bluuebunny/crossref_metadata_2025 huggingface dataset:
The MHC class Ib protein ULBP1 is a nonredundant determinant of leukemia/lymphoma susceptibility to γδ T-cell cytotoxicity
Authors: Lança Telma , Correia Daniel V. , Moita Catarina F. , Raquel Helena , Neves-Costa Ana , Ferreira Cristina , Ramalho José S. , Barata João T. , Moita Luís F. , Gomes Anita Q. , Silva-Santos Bruno
Published: January 2010

On the path to successful immunotherapy of hematopoietic tumors, γδ T cells offer great promise because of their human leukocyte antigen (HLA)–unrestricted targeting of a wide variety of leukemias/lymphomas. However, the molecular mechanisms underlying lymphoma recognition by γδ T cells remain unclear. Here we show that the expression levels of UL16-binding protein 1 (ULBP1) determine lymphoma susceptibility to γδ T cell–mediated cytolysis. Consistent with this, blockade of NKG2D, the receptor for ULBP1 expressed on all Vγ9+ T cells, significantly inhibits lymphoma cell killing. Specific loss-of-function studies demonstrate that the role of ULBP1 is nonredundant, highlighting a thus far unique physiologic relevance for tumor recognition by γδ T cells. Importantly, we observed a very wide spectrum of ULBP1 expression levels in primary biopsies obtained from lymphoma and leukemia patients. We suggest this will impact on the responsiveness to γδ T cell–based immunotherapy, and therefore propose ULBP1 to be used as a leukemia/lymphoma biomarker in upcoming clinical trials.
Structure and function of factor XI
Authors: Emsley Jonas , McEwan Paul A. , Gailani David
Published: January 2010

Factor XI (FXI) is the zymogen of an enzyme (FXIa) that contributes to hemostasis by activating factor IX. Although bleeding associated with FXI deficiency is relatively mild, there has been resurgence of interest in FXI because of studies indicating it makes contributions to thrombosis and other processes associated with dysregulated coagulation. FXI is an unusual dimeric protease, with structural features that distinguish it from vitamin K–dependent coagulation proteases. The recent availability of crystal structures for zymogen FXI and the FXIa catalytic domain have enhanced our understanding of structure-function relationships for this molecule. FXI contains 4 “apple domains” that form a disk structure with extensive interfaces at the base of the catalytic domain. The characterization of the apple disk structure, and its relationship to the catalytic domain, have provided new insight into the mechanism of FXI activation, the interaction of FXIa with the substrate factor IX, and the binding of FXI to platelets. Analyses of missense mutations associated with FXI deficiency have provided additional clues to localization of ligand-binding sites on the protein surface. Together, these data will facilitate efforts to understand the physiology and pathology of this unusual protease, and development of therapeutics to treat thrombotic disorders.
P-selectin–dependent platelet aggregation and apoptosis may explain the decrease in platelet count during Helicobacter pylori infection
Authors: Yeh Jeng-Jung , Tsai Sharon , Wu Deng-Chyang , Wu Jeng-Yih , Liu Ta-Chih , Chen Angela
Published: January 2010

P-selectin expression has been shown in Helicobacter pylori–infected persons, an infection that has been clinically associated with platelet-related diseases, such as idiopathic thrombocytopenic purpura. However, the role of P-selectin expression during H pylori infection remains unclear. In this study, we hypothesized that P-selectin expression was associated with platelet aggregation during H pylori infection. Using flow cytometry, we examined the levels of adhesion between H pylori and platelets as well as the levels of P-selectin expression and platelet phosphatidylserine (PS) expression during H pylori infection. Significantly high levels of adhesion between pro-aggregatory bacteria and platelets were observed. We identified that H pylori IgG is required for bacteria to induce P-selectin expression and that a significant release of P-selectin is essential for H pylori to induce aggregation. In addition, cellular apoptotic signs, such as membrane blebbing, were observed in platelet aggregates. PS expression was also detected in platelets during infection with both pro-aggrogatory and nonaggregatory strains of H pylori. These results suggest that the decrease in platelet counts seen during H pylori infection is the result of P-selection–dependent platelet aggregation and PS expression induced by the bacteria.
Many chronic lymphocytic leukemia antibodies recognize apoptotic cells with exposed nonmuscle myosin heavy chain IIA: implications for patient outcome and cell of origin
Authors: Chu Charles C. , Catera Rosa , Zhang Lu , Didier Sebastien , Agagnina Briana M. , Damle Rajendra N. , Kaufman Matthew S. , Kolitz Jonathan E. , Allen Steven L. , Rai Kanti R. , Chiorazzi Nicholas
Published: January 2010

Many B-cell chronic lymphocytic leukemia (CLL) monoclonal antibodies (mAbs) can be grouped into subsets based on nearly identical stereotyped sequences. Subset 6 CLL mAbs recognize nonmuscle myosin heavy chain IIA (MYHIIA). Herein, we report that during apoptosis, MYHIIA becomes exposed on the cell surface of a subgroup of apoptotic cells, allowing subset 6 CLL mAbs to bind with it. Because other non–subset 6 CLL mAbs interact with apoptotic cells, 26 CLL mAbs, including 24 not belonging to subset 6, were tested for reactivity with MYHIIA-exposed apoptotic cells (MEACs). More than 60% of CLL mAbs bound MEACs well; most of these mAbs expressed unmutated IGHV (15 of 16) and belonged to a stereotyped subset (14 of 16). Binding to MEACs inversely correlated with the degree of IGHV mutation. Interestingly, high binding to MEACs significantly correlated with poor patient survival, suggesting that the basis of IGHV mutation status as a CLL prognostic factor reflects antigen binding. Finally, natural antibodies from human serum also reacted with MEACs. Taken together, our data indicate that a large proportion of CLL clones emerge from natural antibody-producing cells expressing immunoglobulins that recognize MEACs, and that this reactivity is associated with poor clinical outcome.
Distinct clinical and biologic characteristics in adult acute myeloid leukemia bearing the isocitrate dehydrogenase 1 mutation
Authors: Chou Wen-Chien , Hou Hsin-An , Chen Chien-Yuan , Tang Jih-Luh , Yao Ming , Tsay Woei , Ko Bor-Shen , Wu Shang-Ju , Huang Shang-Yi , Hsu Szu-Chun , Chen Yao-Chang , Huang Yen-Ning , Chang Yi-Chang , Lee Fen-Yu , Liu Ming-Chi , Liu Chia-Wen , Tseng Mei-Hsuan , Huang Chi-Fei , Tien Hwei-Fang
Published: January 2010

Mutations of nicotinamide adenine dinucleotide phosphate-dependent isocitrate dehydrogenase gene (IDH1) have been identified in patients with gliomas. Recent genome-wide screening also revealed IDH1 mutation as a recurrent event in acute myeloid leukemia (AML), but its clinical implications in AML are largely unknown. We analyzed 493 adult Chinese AML patients in Taiwan and found 27 patients (5.5%) harboring this mutation. IDH1 mutation was strongly associated with normal karyotype (8.4%, P = .002), isolated monosomy 8 (P = .043), NPM1 mutation (P < .001), and French-American-British M1 subtype (P < .001), but inversely associated with French-American-British M4 subtype (P = .030) and expression of HLA-DR, CD13, and CD14 (P = .002, .003, and .038, respectively). There was no impact of this mutation on patient survival. Sequential analysis of IDH1 mutation was performed in 130 patients during follow-ups. None of the 112 patients without IDH1 mutation at diagnosis acquired this mutation at relapse. In all 18 IDH1-mutated patients studied, the mutation disappeared in complete remission; the same mutation reappeared in all 11 samples obtained at relapse. We conclude that IDH1 is associated with distinct clinical and biologic characteristics and seems to be very stable during disease evolution.
The curvHDR method for gating flow cytometry samples
Authors: Naumann Ulrike , Luta George , Wand Matthew P
Published: January 2010

Background

High-throughput flow cytometry experiments produce hundreds of large multivariate samples of cellular characteristics. These samples require specialized processing to obtain clinically meaningful measurements. A major component of this processing is a form of cell subsetting known as gating. Manual gating is time-consuming and subjective. Good automatic and semi-automatic gating algorithms are very beneficial to high-throughput flow cytometry.

Results

We develop a statistical procedure, named , for automatic and semi-automatic gating. The method combines the notions of significant high negative curvature regions and highest density regions and has the ability to adapt well to human-perceived gates. The underlying principles apply to dimension of arbitrary size, although we focus on dimensions up to three. Accompanying software, compatible with contemporary flow cytometry infor-matics, is developed.

Conclusion

The method is seen to adapt well to nuances in the data and, to a reasonable extent, match human perception of useful gates. It offers big savings in human labour when processing high-throughput flow cytometry data whilst retaining a good degree of efficacy.
Expression profiling of S. pombe acetyltransferase mutants identifies redundant pathways of gene regulation
Authors: Nugent Rebecca L , Johnsson Anna , Fleharty Brian , Gogol Madelaine , Xue-Franzén Yongtao , Seidel Chris , Wright Anthony PH , Forsburg Susan L
Published: January 2010

Background

Histone acetyltransferase enzymes (HATs) are implicated in regulation of transcription. HATs from different families may overlap in target and substrate specificity.

Results

We isolated theelp3+gene encoding the histone acetyltransferase subunit of the Elongator complex in fission yeast and characterized the phenotype of an Δelp3mutant. We examined genetic interactions between Δelp3and two other HAT mutants, Δmst2and Δgcn5and used whole genome microarray analysis to analyze their effects on gene expression.

Conclusions

Comparison of phenotypes and expression profiles in single, double and triple mutants indicate that these HAT enzymes have overlapping functions. Consistent with this, overlapping specificity in histone H3 acetylation is observed. However, there is no evidence for overlap with another HAT enzyme, encoded by the essentialmst1+gene.
A survey in rural China of parent-absence through migrant working: the impact on their children's self-concept and loneliness
Authors: Liu Li-Juan , Sun Xun , Zhang Chun-Li , Wang Yue , Guo Qiang
Published: January 2010

Background

Following the rapid increase of migrant workers in China, the number of "absent migrant parents" children is also rising fast. The "absent migrant parents" children might have an insecure relationship with their parents, have a different view of them, and be prone to have the feeling of loneliness. The purpose of the study was to compare the self-concept and loneliness between the "absent migrant parents" children and comparison children, to examine the relationship between self-concept and loneliness among the two groups, and to study the predictors of self-concept among the two groups.

Methods

Participants were 230 "absent migrant parents" children and 250 comparison children in the rural area of a county, China. The self-concept and loneliness of children were assessed using Piers-Harris Self-Concept Scale and Childhood Loneliness Scale.

Results

The "absent migrant parents" children were more likely to dislike their parents or be uncertain whether they like their parents, and they reported less time spent in physical and leisure time activities, higher loneliness and lower self-concept in comparison with the comparison children. Loneliness was significantly negatively correlated with all the dimensions of self-concept among the two groups. Regression analysis showed that self-concept was positively related to the relationship with parents and guardians and time spent in physical and leisure activities among the "absent migrant parents" children. The same factors (except the relationship with guardians) were found for self-concept among the comparison children.

Conclusions

The "absent migrant parents" children were more inclined to have lower self-concept and higher loneliness. The lower self-concept seemed to contribute to the higher loneliness of the "absent migrant parents" children. The lower self-concept of the "absent migrant parents" children was mainly related with their relationship with parents and guardians. The acceptance and support from their parents could not be fully replaced by that from their guardians.
Comparison of hip fracture incidence and trends between Germany and Austria 1995-2004: An epidemiological study
Authors: Mann Eva , Meyer Gabriele , Haastert Burkhart , Icks Andrea
Published: January 2010

Background

Several studies evaluated variations in hip fracture incidences, as well as trends of the hip fracture incidences. Comparisons of trends are lacking so far. We compared the incidence rates and, in particular, its trends between Austria and Germany 1995 to 2004 analysing national hospital discharge diagnosis register data.

Methods

Annual frequencies of hip fractures and corresponding incidences per 100,000 person years were estimated, overall and stratified for sex and age, assuming Poisson distribution. Multiple Poisson regression models including country and calendar year, age and sex were used to analyse differences in incidence and trend. The difference of annual changes between the two countries was explored using an interaction term (calender year * country).

Results

Overall, the increase of hip fracture risk was 1.31 fold higher (95% CI 1.29-1.34) in Austria compared to Germany, adjusted for age, sex, and calendar year. The risk increase was comparable for both sexes (males: RR 1.35 (1.32-1.37), females: RR 1.31 (1.29-1.33)). Hip fracture trend from 1995 to 2004 indicates an increase in both countries without a statistically significant difference between Austria and Germany (interaction term: p = 0.67).

Conclusion

In this study comparing hip fracture incidences and its trend using pooled data, the incidence in Austria was 30% higher compared to its neighbouring country Germany. For both countries a similar increasing trend of hip fracture incidence over the 10-year study period was calculated. The results need confirmation by other studies.
Cloning, reassembling and integration of the entire nikkomycin biosynthetic gene cluster into Streptomyces ansochromogenes lead to an improved nikkomycin production
Authors: Liao Guojian , Li Jine , Li Lei , Yang Haihua , Tian Yuqing , Tan Huarong
Published: January 2010

Background

Nikkomycins are a group of peptidyl nucleoside antibiotics produced by Streptomyces ansochromogenes. They are competitive inhibitors of chitin synthase and show potent fungicidal, insecticidal, and acaricidal activities. Nikkomycin X and Z are the main components produced by S. ansochromogenes. Generation of a high-producing strain is crucial to scale up nikkomycins production for further clinical trials.

Results

To increase the yields of nikkomycins, an additional copy of nikkomycin biosynthetic gene cluster (35 kb) was introduced into nikkomycin producing strain, S. ansochromogenes 7100. The gene cluster was first reassembled into an integrative plasmid by Red/ET technology combining with classic cloning methods and then the resulting plasmid(pNIK)was introduced into S. ansochromogenes by conjugal transfer. Introduction of pNIK led to enhanced production of nikkomycins (880 mg L-1, 4 -fold nikkomycin X and 210 mg L-1, 1.8-fold nikkomycin Z) in the resulting exconjugants comparing with the parent strain (220 mg L-1 nikkomycin X and 120 mg L-1 nikkomycin Z). The exconjugants are genetically stable in the absence of antibiotic resistance selection pressure.

Conclusion

A high nikkomycins producing strain (1100 mg L-1 nikkomycins) was obtained by introduction of an extra nikkomycin biosynthetic gene cluster into the genome of S. ansochromogenes. The strategies presented here could be applicable to other bacteria to improve the yields of secondary metabolites.
Low-technology cooling box for storage of malaria RDTs and other medical supplies in remote areas
Authors: Chanthap Lon , Ariey Frédéric , Socheat Duong , Tsuyuoka Reiko , Bell David
Published: January 2010

Background

With the increase in use of point-of-care diagnostic tests for malaria and other diseases comes the necessity of storing the diagnostic kits and the drugs required for subsequent management, in remote areas, where temperatures are high and electricity supply is unreliable or unavailable.

Methods

To address the lack of temperature-controlled storage during the introduction of community-based malaria management in Cambodia, the Cambodian National Centre for Parasitology, Entomology and Malaria Control (CNM) developed prototype evaporative cooling boxes (Cambodian Cooler Boxes - CCBs) for storage of perishable medical commodities in remote clinics. The performance of these CCBs for maintaining suitable storage temperatures was evaluated over two phases in 2005 and 2006-7, comparing conditions in CCBs using water as designed, CCBs with no water for evaporation, and ambient storage room temperatures. Temperature and humidity was monitored, together with the capacity of the RDTs recommended for storage between 2 to 30 degree Celsius to detect low-density malaria parasite samples after storage under these conditions.

Results

Significant differences were recorded between the proportion of temperatures within the recommended RDT storage conditions in the CCBs with water and the temperatures in the storage room (p < 0.001) and maximum temperatures were lower. RDTs stored at ambient temperatures were negative when tested with parasitized blood (2,000 parasites per micro litre) at 210 days, while the field RDTs kept in CCBs with water gave positive results until 360 days.

Discussion and Conclusions

The CCB was an effective tool for storage of RDTs at optimal conditions, and extended the effective life-span of the tests. The concept of evaporative cooling has potential to greatly enhance access to perishable diagnostics and medicines in remote communities, as it allows prolonged storage at low cost using locally-available materials, in the absence of electricity.
Impaired plasma lipid profiles in acute hepatitis
Authors: Luo Libo , Pu Xiangke , Wang Yongzhong , Xu Ning
Published: January 2010

The present study examined plasma lipid profiles in thirty patients suffered from acute viral hepatitis. Patients' blood samples were collected at both the debut and recovery of diseases. Thirty sex and age matched normal subjects were included as controls. Plasma total triglycerides (TG), total cholesterol, high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), apolipoprotein AI (ApoAI), apolipoprotein B (ApoB), lipoprotein (a) (Lp(a)), blood coagulation status including prothrombin complex activity and activated partial tromboplastin time (APTT), and hepatic functions were determined by the automatic biochemical analytical instrument. It demonstrated that plasma levels of total cholesterol, HDL-C and apoAI were significantly lower in the patients at the acute phase of hepatitis than those in normal subjects, whereas plasma levels of TG and LDL-C were obviously higher in the patients than in normal subjects (P < 0.05). Moreover, we demonstrated that patients' plasma levels of total cholesterol, LDL-C, HDL-C and apoAI were lower at the active phase of the diseases than at the recovering phase, which indicating that acute liver damage could significant influence lipid metabolism in vivo. No pathological changes of blood coagulation status occurred in these patients during the study as all selected patients had moderate hepatitis. It may conclude that examinations of plasma lipid profile could be considered as a clinical index to reflect liver damage in the active phase of hepatitis.
Lipid measures for prediction of incident cardiovascular disease in diabetic and non-diabetic adults: results of the 8.6 years follow-up of a population based cohort study
Authors: Tohidi Maryam , Hatami Masumeh , Hadaegh Farzad , Safarkhani Maryam , Harati Hadi , Azizi Fereidoun
Published: January 2010

Background

Diabetes is a strong risk factor for cardiovascular disease (CVD).The relative role of various lipid measures in determining CVD risk in diabetic patients is still a subject of debate. We aimed to compare performance of different lipid measures as predictors of CVD using discrimination and fitting characteristics in individuals with and without diabetes mellitus from a Middle East Caucasian population.

Methods

The study population consisted of 1021 diabetic (men = 413, women = 608) and 5310 non-diabetic (men = 2317, women = 2993) subjects, aged ≥ 30 years, free of CVD at baseline. The adjusted hazard ratios (HRs) for CVD were calculated for a 1 standard deviation (SD) change in total cholesterol (TC), log-transformed triglyceride (TG), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), non-HDL-C, TC/HDL-C and log-transformed TG/HDL-C using Cox proportional regression analysis. Incident CVD was ascertained over a median of 8.6 years of follow-up.

Results

A total of 189 (men = 91, women = 98) and 263(men = 169, women = 94) CVD events occurred, in diabetic and non-diabetic population, respectively. The risk factor adjusted HRs to predict CVD, except for HDL-C, TG and TG/HDL-C, were significant for all lipid measures in diabetic males and were 1.39, 1.45, 1.36 and 1.16 for TC, LDL-C, non- HDL-C and TC/HDL-C respectively. In diabetic women, using multivariate analysis, only TC/HDL-C had significant risk [adjusted HR1.31(1.10-1.57)].Among non-diabetic men, all lipid measures, except for TG, were independent predictors for CVD however; a 1 SD increase in HDL-C significantly decreased the risk of CVD [adjusted HR 0.83(0.70-0.97)].In non-diabetic women, TC, LDL-C, non-HDL-C and TG were independent predictors.

There was no difference in the discriminatory power of different lipid measures to predict incident CVD in the risk factor adjusted models, in either sex of diabetic and non-diabetic population.

Conclusion

Our data according to important test performance characteristics provided evidence based support for WHO recommendation that along with other CVD risk factors serum TC vs. LDL-C, non-HDL-C and TC/HDL-C is a reasonable lipid measure to predict incident CVD among diabetic men. Importantly, HDL-C did not have a protective effect for incident CVD among diabetic population; given that the HDL-C had a protective effect only among non- diabetic men.
Delineation of downstream signalling components during acrosome reaction mediated by heat solubilized human zona pellucida
Authors: Bhandari Beena , Bansal Pankaj , Talwar Pankaj , Gupta Satish K
Published: January 2010

Background

Human egg is enveloped by a glycoproteinaceous matrix, zona pellucida (ZP), responsible for binding of the human spermatozoa to the egg and induction of acrosomal exocytosis in the spermatozoon bound to ZP. In the present manuscript, attempts have been made to delineate the downstream signalling components employed by human ZP to induce acrosome reaction.

Methods

Heat-solubilized human ZP (SIZP) was used to study the induction of acrosome reaction in capacitated human spermatozoa using tetramethylrhodamine isothiocyanate conjugatedPisum sativumagglutinin (TRITC-PSA) in absence or presence of various pharmacological inhibitors. In addition, intracellular calcium ([Ca2+]i) levels in sperm using Fluo-3 acetoxymethyl ester as fluorescent probe were also estimated in response to SIZP.

Results

SIZP induces acrosomal exocytosis in capacitated human sperm in a dose dependent manner accompanied by an increase in [Ca2+]i. Human SIZP mediated induction of acrosome reaction depends on extracellular Ca2+ and involves activation of Gi protein-coupled receptor, tyrosine kinase, protein kinases A & C and phosphoinositide 3 (PI3)- kinase. In addition, T-type voltage operated calcium channels and GABA-A receptor associated chloride (Cl-) channels play an important role in SIZP mediated induction of acrosome reaction.

Conclusions

Results described in the present study provide a comprehensive account of the various downstream signalling components associated with human ZP mediated acrosome reaction.
Nuclear factor-kappa B localization and function within intrauterine tissues from term and preterm labor and cultured fetal membranes
Authors: Vora Sonali , Abbas Asad , Kim Chong J , Summerfield Taryn LS , Kusanovic Juan P , Iams Jay D , Romero Roberto , Kniss Douglas A , Ackerman William E
Published: January 2010

Background

The objective of this study was to quantify the nuclear localization and DNA binding activity of p65, the major transactivating nuclear factor-kappa B (NF-kappaB) subunit, in full-thickness fetal membranes (FM) and myometrium in the absence or presence of term or preterm labor.

Methods

Paired full-thickness FM and myometrial samples were collected from women in the following cohorts: preterm no labor (PNL, N = 22), spontaneous preterm labor (PTL, N = 21), term no labor (TNL, N = 23), and spontaneous term labor (STL, N = 21). NF-kappaB p65 localization was assessed by immunohistochemistry, and DNA binding activity was evaluated using an enzyme-linked immunosorbent assay (ELISA)-based method.

Results

Nuclear p65 labeling was rare in amnion and chorion, irrespective of clinical context. In decidua, nuclear p65 labeling was greater in the STL group relative to the TNL cohort, but there were no differences among the TNL, PTL, and PNL cohorts. In myometrium, diffuse p65 nuclear labeling was significantly associated with both term and preterm labor. There were no significant differences in ELISA-based p65 binding activity in amnion, choriodecidual, and myometrial specimens in the absence or presence of term labor. However, parallel experiments using cultured term fetal membranes demonstrated high levels of p65-like binding even the absence of cytokine stimulation, suggesting that this assay may be of limited value when applied to tissue specimens.

Conclusions

These results suggest that the decidua is an important site of NF-kappaB regulation in fetal membranes, and that mechanisms other than cytoplasmic sequestration may limit NF-kappaB activation prior to term.
Enhancement of fibrinogen-triggered pro-coagulant activation of monocytes in vitro by matrix metalloproteinase-9
Authors: Kaneider Nicole C , Mosheimer Birgit , Günther Andrea , Feistritzer Clemens , Wiedermann Christian J
Published: January 2010

Background

Interaction of fibrinogen with specific leukocyte integrins of monocytes may link coagulation and inflammation, however, the precise mechanism of fibrinogen leading to the pro-inflammatory and pro-coagulatory response on monocytes is yet unknown.

Results

Fibrinogen and its digestion fragment D induced pro-coagulant activation of monocytes as assessed in a cellular coagulation assay by reductions in clotting times. Pro-coagulant activation was reversed by blocking antibodies against Mac-1 or LFA-1. Pre-exposure of monocytes to the p38 MAPK inhibitor SB 202190 and the MEK1.2 inhibitor U0126 led to significant increasees in coagulation times whereas blocking JNKII with its inhibitor had no such effect. Blocking NFκB with MG-132 also inhibited pro-coagulant activation of monocytes by fibrinogen. A selective inhibitor of matrix metalloproteinase-9 increased times to clot formation whereas other matrix metalloproteinase inhibitors did not significantly interfere with fibrinogen-augmented clot formation in this assay. Treatment of monocytes with fibrinogen increased concentrations of matrix metalloproteinase-9 immunoreactivity in their supernatants.

Conclusions

Fibrinogen induces monocyte pro-coagulant activation in an integrin-, nuclear factor κB-, p38 MAPK-, and MEK1.2-dependent manner. Activation of monocytes by fibrinogen increases metalloproteinase-9 secretion, metalloproteinase-9 itself enhances monocyte coagulation by an autocrine mechanism. Results provide further evidence that mediators of hemostasis have a profound impact on cells of the immune system and are closely related to inflammatory pathways.
Evaluation of adenovirus capsid labeling versus transgene expression
Authors: Li Jing , Fatima Aiman , Komarova Svetlana , Ugai Hideyo , Uprety Priyanka , Roth Justin C , Wang Minghui , Oster Robert A , Curiel David T , Matthews Qiana L
Published: January 2010

Adenoviral vectors have been utilized for a variety of gene therapy applications. Our group has incorporated bioluminescent, fluorographic reporters, and/or suicide genes within the adenovirus genome for analytical and/or therapeutic purposes. These molecules have also been incorporated as capsid components. Recognizing that incorporations at either locale yield potential advantages and disadvantages, our report evaluates the benefits of transgene incorporation versus capsid incorporation. To this end, we have genetically incorporated firefly luciferase within the early region 3 or at minor capsid protein IX and compared vector functionality by means of reporter readout.
Trigeminal Injury Causes kappa Opioid-Dependent Allodynic, Glial and Immune Cell Responses in Mice
Authors: Aita Megumi , Byers Margaret R , Chavkin Charles , Xu Mei
Published: January 2010

Background:

The dynorphin-kappa opioid receptor (KOR) system regulates glial proliferation after sciatic nerve injury. Here, we investigated its role in cell proliferation following partial ligation of infraorbital nerve (pIONL), a model for trigeminal neuropathic pain. Mechanical allodynia was enhanced in KOR gene deleted mice (KOR−/−) compared to wild type mice. Using bromodeoxyuridine (BrdU) as a mitotic marker, we assessed cell proliferation in three different areas of the trigeminal afferent pathway: trigeminal nucleus principalis (Vp), trigeminal root entry zone (TREZ), and trigeminal ganglion (TG).

Results:

In KOR−/− mice or norBNI-treated mice, the number of proliferating cells in the Vp was significantly less than in WT mice, whereas cell proliferation was enhanced in TREZ and TG. The majority of the proliferating cells were nestin positive stem cells or CD11b positive microglia in the Vp and macrophages in the TG. GFAP-positive astrocytes made a clear borderline between the CNS and the PNS in TREZ, and phosphorylated KOR staining (KOR-p) was detectable only in the astrocytes in CNS in WT mice but not in KOR−/− or norBNI-treated mice.

Conclusions:

These results show that kappa opioid receptor system has different effects after pIONL in CNS and PNS: KOR activation promotes CNS astrocytosis and microglial or stem cell proliferation but inhibits macrophage proliferation in PNS. The trigeminal central root has a key role in the etiology and treatment of trigeminal neuralgia, and these newly identified responses may provide new targets for developing pain therapies.
Regulation of neutrophil-mediated killing of Staphylococcus aureus and chemotaxis by c-jun NH2 terminal kinase
Authors: Yeh Mei-Chun , Mukaro Violet , Hii Charles S , Ferrante Antonio
Published: January 2010

JNK is identified as a key MAP kinase which regulates neutrophil bactericidal activity and chemotaxis.

The role of JNK in neutrophil chemotaxis and killing of microbial pathogens remains unclear. Using a recently described cell-permeable peptide inhibitor of the JNK pathway, based on the JBD of JIP-1, coupled to the protein transduction domain of HIV-TAT (TAT-JIP), in association with control peptides, we demonstrate that the JNK pathway plays a major role in regulating human neutrophil chemotaxis and killing of microbial pathogens. Serum-opsonized Staphylococcus aureus elicited JNK activation and c-jun phosphorylation. The activation of the JNK pathway and bactericidal activity were inhibited by the TAT-JIP peptide. The stimulation of oxygen radical generation by S. aureus was dependent on the JNK signaling pathway, as was the phagocytosis of serum-opsonized bacteria. Chemotaxis to activated serum complement but not random migration was inhibited by the TAT-JIP peptide. The findings demonstrate a major role for the JNK signaling pathway in neutrophil-mediated defense against microbial pathogens.
Inflammation-dependent α5β1 (very late antigen-5) expression on leukocytes reveals a functional role for this integrin in acute peritonitis
Authors: Sampaio André L F , Zahn Grit , Leoni Giovanna , Vossmeyer Doerte , Christner Claudia , Marshall John F , Perretti Mauro
Published: January 2010

Stimulus-specific role for α5β1 in the process of leukocyte recruitment; fibronectin levels are increased in the inflamed tissue so that interaction with α5β1 becomes functional.

The potential role of α5β1 (VLA-5) in leukocyte trafficking in zymosan-induced acute peritonitis was determined. In naïve mice, ∼98% of Gr1high cells (PMN) in bone marrow and circulation were α5β1-negative; these profiles were modestly affected by peritoneal injection of zymosan. In contrast, ∼30% of Gr1high cells recruited by zymosan (24 h) to the peritoneal cavity expressed α5β1. With respect to F4/80+ cells, ∼60% of bone marrow and peripheral blood populations expressed α5β1, with ∼90% positivity in resident cells of noninflamed peritoneum. Analysis of α5β1 expression revealed inflammation-dependent increased expression on Gr1high and F4/80+ cells in bone marrow, blood, and peritoneal cavity. Blockade of α5β1, by an anti-α5 mAb, attenuated zymosan-induced 24 h recruitment of Gr1high and F4/80+ cells. At least one underlying mechanism of this action was reduction of cell adhesion and transmigration across microvascular vessels, as revealed by intravital microscopy. Confocal analyses indicated that deposition of fibronectin, the principal ligand for α5β1, was up-regulated significantly on and around the inflamed mesenteric microvasculature. These data suggest that the effects of α5-blockade may be a result of inhibition of α5β1-dependent leukocyte adhesion to and migration along the fibronectin matrix. This is the first report that identifies a functional role for α5β1 in leukocyte trafficking during acute inflammation.
IL-23 and IL-12p70 production by monocytes and dendritic cells in primary HIV-1 infection
Authors: Louis Stéphanie , Dutertre Charles-Antoine , Vimeux Lene , Fery Ludovic , Henno Lucy , Diocou Seckou , Kahi Sandrine , Deveau Christiane , Meyer Laurence , Goujard Cécile , Hosmalin Anne
Published: January 2010

During HIV primary infection, monocytes and DCs produce high levels of p40 chain with apparent imbalance of IL-23 over IL-12.

IL-12 enhances protective responses against HIV replication. Its production after in vitro stimulation is defective in chronic HIV infection, but higher responses can be found. IL-23 shares the p40 chain and some properties with IL-12 and enhances Th17 responses, but its role in HIV infection is unknown. The production of IL-12 and IL-23 and the respective contribution of monocytes and myeloid conventional DC (cDCs) during primary HIV infection were determined. Sixteen patients included in the French PRIMO-ANRS Cohort without antiretroviral treatment were followed prospectively and compared with uninfected donors. Intracellular p40 expression by monocytes and cDCs, analyzed by flow cytometry, was transiently increased in monocytes and cDCs in response to LPS and more consistently, in monocytes in response to LPS + IFN-γ. IL-23 production, measured by ELISA after PBMC stimulation, was induced by LPS in strong correlation with VLs. IL-12p70 production required the addition of IFN-γ and was transiently increased in patients compared with controls in correlation with VLs, whereas IL-23 was increased sustainedly. Therefore, an apparent domination of IL-23 over IL-12 responses occurred throughout primary HIV infection, and a potential restoration of IL-12 responses might be expected from a treatment mimicking activated T cell signals.
Long-term mental health of Vietnamese refugees in the aftermath of trauma
Authors: Vaage Aina Basilier , Thomsen Per Hove , Silove Derrick , Wentzel-Larsen Tore , Van Ta Thong , Hauff Edvard
Published: January 2010

Background

There is no long-term prospective study (> 20 years) of the mental health of any refugee group.

Aims

To investigate the long-term course and predictors of psychological distress among Vietnamese refugees in Norway.

Method

Eighty Vietnamese refugees, 57% of the original cohort previously interviewed in 1982 (T1) and 1985 (T2), completed a self-report questionnaire prior to a semi-structured interview. Mental health was measured using the Symptom Checklist–90–Revised (SCL–90–R).

Results

The SCL–90–R mean Global Severity Index (GSI) decreased significantly fromT1toT3(2005–6), but there was no significant change in the percentage reaching threshold scores (GSI =1.00). Trauma-related mental disorder on arrival and the trajectory of symptoms over the first 3 years of resettlement predicted mental health after 23 years.

Conclusions

Although the self-reported psychological distress decreased significantly over time, a substantial higher proportion of the refugee group still remained reaching threshold scores after 23 years of resettlement compared with the Norwegian population. The data suggest that refugees reaching threshold scores on measures such as the SCL–90–R soon after arrival warrant comprehensive clinical assessment.
Service use and cost of mental disorder in older adults with
intellectual disability
Authors: Strydom Andre , Romeo Renee , Perez-Achiaga Natalia , Livingston Gill , King Michael , Knapp Martin , Hassiotis Angela
Published: January 2010

Background

The cost of caring for people with intellectual disability currently
makes up a large proportion of healthcare spending in western Europe, and
may rise in line with the increasing numbers of people with intellectual
disability now living to old age.

Aims

To report service use and costs of older people with intellectual
disability and explore the influence of sociodemographic and
illness-related determinants.

Method

We collected data on receipt and costs of accommodation, health and
personal care, physical as well as mental illness, dementia, sensory
impairment and disability in a representative sample of adults with
intellectual disability aged 60 years and older (n =
212).

Results

The average weekly cost in GBP per older person was £790 (£41 080 per
year). Accommodation accounted for 74%. Overall costs were highest for
those living in congregate settings. Gender, intellectual disability
severity, hearing impairment, physical disorder and mental illness had
significant independent relationships with costs. Mental illness was
associated with an additional weekly cost of £202.

Conclusions

Older adults with intellectual disability comprise about 0.15–0.25% of
the population of England but consume up to 5% of the total personal care
budget. Interventions that meet needs and might prove to be
cost-effective should be sought.
The Kraepelinian dichotomy – going, going … but still not
gone
Authors: Craddock Nick , Owen Michael J.
Published: January 2010

Recent genetic studies reinforce the view that current approaches to the
diagnosis and classification of major psychiatric illness are inadequate.
These findings challenge the distinction between schizophrenia and bipolar
disorder, and suggest that more attention should be given to the
relationship between the functional psychoses and neurodevelopmental
disorders such as autism. We are entering a transitional period of several
years during which psychiatry will need to move from using traditional
descriptive diagnoses to clinical entities (categories and/or dimensions)
that relate more closely to the underlying workings of the brain.
Controlled comparison of two crisis resolution and home treatment teams
Authors: Tyrer P. , Gordon F. , Nourmand S. , Lawrence M. , Curran C. , Southgate D. , Oruganti B. , Tyler M. , Tottle S. , North B. , Kulinskaya E. , Kaleekal J. T. , Morgan J.
Published: January 2010

Aims and method

To compare an existing crisis resolution service with a new crisis resolution team (CRT) in Wales. The impact of the new team was measured by changes in bed days and admissions. A random sample of patients from each service was assessed for service satisfaction, social functioning and quality of life after first presentation.

Results

The total number of bed days was reduced following the introduction of the new CRT (27.3%). The frequency and duration of compulsory admissions increased by 31% in the CRT between the first and second years and by 7% in the control service, offset by a greater reduction in informal admissions in the CRT (23.5%) compared with the control group (13.3%); overall bed usage was unchanged. Service satisfaction, social functioning and quality of life showed no important differences between the services.

Clinical implications

Crisis resolution teams may reduce informal admissions in the short term but at the cost of more compulsory admissions later.
Caveolin-1 Ablation Reduces the Adverse Cardiovascular Effects of N-ω-Nitro-l-Arginine Methyl Ester and Angiotensin II
Authors: Pojoga Luminita H. , Romero Jose R. , Yao Tham M. , Loutraris Paul , Ricchiuti Vincent , Coutinho Patricia , Guo Christine , Lapointe Nathalie , Stone James R. , Adler Gail K. , Williams Gordon H.
Published: January 2010

Caveolae are the major cellular membrane structure through which extracellular mediators transmit information to intracellular signaling pathways. In vascular tissue (but not ventricular myocardium), caveolin-1 (cav-1) is the main component of caveolae; cav-1 modulates enzymes and receptors, such as the endothelial nitric oxide synthase and the angiotensin II (AngII) type 1 receptor. Evidence suggests that AngII and aldosterone (ALDO) are important mediators of ventricular injury. We have described a model of biventricular damage in rodents that relies on treatment with N-ω-nitro-l-arginine methyl ester (L-NAME (nitric oxide synthase inhibitor)) and AngII. This damage initiated at the vascular level and was observed only in the presence of ALDO and an activated mineralocorticoid receptor (MR). We hypothesize that cav-1 modulates the adverse cardiac effects mediated by ALDO in this animal model. To test this hypothesis, we assessed the ventricular damage and measures of inflammation, in wild-type (WT) and cav-1 knockout (KO) mice randomized to either placebo or L-NAME/AngII treatment. Despite displaying cardiac hypertrophy at baseline and higher blood pressure responses to L-NAME/AngII, cav-1 KO mice displayed, as compared with WT, decreased treatment-induced biventricular damage as well as decreased transcript levels of the proinflammatory marker plasminogen activator inhibitor-1. Additionally, L-NAME/AngII induced an increase in cardiac MR levels in WT but not cav-1-ablated mice. Moreover and despite similar circulating ALDO levels in both genotypes, the myocardial damage (as determined histologically and by plasminogen activator inhibitor-1 mRNA levels) was less sensitive to ALDO levels in cav-1 KO vs. WT mice, consistent with decreased MR signaling in the cav-1 KO. Thus, we conclude that the L-NAME/AngII-induced biventricular damage is mediated by a mechanism partially dependent on cav-1 and signaling via MR/ALDO.
Hypothalamic Insulin-Like Growth Factor-I Receptors Are Necessary for Hormone-Dependent Luteinizing Hormone Surges: Implications for Female Reproductive Aging
Authors: Todd Brigitte J. , Merhi Zaher O. , Shu Jun , Etgen Anne M. , Neal-Perry Genevieve S.
Published: January 2010

Brain IGF-I receptors are required for maintenance of estrous cycles in young adult female rats. Circulating and hypothalamic IGF-I levels decrease with aging, suggesting a role for IGF-I in the onset of reproductive senescence. Therefore, the present study investigated potential mechanisms of action of brain IGF-I receptors in the regulation of LH surges in young adult and middle-aged rats. We continuously infused IGF-I, the selective IGF-I receptor antagonist JB-1, or vehicle into the third ventricle of ovariectomized young adult and middle-aged female rats primed with estradiol and progesterone. Pharmacological blockade of IGF-I receptors attenuated and delayed the LH surge in young adult rats, reminiscent of the LH surge pattern that heralds the onset of reproductive senescence in middle-aged female rats. Infusion of IGF-I alone had no effect on the LH surge but reversed JB-1 attenuation of the surge in young females. In middle-aged rats, infusion of low doses of IGF-I partially restored LH surge amplitude, and infusion of JB-1 completely obliterated the surge. Intraventricular infusion of IGF-I or JB-1 did not modify pituitary sensitivity to exogenous GnRH or GnRH peptide content in the anterior or mediobasal hypothalamus in either young or middle-aged rats. These findings support the hypothesis that brain IGF-I receptor signaling is necessary for GnRH neuron activation under estrogen-positive feedback conditions and that decreased brain IGF-I signaling in middle-aged females contributes, in part, to LH surge dysfunction by disrupting estradiol-sensitive processes that affect GnRH neuron activation and/or GnRH release.
Isolation of Human Adrenocortical Aldosterone-Producing Cells by a Novel Immunomagnetic Beads Method
Authors: Caroccia Brasilina , Fassina Ambrogio , Seccia Teresa Maria , Recarti Chiara , Petrelli Lucia , Belloni Anna Sandra , Pelizzo Maria Rosa , Rossi Gian Paolo
Published: January 2010

We detected intense CD56 immunostaining in the zona glomerulosa (ZG) and medulla of the normal human adrenal gland and therefore identified CD56, the neural cell adhesion molecule, as a membrane antigen specific for the ZG, aldosterone-producing adenoma (APA), and chromaffin cells. The APA and pheochromocytoma cells, which are histogenetically derived from the ZG and medulla, respectively, also showed intense CD56 immunostaining. Based on these findings we developed a strategy for isolating cells from the ZG and APA using CD56 immunobinding to magnetic beads. Morphology, gene expression studies, and aldosterone measurement confirmed that CD56 positive (+) cells were ZG and APA cells. Analysis of CD56+ cells under light and phase contrast microscopy evidenced that these cells formed clumps, as the ZG cells usually do; with electron microscopy they showed multiple features typical of a steroidogenic phenotype. Expression levels of the CD56 and the aldosterone synthase (CYP11B2) gene were markedly higher in CD56+ cells than CD56− cells (+1600 and +2100% increase, respectively). Moreover, aldosterone secretion was higher (+1380%) from CD56+ cells than from CD56− cells. Hence, this novel methodology allows isolation of a pure population of ZG and APA cells exhibiting multiple characteristics of the aldosterone-producing cells.