domains, we postulated that SAA might mediate lipoprotein retention on atherosclerotic extracellular matrix. Immunohistochemistry was performed for SAA, apolipoprotein A-I (apoA-I), apolipoprotein B (apoB), and perlecan on proximal aortic lesions from chow-fed low-density lipoprotein receptor (LDLR)-/- and apoE-/- mice euthanized at 10, 50, and 70 weeks. SAA was detected on atherosclerotic lesion extracellular matrix at all time points in both strains. SAA area correlated highly with lesion areas (apoE-/-, r=0.76; LDLR-/-, r=0.86), apoA-I areas (apoE-/-, r=0.88; LDLR-/-, r=0.80), apoB areas (apoE-/-, r=0.74; LDLR-/-, r=0.89), and perlecan areas (apoE-/-, r=0.83; LDLR-/-, r=0.79) (all P<0.0001). In vitro, SAA enrichment increased high-density lipoprotein (HDL) binding to heparan sulfate proteoglycans, and immunoprecipitation experiments using plasma from apoE-/- and LDLR-/- mice demonstrated that SAA was present on both apoA-I-containing and apoB-containing lipoproteins. In chow-fed apoE-/- and LDLR-/- mice, SAA is deposited in murine atherosclerosis at all stages of lesion development, and SAA immunoreactive area correlates highly with lesion area, apoA-I area, apoB area, and perlecan area. These findings are consistent with a possible role for SAA-mediated lipoprotein retention in atherosclerosis.

Viewpoint 3

Viewpoint 3

Nitric oxide: potential role for reducing gastro-enteropathy.

The pathogenesis of non-steroidal anti-inflammatory drug (NSAID)-induced gastroenteropathy may involve a number of key events leading to increased intestinal permeability and inflammation (topical effect) and the development of ulcers (micro-vascular effects of COX-1 inhibition and prostaglandin deficiency). Many strategies have been employed in an attempt to reduce the toxic effects of NSAIDs and these have been targeted at the different pathogenic stages of lesion development. One of the latest in this long chain of damage limitation has been the development of nitric oxide (NO) sequestering NSAIDs (NO-NSAIDs). It is suggested that the NO, which is released as the compounds are broken down, may counteract the consequences of the NSAID-induced decrease in mucosal prostaglandins. Here we examine the proposed mechanisms for NSAID-induced gastrointestinal damage together with some of the methods employed to address these mechanisms. We also consider the physiologic roles of NO in the gut together with how it may be potentially employed as an agent for limiting the side effects of NSAIDs in the gastrointestinal tract.

Chronic pain increases brainstem proneurotensin/neuromedin-N mRNA expression: a hybridization-histochemical and immunohistochemical study using three different rat models for chronic nociception

The role of neurotensin in the central nervous system is poorly understood. Exogenous neurotensin has potent antinociceptive effects when injected into the midbrain periaqueductal gray (PAG). Although it is present in terminals, fibers and perikarya within the PAG and other midbrain regions known for their antinociceptive circuits, it is not known whether endogenous neurotensin modulates nociception. We examined the midbrain in three different rat models for nociception to learn whether acute or chronic pain altered neuronal levels of the proneurotensin/neuromedin N mRNA (neurotensin mRNA). The models were: adjuvant-induced polyarthritis, adjuvant-induced unilateral paw inflammation, and unilateral peripheral mononeuropathy caused by ligation of the sciatic nerve. Behavioral observations confirmed that the expected symptoms developed as previously described. Within each of the three experimental models, we performed in situ hybridization histochemistry on coronal sections from three midbrain levels that included the rostral one-third of the PAG, the middle one-third of the PAG, and the caudal one-third of the PAG. At the level of the rostral PAG, we found that neither chronic nor acute nociception altered the frequencies or distributions of neurons containing neurotensin mRNA. In contrast, at the levels of the mid- and caudal one third of the PAG, the early effects of the nociceptive lesions differed from the chronic effects. During the acute phase of each model, increases in either the frequency or field area of neurons that were hybridization-positive for neurotensin mRNA were confined to the ventromedial PAG and the dorsal raphe nucleus. As the nociceptive stimuli became chronic, the early increases in neurotensin mRNA-containing neurons at the level of the middle third of the ventral PAG were diminished but remained above control levels, while increases in neurotensin mRNA began to occur in the midbrain tegmentum lateral to the PAG. The most striking increases in neurotensin mRNA expression were observed 16-17 days after the onset of nociceptive stimuli. At the level of the mid-PAG and caudal PAG, increased hybridization signal intensities and neuron frequencies occurred within the nucleus cuneiformis and the lateral tegmental nuclei, including the pedunculopontine and microcellular tegmental nuclei, as well as the deep mesencephalic nuclei. Hybridization-positive neurons in the tegmental nuclei were not observed at early stages of lesion development, but were a consistent feature of caudal midbrains after nociception became chronic.(ABSTRACT TRUNCATED AT 400 WORDS)

Expression of the interferon-gamma-inducible chemokines IP-10 and Mig and their receptor, CXCR3, in multiple sclerosis lesions.

The recruitment of leucocytes to sites of inflammation is an important feature of multiple sclerosis (MS) pathology. Chemokines are involved in the activation and specific directional migration of monocytes and T-lymphocytes to sites of inflammation. Using immunocytochemistry, the expression of the alpha-chemokines, interferon (IFN)-gamma-inducible protein-10 (IP-10) and monokine induced by IFN-gamma (Mig), and their receptor CXCR3 have been examined in post-mortem central nervous system (CNS) tissue from MS cases at different stages of lesion development. In actively demyelinating lesions both IP-10 and Mig protein were predominantly expressed by macrophages within the plaque and by reactive astrocytes in the surrounding parenchyma. CXCR3 was expressed by T cells and by astrocytes within the plaque. Interferon-gamma may stimulate glial cells to express IP-10 and Mig, which continue the local inflammatory response by selectively recruiting activated T-lymphocytes into the CNS.

IP-10, Mig and CXCR3 expression in multiple sclerosis at different stages of lesion development

IP-10, Mig and CXCR3 expression in multiple sclerosis at different stages of lesion development

Expression of monocyte chemoattractant protein-1 and other β-chemokines by resident glia and inflammatory cells in multiple sclerosis lesions

β-chemokines induce the directional migration of monocytes and T lymphocytes and are thus associated with chronic inflammation. Using immunocytochemistry and in situ hybridisation (ISH) techniques, we have examined the expression of the β-chemokines monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein (MIP)-1 α, MIP-1 β, and RANTES (regulated upon activation, normal T cell expressed and secreted) in post-mortem human brain from multiple sclerosis (MS) cases, at different stages of lesion development. In actively demyelinating MS plaques RANTES expression was restricted to the blood vessel endothelium, perivascular cells and surrounding astrocytes, suggesting a role in the recruitment of inflammatory cells from the circulation. MCP-1 was expressed by astrocytes and macrophages within acute MS lesions, but was restricted to reactive astrocytes in the parenchyma surrounding the lesion. MIP-1 α was expressed by astrocytes and macrophages within the plaque, while MIP-1 β was expressed by macrophages and microglia within the lesion, and by microglia in surrounding white matter. Glial cells may be stimulated to produce chemokines and continue the local inflammatory response by forming chemotactic gradients to attract T cells and mononuclear phagocytes from the circulation and surrounding tissue.

Expression of αB-crystallin in glia cells during lesional development in multiple sclerosis

The small heat shock protein αB-crystallin was recently identified as a dominant human T-cell antigen in myelin derived from multiple sclerosis (MS) patients. Using immunohistochemical techniques, oligodendrocytes as well as astrocytes in MS lesions were shown to express α B-crystallin. In the present study we examined the expression of α B-crystallin, human natural killer cell marker (HNK-1; as a marker for immature oligodendrocytes) and heat shock protein 60 (hsp60) in gila cells at different stages of MS lesion development i.e. in early active lesions; late active lesions and inactive lesions. The results demonstrate that already at the earliest stages of lesional development a subpopulation of oligodendrocytes express detectable levels of αB-crystallin. In active lesions about 5-10% of all oligodendrocytes were found to express αB-crystallin, whereas in inactive lesions the relative number of αB-crystallin-expressing oligodendrocytes was approximately tenfold less. For astrocytes the relative number of αB- crystallin-expressing cells was 40-50% for all three types of lesions. Also, αB-crystallin-expressing oligodendrocytes and astrocytes displayed different patterns of distribution in lesional areas. These data suggest different regulatory pathways for αB-crystallin expression in either type of glia cell. No correlation was found between expression patterns of HNK-1 and αB- crystallin indicating that the subpopulation of αB-crystallin-expressing oligodendrocytes consisted of both mature and immature oligodendrocytes. In addition, no correlation was found between expression of hsp60 and αB- crystallin in MS lesions suggesting different regulatory pathways for either hsp.

Assessing the stage of caries lesion activity on the basis of clinical and microbiological examination

The dynamic nature of caries lesion progression may require that classification of caries lesions makes distinctions in activity status. The aim of the present review was to compile and discuss the literature which pertains to clinical assessment of caries lesion activity, and to examine whether recent developments in microbiological research may justify the use of microbiological methods for evaluation of caries activity. Clinical observations suggest that caries lesion progression can be arrested at any stage of lesion development, provided that clinically plaque-free conditions are obtained. However, there is no universal level of oral hygiene to be recommended. The diagnoses "active" and "inactive/arrested" caries have been validated by a range of histological and chemical methods which have supported a separation into distinct clinical categories. Simple microbiological methods have so far not been useful in differentiating between active and inactive caries lesions. Very few studies have evaluated the inter- and intraexaminer reliability of caries diagnostic criteria based on assessment of the activity state of lesions, but recent data indicate that active and inactive caries lesions can be diagnosed with a high degree of reliability. A decision-making tree for dental caries is presented by means of which it is possible to associate the assessment of caries lesion activity with an appropriate treatment modality. It is concluded that research into better methods of assessing caries lesion activity clinically should be stimulated.