The monocyte cell surface is a unique site of autoantigen generation in rheumatoid arthritis.

Although anti-citrullinated protein autoantibodies (ACPAs) are a hallmark serological feature of rheumatoid arthritis (RA), the mechanisms and cellular sources behind the generation of the RA citrullinome remain incompletely defined. Peptidylarginine deiminase IV (PAD4), one of the key enzymatic drivers of citrullination in the RA joint, is expressed by granulocytes and monocytes; however, the subcellular localization and contribution of monocyte-derived PAD4 to the generation of citrullinated autoantigens remain underexplored. In this study, we demonstrate that PAD4 displays a widespread cellular distribution in monocytes, including expression on the cell surface. Surface PAD4 was enzymatically active and capable of citrullinating extracellular fibrinogen and endogenous surface proteins in a calcium dose-dependent manner. Fibrinogen citrullinated by monocyte-surface PAD4 could be specifically recognized over native fibrinogen by a panel of eight human monoclonal ACPAs. Several unique PAD4 substrates were identified on the monocyte surface via mass spectrometry, with citrullination of the CD11b and CD18 components of the Mac-1 integrin complex being the most abundant. Citrullinated Mac-1 was found to be a target of ACPAs in 25% of RA patients, and Mac-1 ACPAs were significantly associated with HLA-DRB1 shared epitope alleles, higher C-reactive protein and IL-6 levels, and more erosive joint damage. Our findings implicate the monocyte cell surface as a unique and consequential site of extracellular and cell surface autoantigen generation in RA.

Observation of Zitterbewegung in photonic microcavities.

We present and experimentally study the effects of the photonic spin-orbit coupling on the real space propagation of polariton wavepackets in planar semiconductor microcavities and polaritonic analogues of graphene. In particular, we demonstrate the appearance of an analogue Zitterbewegung effect, a term which translates as 'trembling motion' in English, which was originally proposed for relativistic Dirac electrons and consisted of the oscillations of the centre of mass of a wavepacket in the direction perpendicular to its propagation. For a planar microcavity, we observe regular Zitterbewegung oscillations whose amplitude and period depend on the wavevector of the polaritons. We then extend these results to a honeycomb lattice of coupled microcavity resonators. Compared to the planar cavity, such lattices are inherently more tuneable and versatile, allowing simulation of the Hamiltonians of a wide range of important physical systems. We observe an oscillation pattern related to the presence of the spin-split Dirac cones in the dispersion. In both cases, the experimentally observed oscillations are in good agreement with theoretical modelling and independently measured bandstructure parameters, providing strong evidence for the observation of Zitterbewegung.

Developing High-Performance In-Plane Flexible Aqueous Zinc-Ion Batteries with Laser-Scribed Carbon-Supported All Electrodeposited Electrodes.

Developing high-performance, safer, and affordable flexible batteries is of urgent need to power the fast-growing flexible electronics market. In this respect, zinc-ion chemistry employing aqueous-based electrolytes represents a promising combination considering the safety, cost efficiency, and both high energy and high-power output. Herein, we represent a high-performance flexible in-plane aqueous zinc-ion miniaturized battery constructed with all electrodeposited electrodes, i.e., MnO2 cathode and zinc anode with polyimide-derived interdigital patterned laser-scribed carbon (LSC) as the current collector as well as the template for electrodeposition. The LSC possesses a cross-linked network of graphitic carbon sheet, which offers large surface area over low footprint and ensures active materials loading with a robust conductive network. The LSC with high zincophilic characteristic also offers dendrite-free zinc deposition with very low Zn2+ plating stripping overpotential. Benefitting from the Zn//MnO2-rich redox chemistry, the ability of the 3D LSC network to uniformly distribute reaction sites, and the architectural merits of in-plane interdigitated electrode configuration, we report very high capacity values of ∼549 mAh/g (or ∼523 µAh/cm2) and 148 mAh/g (or 140 µAh/cm2) at 0.1 A/g (0.095 mA/cm2) and 2 A/g (1.9 mA/cm2) currents, respectively. The device was also able to maintain a high capacity of 196 mAh/g (areal capacity of 76.19 µAh/cm2) at 1 A/g (0.95 mA/cm2) current after 1350 cycles. The flexibility of the device was demonstrated in polyacryl amide (PAM) gel polymer soaked with a 2 M ZnSO4 and 0.2 M MnSO4 electrolyte, which exhibited a comparable specific capacity of ∼102-110 mAh/g in flat condition and different bending (100° or 160° bending) conditions. The device does not use any conventional current collector, separator, and conductive or polymer additives. The overall process is highly scalable and can be completed in less than a couple of hours.

"Modified Schirmer Test in Assessment of Salivary Flow Rate Among Patients on Antidepressants": A Comparative Study.

AIMS: The objective of this study was to assess salivary flow rate (SFR) among healthy subjects or patients on antidepressant drugs such as tricyclic antidepressants (TCAs) and selective serotinin reuptake inhibitors (SSRIs) by using the "Modified Schirmer Test" (MST). To evaluate and correlate salivary flow rate by using MST and comparing it with the spitting method in patients on antidepressants and healthy control subjects. MATERIALS AND METHODS: Data were collected from the patients visiting the dental college and the psychiatry department. A total of 105 subjects were included in the present study, dividing Group I as control, Group II as SSRIs, and Group III as TCAs. In all subjects, a screening questionnaire was recorded, SFR was determined by the spitting method, and MST was carried out in the morning. The MST was performed by placing a modified Schirmer tear strip (STS) on the floor of the mouth for all subjects, and readings were taken for 3 min. RESULTS: The SFR value obtained among Group I by the spitting method was 0.83 ml at 5 min, and by the MST method was 34.97 mm at 3 min, with a P value of 0.860. The SFR value obtained among Group II by the spitting method was 0.47 ml at 5 min, and by the MST method was 26.25 mm at 3 min, with a P value of 0.001, which was highly significant. The SFR value obtained among Group III by the spitting method was 0.394 ml at 5 min, and by the MST method was 10.71 mm at 3 min, with a P value of 0.041, which was significant. CONCLUSIONS: A significant positive correlation was observed between the SFR value obtained by both the spitting method and MST. From our study, we can conclude that the MST can be used as an effective noninvasive tool to estimate SFR.

PAD enzymes in rheumatoid arthritis: pathogenic effectors and autoimmune targets.

Peptidylarginine deiminases (PADs) have an important role in the pathogenesis of rheumatoid arthritis (RA) owing to their ability to generate citrullinated proteins - the hallmark autoantigens of RA. Of the five PAD enzyme isoforms, PAD2 and PAD4 are the most strongly implicated in RA at both genetic and cellular levels, and PAD inhibitors have shown therapeutic efficacy in mouse models of inflammatory arthritis. PAD2 and PAD4 are additionally targeted by autoantibodies in distinct clinical subsets of patients with RA, suggesting anti-PAD antibodies as possible biomarkers for RA diagnosis and prognosis. This Review weighs the evidence that supports a pathogenic role for PAD enzymes in RA as both promoters and targets of the autoimmune response, as well as discussing the mechanistic and therapeutic implications of these findings in the wider context of RA pathogenesis. Understanding the origin and consequences of dysregulated PAD enzyme activity and immune responses against PAD enzymes will be important to fully comprehend the pathogenic mechanisms involved in this disease and for the development of novel strategies to treat and prevent RA.

Citrulline Not a Major Determinant in the Recognition of Peptidylarginine Deiminase 2 and 4 by Autoantibodies in Rheumatoid Arthritis.

OBJECTIVE: Citrullinated proteins are hallmark targets of autoantibodies in rheumatoid arthritis (RA). Our study was undertaken to determine the effect of autocitrullination on the recognition of peptidylarginine deiminases (PADs) 2 and 4 by autoantibodies in RA. METHODS: Autocitrullination sites in PAD2 and PAD4 were determined by mass spectrometry and literature review. Antibodies against native and autocitrullinated PADs in 184 patients with RA were detected by enzyme-linked immunosorbent assay. Linear regression analysis, outlier calculations, and competition assays were performed to evaluate antibody reactivity to native and citrullinated PADs. RESULTS: Autocitrullination of PAD2 and PAD4 was detected in 16 (48%) of 33 arginine residues and 7 (26%) of 27 arginine residues, respectively. Despite robust autocitrullination, autoantibodies bound similarly to native and citrullinated PAD2 or PAD4 (ρ = 0.927 and ρ = 0.903, respectively; each P < 0.0001). Although subsets of anti-PAD-positive sera were identified as exhibiting preferential recognition of native or citrullinated PAD2 (40.5% or 4.8%, respectively) or PAD4 (11.7% or 10.4%, respectively), competition assays confirmed that the majority of anti-PAD reactivity was attributed to a pool of autoantibodies that bound irrespective of citrullination status. CONCLUSION: Autocitrullination does not affect autoantibody reactivity to PADs in the majority of patients with RA, demonstrating that anti-PAD antibodies are distinct from anti-citrullinated protein antibodies in their dependence on citrullination for binding.

"Analysis of immunohistochemical expression of epidermal growth factor receptor in oral squamous cell carcinoma using tissue microarray technology and whole sections:" A comparative study.

BACKGROUND: Oral squamous cell carcinoma (OSCC) accounts for more than 90% of all oral cancers. Epidermal growth factor receptor (EGFR) dysregulation is associated with essentially all of the key features of cancer. Tissue microarrays (TMAs) allow the simultaneous analysis of many tumours using small-diameter cores sampled from larger blocks of tissue. Hence present study was taken up to validate TMA technology. AIMS AND OBJECTIVES: To analyse and compare the immunohistochemical (IHC) expression of EGFR in OSCC using TMA technology and in whole tissue sections. MATERIALS AND METHODS: Study included 34 cases of OSCC.Three tissue cores, each 1 mm in diameter were placed into a recipient paraffin block using a precision microarray instrument finally containing 102 spots. EGFR expression was analysed. Agreement between whole sections and TMA scores was analysed using Cohen's weighted Kappa. RESULTS: EGFR expression was seen in 61.8% of whole section cases. In TMA out of 102 cores 75.50 % of the disks were confirmed to represent an adequate amount of tumor tissue. In TMA 48.5% cases showed EGFR expression.The EGFR expression of whole. CONCLUSION: Some OSCC express high EGFR and this expression may be an independent Wfactor of certain clinico-pathological variables. TMA may be used as an adjunct with conventional method of evaluation of OSCC especially in larger sample sized studies keeping in mind its limitations.

An LRR Receptor-Teneurin System Directs Planar Polarity at Compartment Boundaries.

Epithelial cells dynamically self-organize in response to extracellular spatial cues relayed by cell-surface receptors. During convergent extension in Drosophila, Toll-related receptors direct planar polarized cell rearrangements that elongate the head-to-tail axis. However, many cells establish polarity in the absence of Toll receptor activity, indicating the presence of additional spatial cues. Here we demonstrate that the leucine-rich-repeat receptor Tartan and the teneurin Ten-m provide critical polarity signals at epithelial compartment boundaries. The Tartan and Ten-m extracellular domains interact in vitro, and Tartan promotes Ten-m localization to compartment boundaries in vivo. We show that Tartan and Ten-m are necessary for the planar polarity and organization of compartment boundary cells. Moreover, ectopic stripes of Tartan and Ten-m are sufficient to induce myosin accumulation at stripe boundaries. These results demonstrate that the Tartan/Ten-m and Toll receptor systems together create a high-resolution network of spatial cues that guides cell behavior during convergent extension.

Autoantibodies to Peptidylarginine Deiminase 2 Are Associated With Less Severe Disease in Rheumatoid Arthritis.

Objective: Peptidylarginine deiminases (PAD) 2 and 4 are key enzymes in rheumatoid arthritis (RA) pathogenesis due to their ability to generate the protein targets of anti-citrullinated protein antibodies (ACPA). Anti-PAD4 antibodies that cross-react with PAD3 (anti-PAD3/4) have been identified and are associated with severe joint and lung disease. Here, we examined whether anti-PAD2 antibodies were present in patients with RA and defined their clinical significance. Patients and Methods: A PAD2 ELISA was established to screen for anti-PAD2 IgG in sera from RA patients from a prospective observational cohort study (n = 184) and healthy controls (n = 100). RA patient characteristics were compared according to anti-PAD2 antibody status. Multivariable models were constructed to explore the independent associations of anti-PAD2 antibodies with clinical variables. Results: Anti-PAD2 antibodies were found in 18.5% of RA patients and 3% of healthy controls (p < 0.001). Among RA patients, anti-PAD2 antibodies were not associated with traditional genetic or serologic RA risk factors, including HLA-DRß1 shared epitope alleles, ACPA, rheumatoid factor (RF), or anti-PAD3/4 antibodies. In addition, antibodies to PAD2 were associated with fewer swollen joints, a lower prevalence of interstitial lung disease, and less progression of joint damage. In subset analyses in which patients were stratified by the baseline presence of ACPA/RF or anti-PAD3/4 antibodies, anti-PAD2 antibodies provided additional value in identifying patients with the least progressive joint disease. Conclusions: Anti-PAD2 antibodies represent a novel serologic marker in RA that identifies a genetically and clinically unique subset of patients with less severe joint and lung disease.

Pathobiology of tobacco smoking and neurovascular disorders: untied strings and alternative products.

Tobacco smoke (TS) is the leading cause of preventable deaths worldwide. In addition to a host of well characterized diseases including chronic obstructive pulmonary disease, oral and peripheral cancers and cardiovascular complications, epidemiological evidence suggests that chronic smokers are at equal risk to develop neurological and neurovascular complications such as multiple sclerosis, Alzheimer's disease, stroke, vascular dementia and small vessel ischemic disease (SVID). Unfortunately, few direct neurotoxicology studies of tobacco smoking and its pathogenic pathways have been produced so far. A major link between TS and CNS disorders is the blood-brain barrier (BBB). In this review article, we summarize the current understanding of the toxicological impact of TS on BBB physiology and function and major compensatory mechanisms such as nrf2- ARE signaling and anti-inflammatory pathways activated by TS. In the same context, we discuss the controversial role of antioxidant supplementation as a prophylactic and/or therapeutic approach in delaying or decreasing the disease complications in smokers. Further, we cover a number of toxicological studies associated with "reduced exposure" cigarette products including electronic cigarettes. Finally, we provide insights on possible avenues for future research including mechanistic studies using direct inhalation rodent models.

Impact of cigarette smoke extract and hyperglycemic conditions on blood-brain barrier endothelial cells.

BACKGROUND: Diabetes and tobacco smoking are significant public health concerns which have been shown to independently impact the blood-brain barrier (BBB). Since smoking is a risk factor for diabetes and shares some of the common pathological pathways leading to metabolic abnormalities, it is hypothesized that their combination would produce additive or synergistic BBB dysfunction. Therefore, the objective of this study was to assess this hypothesis and evaluate the magnitude of these effects in vitro using hCMEC/D3 cells; a well-established human BBB endothelial cell line. METHODS: Monolayers of hCMEC/D3 cells were exposed to hyperglycemic conditions (HG; 35 mM) or 5% soluble cigarette smoke extracts (CSE, model of mainstream smoke exposure) for 12-24 h. Cells were then harvested for subsequent biochemical analyses. Transendothelial electrical resistance (TEER) and paracellular permeability to florescent dextrans were used to assess monolayer integrity. Analysis of released factors and cytokines was carried out by ELISA. Western blot (WB) analysis/immunofluorescence of relevant molecular targets was carried out. P-gp efflux activity was measured using rhodamine 123. RESULTS: Immunofluorescence and WB data showed a significant ZO-1 down-regulation by HG and/or CSE over 24 h exposure. CSE in presence of HG produced a synergistic increase in release of vascular endothelial growth factor that was accompanied by decreased TEER and augmented permeability to labeled dextrans in a size-dependent manner. Moreover, CSE increased the expression of GLUT-1 and SGLT-1 in isolated membrane fractions of hCMEC/D3 cells. The effect was amplified by HG. Both, HG and CSE elicited the membrane upregulation of P-glycoprotein (P-gp) expression which however, was not paralleled by a comparable efflux activity. Interestingly, concomitant exposure to HG and CSE evoked a marked upregulation of PECAM-1 and other pro-inflammatory markers including IL-6 and -8, when compared to each condition alone. Moreover, exposure to all tested conditions amplified (to a different degree) cellular oxidative stress response denoted by increased Nrf2 nuclear translocation. CONCLUSION: Overall, our results have clearly shown an additive pattern in the release of angiogenic and inflammatory factors following concomitant exposure to HG and CSE. This suggests the involvement of common key modulators in BBB impairment by both CS and HG possibly through the activation of oxidative stress responses.

Effect of full flavor and denicotinized cigarettes exposure on the brain microvascular endothelium: a microarray-based gene expression study using a human immortalized BBB endothelial cell line.

BACKGROUND: Tobacco smoke (TS) toxicity to the brain microvasculature is still an understudied area till date. NF-E2 related factor (Nrf2) is a key transcription factor responsible for activating the antioxidant response element (ARE) genes following an oxidative insult. Till date, several studies targeting the blood brain barrier (BBB) have shown some protective role of Nrf2 in ischemia-reperfusion (IR) injury, however, its functional role in chronic smokers subjected to a life-long oxidative stress has never been addressed. This is of crucial importance since smokers have a much higher risk for cerebrovascular stroke and tobacco smoke exposure has been clearly shown to enhance BBB damage following an ischemia/reperfusion injury. Thus, the goal of our study was to investigate the defense pathways activated at the BBB endothelial level by TS exposure. Specifically we focused on Nrf2 and nuclear factor kappa-light-chain-enhancer of activated B signaling response (NF-κß) as the central protective mechanisms related to oxidative insult. RESULTS: With the exception of Nicotine, both full flavor (3R4F) and decotinized (ULN) cigarettes activated Nrf2 and NFκß pathways in hCMEC/D3 endothelial cells. Several detoxification and anti-oxidant genes including downstream products were also activated including NAD(P)H dehydrogenase quinone 1 (NQO-1), heme oxygenase-1 (HMOX-1), catalytic and modifier subunits of glutamate-cysteine ligase (GCL), solute carrier-SLC7A11). Gene expression levels of cytochrome P450s (CYP2S1 and CYP51A1) and efflux transporters P-glycoprotein (P-gp) and multi-drug resistance protein-4 (MRP4) were also enhanced. Increase of P-gp functional activity and depletion of GSH were also observed. Strikingly, toxicity of denicotinized ("reduced exposure") cigarettes was equivalent to 3R4F (or worse). CONCLUSIONS: This study provides a detailed analysis of Nrf2-related cytoprotective mechanisms activated in response to 3R4F and ULN-derived TS exposure correlating the results with their oxidative and inflammatory potential. Toxicants present in soluble cigarette smoke extracts (CSE) and not nicotine seem to be the primary determinant of vascular toxicity. In this respect our results from this and previous studies suggest that chronic TS exposure can overcome Nrf2 and NFκB-p65 dependent cytoprotective mechanisms of the brain microvascular endothelium possibly leading to BBB impairment and loss of BBB integrity.

Epithelial ovarian tumors: Clinicopathological correlation and immunohistochemical study.

BACKGROUND: Ovarian cancer is the third leading site of cancer among women, trailing behind cervix and breast cancer. AIM: This study was undertaken to analyze the immunohistochemical (IHC) profile of estrogen receptors (ER), progesterone receptors (PR), Ki-67, and p53 in various ovarian epithelial tumors and attempt correlation with clinical and histopathological findings. MATERIALS AND METHODS: The present study was conducted over a period of 4 years. A technique of manual tissue array was employed for cases subjected for IHC. The primary antibodies used were ER, PR, p53, and Ki-67. A correlation was attempted between histopathological and IHC findings. Results were subjected to statistical analysis. Software program "the primer of biostatistics 5.0" was used for calculation of interrelationships between the analyzed ER, PR, p53, and Ki-67 expression and histological factors by Pearson's Chi-square test. The results were considered to be significant when the P < 0.05. RESULTS: There were 110 cases of surface epithelial ovarian tumors (SEOT) encountered over the period of 4 years. The expression of ER was more in malignant tumors (13/16, 81.25%) than borderline (9/12, 75%) and benign (20/82, 24.39%). As compared to ER, the expression of PR was more in benign (51/82, 62.19%) than borderline (8/12, 66.67%) and malignant tumors (9/16, 56.25%). The expression of PR was more in benign tumors than borderline and malignant tumors. However, this was not statistically significant (Chi-square = 0.335 with 2 degrees of freedom; P = 0.846). The expression of p53 was less in benign (5/82, 6.1%) than borderline (9/12, 75%) and malignant tumors (13/16, 81.25%). The expression of Ki-67 was more in malignant (4/82, 4.88%) than borderline (10/12, 83.33%) and benign tumors (15/16, 93.75%). In all the above cases, the difference was statistically significant (P < 0.05). There was statistically significant difference in the expression of ER, PR, p53, and Ki-67 in the patients with age <40 years and above 40 years (P = 0.912). A positive correlation was observed in p53 expression and tumor grade. Similar correlation was seen in Ki-67 and tumor grade. It was also noted that mean Ki-67 labeling index (Li) had also increased with tumor grade. In the case of serous tumors, ER was expressed in all high- and low-grade tumors. The expression of PR was more in low-grade tumors than high-grade ones. P53 expression was seen in all high-grade tumors and 33.34% of low-grade tumor. The Ki-67 Li was more in high-grade tumors than low-grade tumors. Expression of ER, p53, and Ki-67 was higher in tumor showing metastasis. The mean Ki-67 Li was also higher in metastasizing tumors. However, PR expression was less in metastasizing tumors than nonmetastasizing tumors. CONCLUSION: IHC marker report of ER, PR status, and Ki-67 if included in each pathology report will pave the way for better understanding of biological behavior and modify treatment strategies.

In vitro cerebrovascular modeling in the 21st century: current and prospective technologies.

The blood-brain barrier (BBB) maintains the brain homeostasis and dynamically responds to events associated with systemic and/or rheological impairments (e.g., inflammation, ischemia) including the exposure to harmful xenobiotics. Thus, understanding the BBB physiology is crucial for the resolution of major central nervous system CNS) disorders challenging both health care providers and the pharmaceutical industry. These challenges include drug delivery to the brain, neurological disorders, toxicological studies, and biodefense. Studies aimed at advancing our understanding of CNS diseases and promoting the development of more effective therapeutics are primarily performed in laboratory animals. However, there are major hindering factors inherent to in vivo studies such as cost, limited throughput and translational significance to humans. These factors promoted the development of alternative in vitro strategies for studying the physiology and pathophysiology of the BBB in relation to brain disorders as well as screening tools to aid in the development of novel CNS drugs. Herein, we provide a detailed review including pros and cons of current and prospective technologies for modelling the BBB in vitro including ex situ, cell based and computational (in silico) models. A special section is dedicated to microfluidic systems including micro-BBB, BBB-on-a-chip, Neurovascular Unit-on-a-Chip and Synthetic Microvasculature Blood-brain Barrier.

Oxidative and pro-inflammatory impact of regular and denicotinized cigarettes on blood brain barrier endothelial cells: is smoking reduced or nicotine-free products really safe?

BACKGROUND: Both active and passive tobacco smoke (TS) potentially impair the vascular endothelial function in a causative and dose-dependent manner, largely related to the content of reactive oxygen species (ROS), nicotine, and pro-inflammatory activity. Together these factors can compromise the restrictive properties of the blood-brain barrier (BBB) and trigger the pathogenesis/progression of several neurological disorders including silent cerebral infarction, stroke, multiple sclerosis and Alzheimer's disease. Based on these premises, we analyzed and assessed the toxic impact of smoke extract from a range of tobacco products (with varying levels of nicotine) on brain microvascular endothelial cell line (hCMEC/D3), a well characterized human BBB model. RESULTS: Initial profiling of TS showed a significant release of reactive oxygen (ROS) and reactive nitrogen species (RNS) in full flavor, nicotine-free (NF, "reduced-exposure" brand) and ultralow nicotine products. This release correlated with increased oxidative cell damage. In parallel, membrane expression of endothelial tight junction proteins ZO-1 and occludin were significantly down-regulated suggesting the impairment of barrier function. Expression of VE-cadherin and claudin-5 were also increased by the ultralow or nicotine free tobacco smoke extract. TS extract from these cigarettes also induced an inflammatory response in BBB ECs as demonstrated by increased IL-6 and MMP-2 levels and up-regulation of vascular adhesion molecules, such as VCAM-1 and PECAM-1. CONCLUSIONS: In summary, our results indicate that NF and ultralow nicotine cigarettes are potentially more harmful to the BBB endothelium than regular tobacco products. In addition, this study demonstrates that the TS-induced toxicity at BBB ECs is strongly correlated to the TAR and NO levels in the cigarettes rather than the nicotine content.

Diabetes Mellitus and Blood-Brain Barrier Dysfunction: An Overview.

A host of diabetes-related insults to the central nervous system (CNS) have been clearly documented in type-1 and -2 diabetic patients as well as experimental animal models. These host of neurological disorders encompass hemodynamic impairments (e.g., stroke), vascular dementia, cognitive deficits (mild to moderate), as well as a number of neurochemical, electrophysiological and behavioral alterations. The underlying causes of diabetes-induced CNS complications are multifactorial and are relatively little understood although it is now evident that blood-brain barrier (BBB) damage plays a significant role in diabetes-dependent CNS disorders. Changes in plasma glucose levels (hyper- or hypoglycemia) have been associated with altered BBB transport functions (e.g., glucose, insulin, choline, amino acids, etc.), integrity (tight junction disruption), and oxidative stress in the CNS microcapillaries. Last two implicating a potential causal role for upregulation and activation of the receptor for advanced glycation end products (RAGE). This type I membrane-protein also transports amyloid-beta (Aß) from the blood into the brain across the BBB thus, establishing a link between type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD, also referred to as "type 3 diabetes"). Hyperglycemia has been associated with progression of cerebral ischemia and the consequent enhancement of secondary brain injury. Difficulty in detecting vascular impairments in the large, heterogeneous brain microvascular bed and dissecting out the impact of hyper- and hypoglycemia in vivo has led to controversial results especially with regard to the effects of diabetes on BBB. In this article, we review the major findings and current knowledge with regard to the impact of diabetes on BBB integrity and function as well as specific brain microvascular effects of hyper- and hypoglycemia.

Fibro-osseous lesions of the oral and maxillo-facial region: Retrospective analysis for 20 years.

BACKGROUND: Fibro-osseous lesions (FOLs) are one of the commonest entities reported in the head and neck region. However, studies on these groups of lesions on Indian population were not carried out before. So this motivated us to analyze the clinico-pathologic correlation of fibro-osseous lesions reported at our hospital. MATERIALS AND METHODS: A retrospective review was made of all the lesions surgically treated in our hospital. A total of 6,175 biopsies were performed during the study period. All the cases which were histopathologically diagnosed as FOLs were included in the study. The demographic data, radiographic features, and histopathologic findings were analyzed and compared with similar studies on other races. RESULTS AND CONCLUSION: We could find 80 cases diagnosed as fibro-osseous lesions and information about them was documented. The most common FOL reported in the region was cemento-ossifying fibroma (COF) (75%) than fibrous dysplasia (FD) (25%). These were commonly occurring in 2(nd) decade without any sex or site predilection. However, COF was showing a slight female predominance and FD with a definite male predominance. COF was commonly seen in mandible (posterior region) whereas FD mainly confined to the maxilla (as a whole bone). Radiographically, most of COF showed well-defined mixed opaque and lucent areas whereas FD showed diffuse borders. Cortical plate expansion and resorption of associated teeth was a frequent finding in COF when compared with FD. Histopathologically, stroma was fibrocellular in many cases of COF, whereas most FDs showed fibrous stroma, interspersed with mainly woven bone.