Cerebellar Liponeurocytoma,an Unusual Tumor of the Central Nervous System – Ultrastructural Examination

Cerebellar liponeurocytoma is a rare tumor of the central nervous system which shows neuronal and variable astrocytic differentiation, along with foci of lipomatous differentiation. It is usually located in the cerebellum, and may be mistaken for medulloblastoma with lipidized cells or lipomatous ependymoma. Histopathological examination, supplemented by immunohistochemistry and electron microscopy, is required to distinguish between these entities. This 35-year-old male presented with vomiting and headache for three months, followed by gait imbalance. Neurological examination showed positive cerebellar signs with ataxic gait. Magnetic resonance imaging showed a lesion measuring 4.4?cm×?4.3?cm×?3.9?cm involving the cerebellum. The patient underwent midline suboccipital craniotomy to excise the tumor. Histopathological examination showed a circumscribed, cellular tumor composed of round to polygonal cells with moderate cytoplasm and minimal pleomorphism. Clear intracytoplasmic vacuoles were seen within the tumor cells. These tumor cells were immunopositive for synaptophysin, NSE, and MAP-2, confirming their neurocytic origin. On ultrastructural examination, lipid vacuoles as well as dense-core neurosecretory granules were identified within these neurocytic cells, confirming the diagnosis of liponeurocytoma. No cilia, microvilli, or gap junctions were identified in the tumor cells, ruling out the possibility of lipomatous ependymoma. The differentiation of liponeurocytoma from its morphological mimics is imperative, as their treatment differs drastically. The role of electron microscopy is extremely important in this differential diagnosis.     

Central Nervous System Toxoplasmosis with an Increased Proportion of Circulating γδ T Cells in a Patient with Hyper-IgM Syndrome

Hyper-IgM syndrome represents a diverse group of immunodeficiencies characterized by normal or high serum IgM concentrations with decreased or absent IgG, IgA, and IgE. The X-linked form of hyper-IgM syndrome is caused by mutations in the CD40 ligand gene, preventing its expression on activated T cells. The CD40 ligand–CD40 interaction is critical for effective isotype switching and for initiating antigen-specific T cell responses. In addition to recurrent pyogenic infections, patients with the CD40L defect also have opportunistic infections. An increased proportion of circulating T cells, shown to be important early during primary infections, has been demonstrated in numerous infectious diseases including toxoplasmosis. Here, we report a patient with hyper-IgM syndrome and CNS toxoplasmosis, who showed a marked increase in T cells in his peripheral blood and who has responded well to treatment of his toxoplasmosis and to high-dose immunoglobulin replacement therapy.     

Catecholamines, α-, and β-Adrenoceptors Are Not Responsible for Activation of Duodenum Motility Induced by Sympathetic Nerve Stimulation

Stimulation of sympathetic nerve in anesthetized dogs not treated with adrenergic blockers more frequently exerted stimulating rather than inhibitory effect on duodenal motility. Blockade of α- and β-adrenoceptors with phentolamine and propranolol, respectively, did not prevent the excitatory action of the sympathetic nerve stimulation, but even potentiated this effect. The data showed that catecholamines as well as α- and β-adrenoceptors are not involved in the excitatory effect of sympathetic origin.     

LDL Receptor–Related Protein-1: A Regulator of Inflammation in Atherosclerosis,Cancer, and Injury to the Nervous System

Low-density lipoprotein receptor–related protein-1 (LRP1) is an endocytic receptor for numerous proteins that are both structurally and functionally diverse. In some cell types, LRP1-mediated endocytosis is coupled to activation of cell signaling. LRP1 also regulates the composition of the plasma membrane and may, thereby, indirectly regulate the activity of other cell-signaling receptors. Given the scope of LRP1 ligands and its multifunctional nature, it is not surprising that numerous biological activities have been attributed to this receptor. LRP1 gene deletion is embryonic-lethal in mice. However, elegant studies using Cre-LoxP recombination have helped elucidate the function of LRP1 in mature normal and pathological tissues. One major theme that has emerged is the role of LRP1 as a regulator of inflammation. In this review, we will describe evidence for LRP1 as a regulator of inflammation in atherosclerosis, cancer, and injury to the nervous system.Low-density lipoprotein (LDL) receptor–related protein-1 (LRP1/CD91) is a type 1 transmembrane protein, which is processed by furin-like endoproteases in the trans-Golgi compartment to generate the mature two-chain structure.^1,2 The 515-kDa α-chain is entirely extracellular and coupled to the cell surface through strong noncovalent interactions with the transmembrane 85-kDa β-chain. Although LRP1 may localize transiently in lipid rafts, the receptor migrates in the plasma membrane to clathrin-coated pits, where it undergoes constitutive endocytosis and recycling with extremely high efficiency.^3–5 In most cells, including macrophages, hepatocytes, and neurons, LRP1-associated ligands dissociate in acidified endosomes and are transferred to lysosomes.^3,4,6 In endothelial cells, LRP1 ligands may undergo transcytosis.^7,8LRP1 is a member of the LDL receptor gene family, which includes receptors such as megalin/LRP2, apolipoprotein E receptor 2/LRP8, and the VLDL receptor. These receptors demonstrate similarities in domain organization and, in some cases, partially overlapping function.⁹ As shown in Figure 1A, the LRP1 α-chain includes four clusters of complement-like repeats (CCRs), numbered from the N-terminus.^9,10 CCR2 and CCR4 contain 8 and 11 complement-like repeats, respectively, and are responsible for most of the ligand-binding activity of LRP1.¹⁰ The LRP1 β-chain includes YxxL and dileucine motifs that serve as principal endocytosis signals¹¹ and two NPxY motifs that function as secondary endocytosis signals and as binding sites for signaling adapter proteins.^11–13Open in a separate windowFigure 1Molecular models showing the organization of structural domains in LRP1 and the docking of a representative ligand to complement-like repeats in LRP1. A: The depicted domains in LRP1 are common to the LDL receptor family. Stars are present in the intracellular region of LRP1 to represent motifs that function as endocytosis signals and/or as docking sites for cell-signaling proteins including NPXY, YxxL, and dileucine. B: A representative LRP1 ligand, the 18-kDa receptor-binding domain of α₂-macroglobulin, which is a free-standing domain in the activated state of the protein, is shown in pink. Two lysine residues in a single α-helix, highlighted in blue, are essential for binding to LRP1. These lysine residues interact with acidic amino acids in the LRP1 complement-like repeats. The fourth and fifth complement-like repeats in CCR2 are shown in orange, and the acidic amino acids in these domains are highlighted in black. The approximate positions of calcium are shown. EGF, epidermal growth factor.The first identified LRP1 ligand was apolipoprotein E–containing β-VLDL.¹⁴ Subsequently, LRP1 was identified as the receptor for activated α₂-macroglobulin (α₂M),¹⁵ bringing forward a considerable body of literature in which LRP1 was referred to as the activated α₂M receptor. Figure 1B shows a model in which the 18-kDa LRP1-binding domain of α₂M (called the receptor-binding domain or RBD) is engaging tandem complement-like repeats from CCR2 of LRP1. As is typical for LRP1-ligand interactions, Lys residues in the structure of the RBD, positioned in parallel orientation within the same α-helix, interact with negatively charged amino acids in the complement-like repeats.^16,17 Hydrophobic residues exposed on the surface of the RBD also may be involved.¹⁶ The integral association of calcium with the complement-like repeats is necessary for structural integrity and function.^1,17Currently identified LRP1 ligands include proteases, protease inhibitor complexes, extracellular matrix proteins, growth factors, toxins, and viral proteins.⁹ LRP1 ligands are present in myelin, including myelin basic protein and myelin-associated glycoprotein (MAG),^18,19 explaining why in the injured central nervous system, LRP1 may participate in the phagocytosis of myelin debris.¹⁸ By binding calreticulin, LRP1 associates with members of the collectin family, including C1q and mannose-binding lectin, and participates in the phagocytosis of apoptotic cells.^20,21 LRP1 also serves as an endocytic receptor for many intracellular proteins released by necrotic cells.²² These LRP1 activities are important because failure to efficiently clear intracellular proteins, apoptotic cells, and cell debris may be associated with the onset of autoimmune disease.²³     

Central Nervous System Fungal Infections,Diagnostics, and Antifungals: Is There “Mush-room” for Improvement?

The blood brain barrier (BBB) controls the passage of molecules between the circulatory system and the central nervous system. Despite this, some fungi find ways to bypass the BBB, resulting in infections of the central nervous system (CNS) including meningitis, meningoencephalitis, and abscesses. While these infections are rare, the resultant mortality rates range from 30 to 99%, in part due to the poor penetration of most commercially available antifungals. Additionally, laboratory diagnostics can lack sensitivity and/or specificity and may require specialized diagnostic testing facilities, also contributing to the high mortality rate seen in CNS mycoses. Despite the high risk of mortality, detailed understanding of how these infections occur is limited to only a few of the most common fungi, and there is a dearth of research examining novel therapies to aid in the treatment of these infections.     

Evaluation of a Commercial Microarray System for Detection of SHV-, TEM-, CTX-M-, and KPC-Type β-Lactamase Genes in Gram-Negative Isolates

We evaluated the ability of a commercial microarray system (Check KPC/ESBL; Check-Points Health BV) to detect clinically important class A β-lactamase genes. A total of 106 Gram-negative strains were tested. The following sensitivity and specificity results were recorded, respectively: for bla_SHV, 98.8% and 100%; for bla_TEM, 100% and 96.4%; and for bla_CTX-M and bla_KPC, 100% and 100%.The spread of class A or group 2be extended-spectrum β-lactamases (ESBLs) represents an emerging public-health concern (1, 17). Among the organisms of the Enterobacteriaceae family (e.g., Klebsiella pneumoniae and Escherichia coli), the most frequently detected and clinically important ESBLs belong to the TEM, SHV, and CTX-M families (17). While TEM- and SHV-type ESBLs arise via substitutions in strategically positioned amino acids (e.g., Gly238 and Arg164) from the natural narrow-spectrum TEM-1, TEM-2, or SHV-1 β-lactamase genes, all currently identified CTX-M enzymes demonstrate an ESBL phenotype (7, 14).The ability to rapidly identify narrow-spectrum β-lactamases (e.g., SHV-11 and TEM-1) and ESBLs (e.g., SHV-5 and SHV-12 or TEM-10) has important clinical implications. Usually, Enterobacteriaceae species producing narrow-spectrum enzymes are resistant to penicillins and narrow-spectrum cephalosporins, whereas those producing ESBLs manifest resistance to extended-spectrum oxyimino-cephalosporins and aztreonam (14). Since resistance to quinolones and aminoglycosides is frequently observed among ESBL producers, carbapenems represent one of the therapeutic options of last resort for life-threatening infections due to these organisms (6, 14).In some geographic areas, the spread of carbapenemases belonging to class A (e.g., KPCs), class B (e.g., VIMs and IMPs), and class D (e.g., OXA-48) has significantly compromised the clinical use of carbapenems, consigning clinicians to the use of “last-line” antimicrobials such as colistin (2, 19). In particular, the KPC β-lactamases (primarily KPC-2 and KPC-3) are the serine carbapenemases that are most widespread in the United States, and strains producing these enzymes are responsible for numerous outbreaks with high mortality rates (3, 9, 13). Although nine KPC-type β-lactamases have been described, their susceptibility profiles are similar, rendering the differentiation of these variants less clinically relevant (13, 22).Prompt and appropriate antibiotic treatment for infections due to ESBLs- and/or KPC-producing Enterobacteriaceae may positively affect the final outcome for infected patients (6, 13). Unfortunately, standard and confirmatory phenotypic tests may fail to identify ESBL- and, more frequently, KPC-producing organisms. For the latter group, the use of the modified Hodge test delays the final report by an additional 24 h (11, 12, 21). Therefore, a rapid and reliable method is needed to perform a quick and accurate analysis of the most important bla genes possessed by clinical isolates.Microarray technologies are promising genotyping systems that possess a high multiplexing capacity and can be used for detecting different β-lactamase genes that are present in a single strain (8, 10, 23). This ability can assist clinicians in directing antimicrobial therapy. In the present work, we evaluated the ability of Check KPC/ESBL (Check-Points Health BV, Wageningen, Netherlands), the first rapid, commercially available, microarray-based diagnostic test system for detection and identification of bla genes belonging to the TEM, SHV, CTX-M, and KPC types. This system can detect single nucleotide polymorphisms found in the most important TEM- and SHV-type ESBLs (www.lahey.org/studies), including single mutations corresponding to amino acid positions Val84Ile, Glu104Lys, Arg164Ser/His/Cys, and Gly238Ser in TEMs and Gly238Ser/Ala and/or Glu240Lys in SHVs (7).A total of 102 Enterobacteriaceae and four Acinetobacter baumannii isolates possessing different bla genes were tested (Table ​(Table1;1; see also Table S1 in the supplemental material). The majority of strains (n = 61) had previously been characterized (3-5, 15), whereas the bla genes of the remaining isolates were characterized by PCR amplification, standard DNA sequencing, and analytical isoelectric focusing (aIEF) as previously described (4). In this collection, isolates possessed an average of three different bla genes (range, one to five; see Table S1 in the supplemental material). The collection also included K. pneumoniae ATCC 700603, which produces the SHV-18 ESBL (20), and six E. coli DH10B control strains in which single bla genes are carried in different plasmid vectors (see Table S1 in the supplemental material).

TABLE 1.

Performance of the Check KPC/ESBL microarray assay in identification of β-lactamase genes^a

Pattern of neurobehavioral and organ-specific toxicities of β, β’-iminodipropionitrile in mice

Introduction

β, β’-iminodipropionitrile (IDPN) is a synthetic nitrile that produces a permanent movement disorder in rodents. Although IDPN-induced vestibular pathology is well documented, the mode of IDPN interaction with other organ systems is poorly understood. We examined the behavioral signs and histopathological changes in the vestibular labyrinth, brain, liver and kidneys of mice exposed to IDPN.

Material and methods

Adult male SWR/J mice were divided into 2 groups of 6 animals each. One group of mice received normal saline (control group) and the other group was treated with IDPN (400 mg/kg, i.p.) daily for 7 days. Dyskinetic movements including vertical and horizontal head weaving, circling and backward walking were quantified on days 7, 8 and 9.

Results

We observed a direct correlation between the severity of IDPN-induced behavioral deficits and the degeneration of vestibular hair cells in the crista ampullaris of mice. The brain cortex of both groups appeared similar, whereas the kidney histopathology revealed mild nephrotoxicity in some of the IDPN-treated mice. Administration of IDPN caused severe hepatotoxicity, but the intensity of hepatic damage was not correlated with the severity of behavioral deficits.

Conclusions

Degeneration of vestibular sensory hair cells plays an important role in the development of IDPN-induced behavioral deficits in mice. Exposure to IDPN also caused severe hepatotoxicity which was independent of the behavioral symptoms. These findings could be of potential relevance to human health, particularly after the observation that IDPN not only causes a movement disorder but also produces acute liver injury.     

Differential expression of β1, β3 and β4 integrins in sarcomas of the small,round, blue cell category

Integrins are a large and complex family of membrane spanning heterodimeric cell surface glycoproteins mediating cell/cell and cell/matrix interactions. Small, round, blue cell sarcomas (SRBCS) are a group of poorly differentiated tumours of various and in part uncertain histogenesis displaying similar cytomorphology. Among them are rhabdomyosarcomas (RMS), ganglioneuroblastomas [(G)NB], primitive peripheral neuroectodermal tumours (pPNET) and Ewing's sarcomas (ES). Thirty-two SRBCS were studied immunohistochemically for the distribution of 1, 3 and 4 integrins in situ. We found complex and to some extent differential patterns of 1, 3 and 4 integrin subunit expression in different types of SRBCS: all of the sarcomas studied were consistently 1⁺, 4^–, 2^–. Four of nine RMS were completely negative for all other integrin subunits studied while one RMS was 5⁺ throughout and three RMS were focally 5⁺. Three RMS expressed the 6 and v chains. In contrast to RMS, pPNET and ES, all of which were 1^–, 3^–, (G)NB were 3⁺ and frequently co-expressed 1. The eight pPNET and seven ES studied showed a similarily restricted integrin profile that was limited to the expression of 1 and 5 in nearly all cases. In summary, RMS were 1⁺, 1^–, 3^– and heterogeneously expressed 5 and 6. (G)NB were generally 1⁺, 1⁺, 3⁺, 5^–, 6^–. pPNET and ES were 1⁺, 1^–, 3^–, 5⁺, 6^–. The data illustrate a complex expression pattern of various integrins in SRBCS, a differential expression pattern of some of the integrin subunits among different types of SRBCS and almost identical integrin profiles in pPNET and ES.This paper is dedicated to Prof. Dr. Dres. h.c. Wilhelm Doerr on the occasion of his 80^th birthday     

In situ expression of β1, β3 and β4 integrin subunits in non-neoplastic endothelium and vascular tumours

Endothelial cells play an important role in adhesive interactions between circulating cells and extracellular matrix proteins. In vitro studies have shown that many of these processes are mediated by a superfamily of heterodimeric transmembrane glycoproteins called integrins. The distribution patterns of 1, 3 and 4 integrin subunits in endothelial cells (EC) in situ were examined immunohistochemically on serial forzen sections of a wide range of non-neoplastic tissues and of vascular tumours, both benign and malignant. Expression of the 1 subunit was a constitutive feature of EC. Among the 1-associated subunits, 5 and 6 were broadly distributed in EC, irrespective of vessel size and microenvironment. The 3 subunit displayed intermediate levels of expression with a slight preference for small vessel EC. Presence of 1 was confined to EC of capillaries and venules/small veins. Expression of 2 in EC was inconsistent. With rare exceptions, the 4 chain was absent in EC. The 3 and v subunits were expressed in most EC, though not always concomitantly. In contrast to the 1 chain, however, these integrin subunits were absent in EC of glomerular capillaries and were expressed variably in sinusoidal EC. The 4 chain was evenly present in the great majority of EC, except for those of large vessels. In vascular tumours, the patterns of 1 and 1 to 6 subunit expression generally corresponded to those found in their non-neoplastic counterparts. Expression of 3, v and 4 chains, however, decreased in neoplasia, especially in angiosarcomas. These data show that EC dispose of broad and at the same time differential repertoires of integrin subunits that presumably reflect vessel-type associated functional differences among these cells. In vascular tumours, the orthologous distribution patterns of 1 and 1 to 6 chains are conserved in most instances while the amounts of 3, v and 4 subunits expressed in EC tend to decrease in the course of malignant transformation.Dedicated to Prof. Dr. med. Dres. h.c. Wilhelm Doerr on the occasion of his 80th birthday     

Prevalence and Clinical Correlations of Antibodies Against Six β2-Glycoprotein-I-Related Peptides in the Antiphospholipid Syndrome

Two-hundred ninety five patients with the antiphospholipid syndrome (APS) were studied for the presence of antibodies against six anti-2GPI-related peptides Abs. The prevalence of a wide spectrum of clinical and laboratory parameters of APS was evaluated in all patients, and correlated with the presence of each anti-2GPI peptide antibody. The rates of the various antipeptides Abs ranged from 18.0 to 63.7%. Altogether, 87.1% of the patients had antibody reactivity against at least one of the six 2GPI-related peptides. A high degree of simultaneous reactivity against several 2GPI-peptides was found. Positive and negative correlations were found between several antipeptides Abs and the rates of thrombosis and fetal loss. Our results point to a heterogeneous activity of anti-phospholipid Abs in APS patients, directed, often concurrently, against various epitopes of the 2GPI molecule. Evaluation of APS patients for the presence of specific antipeptides Abs may be of a value in predicting the risk for future thrombotic and obstetrical complication, as well as for specific therapeutic purposes.     

Association of CD98, integrin β1, integrin β3 and Fak with the progression and liver metastases of colorectal cancer

CD98-mediated β1 and β3 integrins activation can induce Fak phosphorylation which eventually promotes cell survival, proliferation, and migration. We evaluated the expression of CD98, integrin β1, integrin β3 and Fak in 45 cases of matched colorectal cancer (CRC) and liver metastases as well as 35 cases of CRC without liver metastases.     

Effects of glycinin and β-conglycinin on enterocyte apoptosis,proliferation and migration of piglets

Glycinin and β-conglycinin have been identified as major food/feed allergens. But effects of glycinin and β-conglycinin on enterocyte migration in piglets are scare. Fifteen weanling (7.06±0.18 kg) General No. 1 barrows, weaned at 28 days, were used. The piglets were randomly allotted to three (A, B and C) treatments with five replicates. The piglets in the A group (control group) were fed diets without ingredients originating from leguminous products, while the piglets in the B or C groups were fed the diets containing purified glycinin or β-conglycinin, which replaced protein in Group A by 4%. All the experimental periods were followed for 7 days. Five-micrometre thick sections of small intestinal tissue were stained with the TUNEL method to assess apoptotic activity, and with Ki-67 immunohistochemistry to assess cellular proliferation. The results indicated that glycinin or β-conglycinin increased proliferative index and apoptotic index in duodenum for piglets (P<0.05).     

DOCK2 Is a Microglial Specific Regulator of Central Nervous System Innate Immunity Found in Normal and Alzheimer’s Disease Brain

Neuroinflammation is a hallmark of several neurodegenerative diseases, including Alzheimer’s disease (AD). Strong epidemiological and experimental evidence supports the use of nonsteroidal anti-inflammatory drugs to reduce AD risk. However, poor outcome in clinical trials and toxicity in a prevention trial have shifted focus away from these cyclooxygenase (COX) inhibitors to seek additional therapeutic targets in the prostaglandin pathway. Previously, the prostaglandin E2 receptor, EP2, was shown to regulate neuroinflammation and reduce Aβ plaque burden in transgenic mice. Unfortunately, widespread EP2 distribution and a direct effect on COX2 induction make EP2 a less desirable target. In this study, we link dedicator of cytokinesis 2 (DOCK2) to the prostaglandin pathway in the brain. Additionally, we show that DOCK2 regulates microglial innate immunity independent of COX2 induction and that DOCK2⁺ microglia are associated with human AD pathology. Together, these results suggest DOCK2 as a COX2 expression-independent therapeutic target for neurodegenerative diseases such as AD.Innate immune activation of the central nervous system is associated with several neurodegenerative diseases including Alzheimer’s disease (AD).^1,2,3,4 The major cellular component of this response, activated microglia, demonstrates both beneficial and deleterious effects on surrounding neurons.^4,5,6,7,8,9 The deleterious effects include microglial secretion of a variety of molecules including prostaglandins (PGs) that can mediate paracrine neurotoxicity. Indeed, activation of the PG pathway has been linked with neurotoxicity in a number of cell culture and in vivo models.^{2,6,10,11,12,13} This is especially compelling because there are existing drugs that target the PG pathway, such as the cyclooxygenase (COX) inhibitors that inhibit PG production.Strong epidemiological evidence supports the efficacy of COX isozyme suppression in PG signaling by nonsteroidal anti-inflammatory drugs (NSAIDs) for AD therapy (reviewed in¹⁴). Recently, hard-gained knowledge about COX2 toxicity associated with NSAIDs has led academic and industry laboratories to pursue more specific targets.^15,16,17 Through a series of studies we and others have demonstrated the pro-inflammatory, pro-oxidative, and pro-amyloidogenic nature of the prostaglandin E2 receptor (EP2) in mouse brain or primary cultures from mouse brain, suggesting it as a potentially beneficial therapeutic target for AD.^4,9,18,19,20 While work to date with EP2 highlights a promising approach to PG-related therapeutics in neurodegenerative diseases, widespread organ and cellular distribution of EP make it a nonspecific therapeutic target. Moreover, EP2 activation regulates COX2 expression, at least in microglia, and so EP2 targeting may lead to a similar toxicity profile as relatively COX2-selective NSAIDs.^20,21,22,23The aims of this study were to discover and evaluate EP2-dependent regulators of microglial innate immune response that did not regulate COX2 expression. Indeed, we identified dedicator of cytokinesis 2 (DOCK2) expression as being nearly completely dependent on EP2 expression in microglia. DOCK2 was identified in 1999 as a member of the CDM family of proteins, which includes Caenorhabditis Elegans CED-5, human DOCK180, and Drosophila Melanogaster Myoblast City.²⁴ To date, the majority of studies concerning DOCK2 have shown it to act as a guanyl-nucleotide exchange factor (GEF), which positively regulates Rac- (a Rho family small GTPase) mediated cellular processes such as lymphocyte migration.^{24,25,26,27,28,29,30,31} The Rho family of small GTPases, including Rac, is known to be intimately associated with actin cytoskeleton processes as well as oxidative processes in phagocytic cells. In primary and immortalized microglial cell cultures, Rac1 activation has been shown to promote phagocytosis, including Aβ_1-42 clearance.^32,33 With the exception of DOCK2’s role in neutrophil chemotaxis, there has been no literature describing its function in phagocytic cells even though it has been implicated in macrophage phagocytosis and NADPH oxidation.^24,34,35Following our discovery, we further investigated the role of DOCK2 in microglial function relating to phagocytosis and neurotoxicity as well as regulation of COX2 expression. We also sought to establish relevance of DOCK2 expression to AD pathogenesis by evaluating its expression pattern in human brain. To date, there has been no literature providing evidence for DOCK2 expression or function in the brain. Our identification and subsequent characterization of DOCK2 in brain may highlight its potential as a microglial-specific, COX2-expression independent therapeutic target for neurodegenerative diseases, such as AD.     

Daily variations of epinephrine, norepinephrine, and β-adrenoceptors in the blood and lymphoid organs of intact rats

Daily variations of catecholamine concentrations in the blood and lymphoid organs in Wistar rats were revealed. Daily fluctuations of epinephrine and norepinephrine levels in the spleen and blood were synchronous. Circadian variations of epinephrine in the thymus, lymph nodes, and plasma were synphasic. A relationship between neurotransmitter concentrations and expression of β-adrenoceptors on thymic and splenic lymphocytes was noted. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 128, No. 9, pp. 344–346, September, 1999     

Increased Expressions of Integrin Subunit β1, β2 and β3 in Patients with Acute Infection

Objective: Our previous studies have shown that integrin subunits β1, β2 and β3 were the core proteins of venous thrombi and potential useful biomarker of venous thromboembolism (VTE). Patients with acute infection have a high risk of VTE. In this study we explored that is there any relevance between core proteins and acute infection.Methods: A total of 230 patients (112 females) with clinically proven acute infection in the emergency unit were recruited into this study, meanwhile 230 patients without acute infection matched in sex and age were recruited as control group. Flow cytometry was done to measure the expressions of blood integrin β1, β2, β3 and cellular immunity (CD3, CD4, CD8, CD4/CD8, CD16CD56 and CD19). The association degree between increased core proteins and acute infection was analyzed by calculating the relative risk (RR).Results: The expression of integrin β1, β2 and β3 was markedly increased in patients with acute infection (P=0.000, 0.000 and 0.015, respectively). The relative risk ratio (RR) of increased integrin β1, β2 and β3 in acute infection patients was 1.424 (95%CI: 1.156-1.755, P=0.001), 1.535 (95%CI: 1.263-1.865, P=0.000) and 1.20 (95%CI: 0.947-1.521, P=0.148), respectively. Combined integrin β1, β2 and β3 analysis showed that the relative risk ratio (RR) of increased in patients with acute infection was 2.962 (95%CI: 1.621-5.410, P=0.001), and this relative risk (RR) rise to 3.176 (95%CI: 1.730-5.829, P=0.000) in patients with respiratory tract infection (RTI).Conclusion: As the core proteins of venous thrombi, integrinβ1, β2 and β3 were markedly increased expression in patients with acute infection, which maybe explain the increased risk of VTE in acute infection patients. A weakened immune system could be the basic condition of VTE occurrence.     

Effect of Active Fraction of Cerebral on Expression of Caspase-3 and β-Amyloid Precursor Protein during Therapy of Hemorrhagic Stroke in the Acute and Delayed Periods

Active anti-stroke fraction of Cerebral preparation (extract of water-soluble molecules from brain tissue of animals with hemorrhagic stroke) decreased caspase-3 expression and improved survival of experimental animals in the acute period after hemorrhagic stroke.__________Translated from Byulleten Eksperimentalnoi Biologii i Meditsiny, Vol. 139, No. 2, pp. 175–177, February, 2005     

Effect of Nonselective β-Adrenoblockers on the State of Sympathoadrenal System and Ratio of Neuroactive Amino Acids in Rat Medulla Oblongata

Experiments on rats showed that injection of propranolol into the medulla oblongata increased the contents of epinephrine, norepinephrine, dopamine, and L-DOPA by 3.76, 1.4, 2.0, and 1.7 times, respectively. These propranolol-induced changes in the levels and ratio of neuro-transmitters were not accompanied by variations in serotonin content. Propranolol had no significant effects on the content of excitatory amino acids, except marked increase in aspartate content. The level of inhibitory amino acids increased mainly due to an increase in GABA content. The balance between excitatory and inhibitory amino acids was shifted towards inhibitory compounds.__________Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 139, No. 5, pp. 525–527, May, 2005