bluuebunny/crossref_metadata_2025 huggingface dataset:
Community based intervention to optimize osteoporosis management: randomized controlled trial
Authors: Ciaschini Patricia M , Straus Sharon E , Dolovich Lisa R , Goeree Ron A , Leung Karen M , Woods Carol R , Zimmerman Greg M , Majumdar Sumit R , Spadafora Silvana , Fera Luke A , Lee Hui N
Published: August 2010

Background

Osteoporosis-related fractures are a significant public health concern. Interventions that increase detection and treatment of osteoporosis are underutilized. This pragmatic randomised study was done to evaluate the impact of a multifaceted community-based care program aimed at optimizing evidence-based management in patients at risk for osteoporosis and fractures.

Methods

This was a 12-month randomized trial performed in Ontario, Canada. Eligible patients were community-dwelling, aged ≥55 years, and identified to be at risk for osteoporosis-related fractures. Two hundred and one patients were allocated to the intervention group or to usual care. Components of the intervention were directed towards primary care physicians and patients and included facilitated bone mineral density testing, patient education and patient-specific recommendations for osteoporosis treatment. The primary outcome was the implementation of appropriate osteoporosis management.

Results

101 patients were allocated to intervention and 100 to control. Mean age of participants was 71.9 ± 7.2 years and 94% were women. Pharmacological treatment (alendronate, risedronate, or raloxifene) for osteoporosis was increased by 29% compared to usual care (56% [29/52] vs. 27% [16/60]; relative risk [RR] 2.09, 95% confidence interval [CI] 1.29 to 3.40). More individuals in the intervention group were taking calcium (54% [54/101] vs. 20% [20/100]; RR 2.67, 95% CI 1.74 to 4.12) and vitamin D (33% [33/101] vs. 20% [20/100]; RR 1.63, 95% CI 1.01 to 2.65).

Conclusions

A multi-faceted community-based intervention improved management of osteoporosis in high risk patients compared with usual care.

Trial Registration

This trial has been registered with clinicaltrials.gov (ID: NCT00465387)
Levels of high-density lipoprotein cholesterol (HDL-C) among children with steady-state sickle cell disease
Authors: Seixas Magda O , Rocha Larissa C , Carvalho Mauricio B , Menezes Joelma F , Lyra Isa M , Nascimento Valma ML , Couto Ricardo D , Atta Ájax M , Reis Mitermayer G , Goncalves Marilda S
Published: August 2010

Background

The search for sickle cell disease (SCD) prognosis biomarkers is a challenge. These markers identification can help to establish further therapy, later severe clinical complications and with patients follow-up. We attempted to study a possible involvement of levels of high-density lipoprotein cholesterol (HDL-C) in steady-state children with SCD, once that this lipid marker has been correlated with anti-inflammatory, anti-oxidative, anti-aggregation, anti-coagulant and pro-fibrinolytic activities, important aspects to be considered in sickle cell disease pathogenesis.

Methods

We prospectively analyzed biochemical, inflammatory and hematological biomarkers of 152 steady-state infants with SCD and 132 healthy subjects using immunochemistry, immunoassay and electronic cell counter respectively. Clinical data were collected from patient medical records.

Results

Of the 152 infants investigated had a significant positive association of high-density lipoprotein cholesterol with hemoglobin (P < 0.001), hematocrit (P < 0.001) and total cholesterol (P < 0.001) and a negative significant association with reticulocytes (P = 0.046), leukocytes (P = 0.015), monocytes (P = 0.004) and platelets (P = 0.005), bilirubins [total bilirubin (P < 0.001), direct bilirubin (P < 0.001) and indirect bilirubin (P < 0.001], iron (P < 0.001), aminotransferases [aspartate aminotransferase (P = 0.004), alanine aminotransferase (P = 0.035)], lactate dehydrogenase (P < 0.001), urea (P = 0.030), alpha 1-antitrypsin (P < 0.001), very low-density lipoprotein cholesterol (P = 0.003), triglycerides (P = 0.005) and hemoglobin S (P = 0.002). Low high-density lipoprotein cholesterol concentration was associated with the history of cardiac abnormalities (P = 0.025), pneumonia (P = 0.033) and blood transfusion use (P = 0.025). Lipids and inflammatory markers were associated with the presence of cholelithiasis.

Conclusions

We hypothesize that some SCD patients can have a specific dyslipidemic subphenotype characterized by low HDL-C with hypertriglyceridemia and high VLDL-C in association with other biomarkers, including those related to inflammation. This represents an important step toward a more reliable clinical prognosis. Additional studies are warranted to test this hypothesis and the probably mechanisms involved in this complex network of markers and their role in SCD pathogenesis.
Antioxidant rich grape pomace extract suppresses postprandial hyperglycemia in diabetic mice by specifically inhibiting alpha-glucosidase
Authors: Hogan Shelly , Zhang Lei , Li Jianrong , Sun Shi , Canning Corene , Zhou Kequan
Published: August 2010

Background

Postprandial hyperglycemia is an early defect of type 2 diabetes and one of primary anti-diabetic targets. Treatment of postprandial hyperglycemia can be achieved by inhibiting intestinal α-glucosidase, the key enzyme for oligosaccharide digestion and further glucose absorption. Grape pomace is winemaking byproduct rich in bioactive food compounds such as phenolic antioxidants. This study evaluated the anti-diabetic potential of two specific grape pomace extracts by determining their antioxidant and anti-postprandial hyperglycemic activitiesin vitroandin vivo.

Methods

The extracts of red wine grape pomace (Cabernet Franc) and white wine grape pomace (Chardonnay) were prepared in 80% ethanol. An extract of red apple pomace was included as a comparison. The radical scavenging activities and phenolic profiles of the pomace extracts were determined through the measurement of oxygen radical absorbance capacity, DPPH radical scavenging activity, total phenolic content and flavonoids. The inhibitory effects of the pomace extracts on yeast and rat intestinal α-glucosidases were determined. Male 6-week old C57BLKS/6NCr mice were treated with streptozocin to induce diabetes. The diabetic mice were then treated with vehicle or the grape pomace extract to determine whether the oral intake of the extract can suppress postprandial hyperglycemia through the inhibition of intestinal α-glucosidases.

Results

The red grape pomace extract contained significantly higher amounts of flavonoids and phenolic compounds and exerted stronger oxygen radical absorbance capacity than the red apple pomace extract. Both the grape pomace extracts but not the apple pomace extract exerted significant inhibition on intestinal α-glucosidases and the inhibition appears to be specific. In the animal study, the oral intake of the grape pomace extract (400 mg/kg body weight) significantly suppressed the postprandial hyperglycemia by 35% in streptozocin-induced diabetic mice following starch challenge.

Conclusion

This is the first report that the grape pomace extracts selectively and significantly inhibits intestinal α-glucosidase and suppresses postprandial hyperglycemia in diabetic mice. The antioxidant and anti-postprandial hyperglycemic activities demonstrated on the tested grape pomace extract therefore suggest a potential for utilizing grape pomace-derived bioactive compounds in management of diabetes.
RPL30 regulation of splicing reveals distinct roles for Cbp80 in U1 and U2 snRNP cotranscriptional recruitment
Authors: Bragulat Mireia , Meyer Markus , Macías Sara , Camats Maria , Labrador Mireia , Vilardell Josep
Published: August 2010

Pre-mRNA splicing is catalyzed by the spliceosome, and its control is essential for correct gene expression. While splicing repressors typically interfere with transcript recognition by spliceosomal components, the yeast protein L30 blocks spliceosomal rearrangements required for the engagement of U2 snRNP (small ribonucleoprotein particle) to its own transcript RPL30. Using a mutation in the RPL30 binding site that disrupts this repression, we have taken a genetic approach to reveal that regulation of splicing is restored in this mutant by deletion of the cap-binding complex (CBC) component Cbp80. Indeed, our data indicate that Cbp80 plays distinct roles in the recognition of the intron by U1 and U2 snRNP. It promotes the initial 5′ splice site recognition by U1 and, independently, facilitates U2 recruitment, depending on sequences located in the vicinity of the 5′ splice site. These results reveal a novel function for CBC in splicing and imply that these molecular events can be the target of a splicing regulator.
A New Assay for Measurement of the Liberated Domain I of the Urokinase Receptor in Plasma Improves the Prediction of Survival in Colorectal Cancer
Authors: Thurison Tine , Lomholt Anne F , Rasch Morten G , Lund Ida K , Nielsen Hans J , Christensen Ib J , Høyer-Hansen Gunilla
Published: August 2010

BACKGROUND

The liberated domain I of the urokinase plasminogen activator receptor [uPAR(I)] is a significant prognostic marker in lung and ovarian cancer, although the uPAR(I) concentration is below the limit of quantification (LOQ) in a substantial proportion of patient samples (Lung Cancer 2005;48:349–55; Clin Cancer Res 2008;14:5785–93; APMIS 2009;117:755–61). This study was undertaken to design an immunoassay with improved functional sensitivity for measuring uPAR(I) and to evaluate the prognostic value of uPAR(I) for colorectal cancer (CRC) patients.

METHODS

Surface plasmon resonance analysis identified 2 monoclonal antibodies, R3 and R20, that simultaneously bind to the liberated uPAR(I) but not to intact uPAR. We used R3 for capture and Eu-labeled R20 for detection in designing a 2-site sandwich time-resolved fluorescence immunoassay (TR-FIA 4) for measuring liberated uPAR(I). TR-FIA 4 was validated for use with citrated plasma. The prognostic value of the uPAR(I) concentration was evaluated in 298 CRC patients. The Cox proportional hazards model was used for the uni- and multivariate survival analyses.

RESULTS

The LOQ was 0.65 pmol/L. Liberated uPAR(I) was measurable in all patient samples with TR-FIA 4. In the multivariate analysis that included sex, age, tumor stage, tumor localization, and adjuvant treatment, the uPAR(I) concentration measured with TR-FIA 4 (hazard ratio, 1.72; 95% CI, 1.15–2.57; P = 0.009), as well as the concentration of intact soluble uPAR plus the cleaved uPAR fragment containing domains II and III, tumor stage, and age were independent predictors of prognosis.

CONCLUSIONS

TR-FIA 4 has a functional sensitivity improved 4-fold over that of the previous uPAR(I) assay. The uPAR(I) concentration measured with TR-FIA 4 is an independent predictor of prognosis in CRC patients.
The RET polymorphic allele S836S is associated with early metastatic disease in patients with hereditary or sporadic medullary thyroid carcinoma
Authors: Siqueira Débora R , Romitti Mírian , Rocha Andreia P da , Ceolin Lucieli , Meotti Camila , Estivalet Aline , Puñales Marcia K , Maia Ana Luiza
Published: August 2010

The possible role of RET variants in modifying the natural course of medullary thyroid carcinoma (MTC) is still a matter of debate. Here, we investigate whether the RET variants L769L, S836S, and G691S/S904S influence disease presentation in hereditary or sporadic MTC patients. One hundred and two patients with hereditary MTC and 81 patients with sporadic MTC attending our institution were evaluated. The frequencies of RET polymorphisms in hereditary MTC were as follows: L769L, 17.3%; S836S, 7.95%; and S904S/G691S, 18.2%. No associations were observed between these polymorphisms and pheochromocytoma, hyperparathyroidism, lymph node, or distant metastasis. However, patients harboring the S836S variant were younger than those without this allele (17±8.2 vs 28.6±14.4 years, P=0.01), suggesting that these patients had metastases at a young age. Accordingly, the cumulative frequency of local and/or distant metastases as estimated by Kaplan–Meier curves showed that lymph node and distant metastases occurred earlier in patients harboring the S836S variant (P=0.003 and P=0.026 respectively). The S836S allele frequency was higher in sporadic MTC patients than in controls (10.5 vs 3.1%, P=0.01). Individuals harboring the S836S variant were younger (38.6±13.3 vs 48.5±16.7 years, P=0.02) and showed a higher percentage of lymph node and distant metastases (P=0.02 and P=0.04 respectively). Kaplan–Meier estimates of lymph node and distant metastases yielded distinct curves for patients with or without the S836S allele (P=0.002 and P=0.001 respectively). Additional analyses using a COX regression model showed that the S836S variant was independently associated with metastatic disease (hazard ratio 2.82 (95% confidence interval 1.51–5.26), P=0.001). In conclusion, the RET S836S variant is associated with early onset and increased risk for metastatic disease in patients with hereditary or sporadic MTC.
Mammalian target of rapamycin inhibition abrogates insulin-mediated mammary tumor progression in type 2 diabetes
Authors: Fierz Yvonne , Novosyadlyy Ruslan , Vijayakumar Archana , Yakar Shoshana , LeRoith Derek
Published: August 2010

Type 2 diabetes increases breast cancer risk and mortality, and hyperinsulinemia is a major mediator of this effect. The mammalian target of rapamycin (mTOR) is activated by insulin and is a key regulator of mammary tumor progression. Pharmacological mTOR inhibition suppresses tumor growth in numerous mammary tumor models in the non-diabetic setting. However, the role of the mTOR pathway in type 2 diabetes-induced tumor growth remains elusive. Herein, we investigated whether the mTOR pathway is implicated in insulin-induced mammary tumor progression in a transgenic mouse model of type 2 diabetes (MKR mice) and evaluated the impact of mTOR inhibition on the diabetic state. Mammary tumor progression was studied in the double transgenic MMTV-Polyoma Virus middle T antigen (PyVmT)/MKR mice and by orthotopic inoculation of PyVmT- and Neu/ErbB2-driven mammary tumor cells (Met-1 and MCNeuA cells respectively). mTOR inhibition by rapamycin markedly suppressed tumor growth in both wild-type and MKR mice. In diabetic animals, however, the promoting action of insulin on tumor growth was completely blunted by rapamycin, despite a worsening of the carbohydrate and lipid metabolism. Taken together, pharmacological mTOR blockade is sufficient to abrogate mammary tumor progression in the setting of hyperinsulinemia, and thus mTOR inhibitors may be an attractive therapeutic modality for breast cancer patients with type 2 diabetes. Careful monitoring of the metabolic state, however, is important as dose adaptations of glucose- and/or lipid-lowering therapy might be necessary.
Identification of Early Response Genes in Human Peripheral Leukocytes Infected with Orientia tsutsugamushi: The Emergent of a Unique Gene Expression Profile for Diagnosis of O. tsutsugamush Infection
Authors: Chao Chien-Chung , Li Xuan , Hammamieh Rasha , O'Leary Brian , Jett Marti , Ching Wei-Mei
Published: August 2010

Scrub typhus, caused by infection with Orientia tsutsugamushi, is one of the most common rickettsial diseases in the Asia-Pacific region. The disease can cause up to 35% mortality if left untreated. In order to get a better understanding of the host responses to O. tsutsugamushi infection, freshly isolated peripheral blood mononuclear cells (PBMC) were infected with O. tsutsugamushi. The infected cells were collected at 1 h, 4 h, 8 h or 18 h post infection. The gene expression profiles were monitored by cDNA microarray. Among the 7,489 genes, 658 genes were up or down regulated by 2-fold upon infection. ANOVA t-test revealed 432 genes with statistically significant fold change (p < 0.05). Semi-quantitative PCR using specific primers that flank the mRNA splicing sites of these 658 genes was carried out to verify the microarray results. More than 9000 semi-quantitative PCR reactions were performed using glyceraldehyde 3- phosphate dehydrogenase (GAPDH) as the reference gene. Of these reactions, 22 genes were confirmed to exhibit up or down regulation. Quantitative PCR using 18S rRNA as the reference further confirmed two genes (NM_001547 and NM_006187) that exhibited significant increase of expression. Analysis of these 22 genes and the specific increase of both NM_001547 and NM_006187 suggest that the 22 genes are unique to O. tsutsugamushi infection and have the potential use for differentiating infections caused by virus, bacteria, parasites and other pathogens.
Effect of Flubendazole on Biotransformation Enzymes Activities in Haemonchus contortus
Authors: Vokřál Ivan , Křížová Veronika , Lamka Jiří , Kubíček Vladimír , Szotáková Barbora , Várady Marian , Nobilis Milan , Skálová Lenka
Published: August 2010

The aim of present project was to find out if in vivo contact of Haemonchus contortus with benzimidazole anthelmintic
flubendazole (FLU) during treatment of its hosts (sheep) with low doses of FLU affects helminths’ drugmetabolizing
enzyme activities. Four groups of lambs, experimentally infected with H. contortus , were treated three-times
orally with 0.0, 0.25, 0.50 or 1.00 mg per kg of body weight of FLU in three consecutive days. Twenty four hours after
the last FLU dose, the nematodes were isolated, homogenized and subcellular fractions were prepared. In these subcellular
fractions, biotransformation of FLU and the activities of carbonyl reducing enzymes and conjugation enzymes were assayed.
The results showed that H . contortus enzymes were able to conjugate p-nitrophenol with glucose but not with glucuronic
acid. The exposure of H.contortus to FLU (the highest FLU dose) caused a significant increase in activities of
FLU reductases, D,L-glyceraldehyde reductases and glutathion S-transferases.
Sexuality Among Middle-Aged and Older Adults With Diagnosed and Undiagnosed Diabetes
Authors: Lindau Stacy Tessler , Tang Hui , Gomero Ada , Vable Anusha , Huang Elbert S. , Drum Melinda L. , Qato Dima M. , Chin Marshall H.
Published: August 2010

OBJECTIVE

To describe sexual activity, behavior, and problems among middle-age and older adults by diabetes status.

RESEARCH DESIGN AND METHODS

This was a substudy of 1,993 community-residing adults, aged 57–85 years, from a cross-sectional, nationally representative sample (N = 3,005). In-home interviews, observed medications, and A1C were used to stratify by diagnosed diabetes, undiagnosed diabetes, or no diabetes. Logistic regression was used to model associations between diabetes conditions and sexual characteristics, separately by gender.

RESULTS

The survey response rate was 75.5%. More than 60% of partnered individuals with diagnosed diabetes were sexually active. Women with diagnosed diabetes were less likely than men with diagnosed diabetes (adjusted odds ratio 0.28 [95% CI 0.16–0.49]) and other women (0.63 [0.45–0.87]) to be sexually active. Partnered sexual behaviors did not differ by gender or diabetes status. The prevalence of orgasm problems was similarly elevated among men with diagnosed and undiagnosed diabetes compared with that for other men, but erectile difficulties were elevated only among men with diagnosed diabetes (2.51 [1.53 to 4.14]). Women with undiagnosed diabetes were less likely to have discussed sex with a physician (11%) than women with diagnosed diabetes (19%) and men with undiagnosed (28%) or diagnosed (47%) diabetes.

CONCLUSIONS

Many middle-age and older adults with diabetes are sexually active and engage in sexual behaviors similarly to individuals without diabetes. Women with diabetes were more likely than men to cease all sexual activity. Older women with diabetes are as likely to have sexual problems but are significantly less likely than men to discuss them.
TRPC expression in mesenchymal stem cells
Authors: Torossian Frederic , Bisson Aurelie , Vannier Jean-Pierre , Boyer Olivier , Lamacz Marek
Published: August 2010

Transient receptor potential canonical (TRPC) channels are key players in calcium homeostasis and various regulatory processes in cell biology. Little is currently known about the TRPC subfamily members in mesenchymal stem cells (MSC), where they could play a role in cell proliferation. We report on the presence of TRPC1, 2, 4 and 6 mRNAs in MSC. Western blot and immunofluorescence staining indicate a membrane and intracellular distribution of TRPC1. Furthermore, the decrease in the level of TRPC1 protein caused by RNA interference is accompanied by the downregulation of cell proliferation. These results indicate that MSC express TRPC1, 2, 4 and 6 mRNA and that TRPC1 may play a role in stem cell proliferation.
Vibration as an occupational hazard in the work environment of Latvia
Authors: Dundurs Jānis , Martinsone Žanna
Published: August 2010

Vibration as an occupational hazard in the work environment of Latvia

The aim of our study was to investigate vibration as an occupational health risk, conduct a survey and self-evaluation of health of the employees, carry out vibration measurements in different workplaces and to recommend practises for optimisation of work conditions. The results of analysis of employee's questionnaires and of measurements show that the vibration risk factor is a very topical issue and has been underestimated, particularly in branches like manufacture of timber wood products construction, metal processing etc. The number of vibration-caused occupational diseases in recent years has grown both in absolute figures and as percentage of the total number of occupational diseases indicating that the ratio of vibration-caused occupational diseases in Latvia is growing.
Effects of art therapy on stress and anxiety of employees
Authors: Visnola Dace , Sprūdža Dagmāra , Ārija Baķe Mārīte , Piķe Anita
Published: August 2010

Effects of art therapy on stress and anxiety of employees

The study was designed to determine if art therapy has any effect on the stress and anxiety of employees. The results demonstrated that before and after art therapy in the study group, the level of the stress indicator (cortisol) over twenty-four hours and also the state of anxiety decreased significantly (P< 0.05). The mean final stress level and situational anxiety for the study group were significantly lower (P< 0.05) than those for the control group. No significant changes were found for trait anxiety in any of the groups. These findings suggest that art therapy for employees is a preventive measure for a person to understand stress situations and to be capable to manage their anxiety, react adequately and to cope with stress, thus improving the quality of life by creative means.
Immunomodulation of Delayed-Type Hypersensitivity Responses by Mesenchymal Stem Cells Is Associated with Bystander T Cell Apoptosis in the Draining Lymph Node
Authors: Lim Jong-Hyung , Kim Jung-Sik , Yoon Il-Hee , Shin Jun-Seop , Nam Hye-Young , Yang Seung-Ha , Kim Sang-Joon , Park Chung-Gyu
Published: August 2010

Disease amelioration by mesenchymal stem cells (MSCs) has been shown to be closely related to their immunomodulatory functions on the host immune system in many disease models. However, the underlying mechanisms of how these cells affect the immune cells in vivo are not fully understood. In this study, we report findings that a small but significant number of MSCs accumulate in the secondary lymphoid organs and attenuate delayed-type hypersensitivity (DTH) response by inducing apoptotic cell death of surrounding immune cells in the draining lymph node (LN). In the migration study, i.v. infused GFP-MSCs preferentially accumulated at the boundary between the paracortical area and the germinal center in the LNs, in close proximity to various types of immune cells including T, B, and dendritic cells in a dose-dependent manner. As a result, accumulated MSCs markedly attenuated DTH response in proportion to the number of MSCs infused. During the DTH response, the infiltration of T cells in the challenged site was significantly decreased, whereas a number of apoptotic T cells were remarkably increased in the draining LN. Apoptosis was significantly induced in activated T cells (CD3+ and BrdU+), but not in the resting T cells (CD3+ and BrdU−). NO was associated with these apoptotic events. Taken together, we conclude that significant numbers of i.v. infused MSCs preferentially localize in the draining LN, where they induce apoptosis of the activated T cells by producing NO and thus attenuate the DTH response.
Suppression of Th2-Driven Airway Inflammation by Allergen Immunotherapy Is Independent of B Cell and Ig Responses in Mice
Authors: Shirinbak Soheila , Taher Yousef A. , Maazi Hadi , Gras Renée , van Esch Betty C. A. M. , Henricks Paul A. J. , Samsom Janneke N. , Verbeek J. Sjef , Lambrecht Bart N. , van Oosterhout Antoon J. M. , Nawijn Martijn C.
Published: August 2010

Allergen-specific immunotherapy (IT) uniquely renders long-term relief from allergic symptoms and is associated with elevated serum levels of allergen-specific IgG and IgA. The allergen-specific IgG response induced by IT treatment was shown to be critical for suppression of the immediate phase of the allergic response in mice, and this suppression was partially dependent on signaling through FcγRIIB. To investigate the relevance of the allergen-specific IgG responses for suppression of the Th2-driven late-phase allergic response, we performed IT in a mouse model of allergic asthma in the absence of FcγRIIB or FcγRI/FcγRIII signaling. We found that suppression of Th2 cell activity, allergic inflammation, and allergen-specific IgE responses is independent of FcγRIIB and FcγRI/FcγRIII signaling. Moreover, we show that the IT-induced allergen-specific systemic IgG or IgA responses and B cell function are dispensable for suppression of the late-phase allergic response by IT treatment. Finally, we found that the secretory mucosal IgA response also is not required for suppression of the Th2-driven allergic inflammation by IT. These data are in contrast to the suppression of the immediate phase of the allergic response, which is critically dependent on the induced allergen-specific serum IgG response. Hence, IT-induced suppression of the immediate and late phases of the allergic response is governed by divergent and independent mechanisms. Our data show that the IT-induced suppression of the Th2 cell-dependent late-phase allergic response is independent of the allergen-specific IgG and IgA responses that are associated with IT treatment.
Cutting Edge: Expression of the Transcription Factor E74-Like Factor 4 Is Regulated by the Mammalian Target of Rapamycin Pathway in CD8+ T Cells
Authors: Yamada Takeshi , Gierach Kirsten , Lee Ping-Hsien , Wang Xiaohong , Lacorazza H. Daniel
Published: August 2010

T cell receptor activation inhibits expression of the E74-like factor (ELF) 4 and Krüppel-like factor 4 genes to release naive CD8+ T cells from their quiescent state. In this study, we show that ELF4 controls the ERK-mediated proliferative response by maintaining normal levels of dual-specificity phosphatases 1 and 5 in CD8+ T cells. In activated CD8+ T cells, the mammalian target of rapamycin pathway inhibits ELF4 and Krüppel-like factor 4 expression downstream of ERK and PI3K signaling. Our findings demonstrate that rapamycin could be used to modulate expression of this transcriptional network involved in cell-cycle regulation.
Inflammasome-Dependent Release of the Alarmin HMGB1 in Endotoxemia
Authors: Lamkanfi Mohamed , Sarkar Anasuya , Vande Walle Lieselotte , Vitari Alberto C. , Amer Amal O. , Wewers Mark D. , Tracey Kevin J. , Kanneganti Thirumala-Devi , Dixit Vishva M.
Published: August 2010

Endotoxin administration recapitulates many of the host responses to sepsis. Inhibitors of the cysteine protease caspase 1 have long been sought as a therapeutic because mice lacking caspase 1 are resistant to LPS-induced endotoxic shock. According to current thinking, caspase 1-mediated shock requires the proinflammatory caspase 1 substrates IL-1β and IL-18. We show, however, that mice lacking both IL-1β and IL-18 are normally susceptible to LPS-induced splenocyte apoptosis and endotoxic shock. This finding indicates the existence of another caspase 1-dependent mediator of endotoxemia. Reduced serum high mobility group box 1 (HMGB1) levels in caspase 1-deficient mice correlated with their resistance to LPS. A critical role for HMGB1 in endotoxemia was confirmed when mice deficient for IL-1β and IL-18 were protected from a lethal dose of LPS by pretreatment with HMGB1-neutralizing Abs. We found that HMGB1 secretion from LPS-primed macrophages required the inflammasome components apoptotic speck protein containing a caspase activation and recruitment domain (ASC), caspase 1 and Nalp3, whereas HMGB1 secretion from macrophages infected in vitro with Salmonella typhimurium was dependent on caspase 1 and Ipaf. Thus, HMGB1 secretion, which is critical for endotoxemia, occurs downstream of inflammasome assembly and caspase 1 activation.
Immature NK Cells, Capable of Producing IL-22, Are Present in Human Uterine Mucosa
Authors: Male Victoria , Hughes Tiffany , McClory Susan , Colucci Francesco , Caligiuri Michael A. , Moffett Ashley
Published: August 2010

NK cells are the dominant population of immune cells in the endometrium in the secretory phase of the menstrual cycle and in the decidua in early pregnancy. The possibility that this is a site of NK cell development is of particular interest because of the cyclical death and regeneration of the NK population during the menstrual cycle. To investigate this, we searched for NK developmental stages 1–4, based on expression of CD34, CD117, and CD94. In this study, we report that a heterogeneous population of stage 3 NK precursor (CD34−CD117+CD94−) and mature stage 4 NK (CD34−CD117−/+CD94+) cells, but not multipotent stages 1 and 2 (CD34+), are present in the uterine mucosa. Cells within the uterine stage 3 population are able to give rise to mature stage 4-like cells in vitro but also produce IL-22 and express RORC and LTA. We also found stage 3 cells with NK progenitor potential in peripheral blood. We propose that stage 3 cells are recruited from the blood to the uterus and mature in the uterine microenvironment to become distinctive uterine NK cells. IL-22 producers in this population might have a physiological role in this specialist mucosa dedicated to reproduction.
Th17 Cells Contribute to Viral Replication in Coxsackievirus B3-Induced Acute Viral Myocarditis
Authors: Yuan Jing , Yu Miao , Lin Qiong-Wen , Cao Ai-Lin , Yu Xian , Dong Ji-Hua , Wang Jin-Ping , Zhang Jing-Hui , Wang Min , Guo He-Ping , Cheng Xiang , Liao Yu-Hua
Published: August 2010

Acute viral myocarditis (AVMC) is characterized by virus-triggered myocardial inflammation, and Coxsackievirus B3 (CVB3) is the primary pathogen. We previously proved that Th17 cells, besides having proinflammatory effects, were involved in AVMC by enhancing humoral response. However, the relationship between Th17 cells and CVB3 replication remains unknown. In this experiment, we infected BALB/c mice with CVB3 for establishing AVMC models and then found that, with the increase of viral replication, the expressions of splenic Th17 cells, serum IL-17, and cardiac IL-17 mRNA were elevated significantly, accompanied by the progressive cardiac injuries of AVMC. Furthermore, on day 5, the peak time for viral replication, correlation was positive between cardiac IL-17 mRNA and CVB3 RNA (correlation index = 0.835; p < 0.01). Although the expressions of Th1 and CD8+ T cells, which could secrete the antiviral cytokine IFN-γ and damage the heart, were also elevated, along with Th17 cells, in AVMC, the neutralization of IL-17 further upregulated the percentages of splenic Th1 and CD8+ T cells and the levels of cardiac IFN-γ mRNA. The cardiac pathological changes were obviously improved after neutralization, with reduced viral replication followed by decreases in the cardiac inflammatory cytokines IL-17, TNF-α, and IL-1β. These data suggest that Th17 cells contribute to CVB3 replication in AVMC, and that IL-17 might be an important target for regulating the balance of antiviral immunities.
Humans Differ from Other Hominids in Lacking an Activating NK Cell Receptor That Recognizes the C1 Epitope of MHC Class I
Authors: Moesta Achim K. , Graef Thorsten , Abi-Rached Laurent , Older Aguilar Anastazia M. , Guethlein Lisbeth A. , Parham Peter
Published: August 2010

Modulation of human NK cell function by killer cell Ig-like receptors (KIR) and MHC class I is dominated by the bipartite interactions of inhibitory lineage III KIR with the C1 and C2 epitopes of HLA-C. In comparison, the ligand specificities and functional contributions of the activating lineage III KIR remain poorly understood. Using a robust, sensitive assay of KIR binding and a representative panel of 95 HLA class I targets, we show that KIR2DS1 binds C2 with ~50% the avidity of KIR2DL1, whereas KIR2DS2, KIR2DS3, and KIR2DS5 have no detectable avidity for C1, C2, or any other HLA class I epitope. In contrast, the chimpanzee has activating C1- and C2-specific lineage III KIR with strong avidity, comparable to those of their paired inhibitory receptors. One variant of chimpanzee Pt–KIR3DS2, the activating C2-specific receptor, has the same avidity for C2 as does inhibitory Pt–KIR3DL4, and a second variant has ~73% the avidity. Chimpanzee Pt–KIR3DS6, the activating C1-specific receptor, has avidity for C1 that is ~70% that of inhibitory Pt–KIR2DL6. In both humans and chimpanzees we observe an evolutionary trend toward reducing the avidity of the activating C1- and C2-specific receptors through selective acquisition of attenuating substitutions. However, the extent of attenuation has been extreme in humans, as exemplified by KIR2DS2, an activating C1-specific receptor that has lost all detectable avidity for HLA class I. Supporting such elimination of activating C1-specific receptors as a uniquely human phenomenon is the presence of a high-avidity activating C1-specific receptor (Gg–KIR2DSa) in gorilla.
Viral Inhibitory Peptide of TLR4, a Peptide Derived from Vaccinia Protein A46, Specifically Inhibits TLR4 by Directly Targeting MyD88 Adaptor-Like and TRIF-Related Adaptor Molecule
Authors: Lysakova-Devine Tatyana , Keogh Brian , Harrington Barry , Nagpal Kamalpreet , Halle Annett , Golenbock Douglas T. , Monie Tom , Bowie Andrew G.
Published: August 2010

TLRs are critical pattern recognition receptors that recognize bacterial and viral pathogen-associated molecular patterns leading to innate and adaptive immune responses. TLRs signal via homotypic interactions between their cytoplasmic Toll/IL-1R (TIR) domains and TIR domain-containing adaptor proteins. Over the course of evolution, viruses have developed various immune evasion strategies, one of which involves inhibiting TLR signaling pathways to avoid immune detection. Thus, vaccinia virus encodes the A46 protein, which binds to multiple TIR-domain containing proteins, ultimately preventing TLRs from signaling. We have identified an 11-aa–long peptide from A46 (termed viral inhibitor peptide of TLR4, or VIPER), which, when fused to a cell-penetrating delivery sequence, potently inhibits TLR4-mediated responses. VIPER was TLR4 specific, being inert toward other TLR pathways, and was active in murine and human cells and in vivo, where it inhibited LPS-induced IL-12p40 secretion. VIPER also prevented TLR4-mediated MAPK and transcription factor activation, suggesting it acted close to the TLR4 complex. Indeed, VIPER directly interacted with the TLR4 adaptor proteins MyD88 adaptor-like (Mal) and TRIF-related adaptor molecule (TRAM). Viral proteins target host proteins using evolutionary optimized binding surfaces. Thus, VIPER possibly represents a surface domain of A46 that specifically inhibits TLR4 by masking critical binding sites on Mal and TRAM. Apart from its potential therapeutic and experimental use in suppressing TLR4 function, identification of VIPER’s specific binding sites on TRAM and Mal may reveal novel therapeutic target sites. Overall, we demonstrate for the first time disruption of a specific TLR signaling pathway by a short virally derived peptide.
Assessing physical activity in persons with knee osteoarthritis using accelerometers: Data from the osteoarthritis initiative
Authors: Song Jing , Semanik Pamela , Sharma Leena , Chang Rowland W. , Hochberg Marc C. , Mysiw W. Jerry , Bathon Joan M. , Eaton Charles B. , Jackson Rebecca , Kwoh C. Kent , Nevitt Michael , Dunlop Dorothy D.
Published: August 2010

Objective

Physical activity measured by accelerometers requires basic assumptions to translate the output into meaningful measures. We used accelerometer data from the Osteoarthritis Initiative to investigate in the context of knee osteoarthritis (OA) the following data processing assumptions derived from the general US adult population: nonwear (a period the monitor was removed), based on zero activity exceeding 60 minutes; and a valid day of monitoring, based on wear time evidence exceeding 10 hours.

Methods

We examined the influence of nonwear thresholds ranging from 20 to 300 minutes of zero activity on mean daily activity minutes (counts >0), mean daily activity counts, and mean daily moderate to vigorous physical activity minutes. The effect of selecting minimums of 8, 10, or 12 wear hours to signify a valid day of monitoring on data retention was examined.

Results

Our sample of 3,536 days of accelerometer data from 519 persons with knee OA showed that mean daily activity minutes increased with the nonwear threshold until stabilizing at 463 minutes per day, corresponding to the 90‐minute nonwear threshold. Similar patterns were observed for mean daily activity counts. Varying the nonwear threshold had no effect on mean daily moderate to vigorous physical activity minutes. Choosing the 90‐minute nonwear threshold and a minimum of 10 wear hours to constitute a valid day provided 94% data retention.

Conclusion

Data supported applying the 90‐minute nonwear threshold to the knee OA population instead of the 60‐minute threshold for the general population, while retaining the 10‐hour valid day threshold.
Fibronectin Functionalized Hydroxyapatite Coatings: Improving Dermal Fibroblast Adhesion In Vitro and In Vivo
Authors: Pendegrass Catherine J. , Middleton Claire A. , Blunn Gordon W.
Published: August 2010

Skin‐penetrating devices including intraosseous transcutaneous amputation prostheses (ITAP) and external fixator pins rely on a skin‐implant seal to prevent infection. In this study, we assess the effectiveness of fibronectin (Fn) functionalized hydroxyapatite (HA) coatings for promoting dermal fibroblast and dermal tissue attachment and ingrowth in vitro and in vivo. By measuring the number of focal adhesions per unit cell area we have demonstrated that HA significantly promotes dermal fibroblast attachment compared with titanium alloy. Dermal fibroblast attachment is promoted further using Fn functionalized HA coatings incorporated into an implant design with 700 µm pores, which significantly increased dermal tissue ingrowth and attachment compared with non‐functionalized HA and titanium alloy controls incorporating 500 or 1000 µm pores. We postulate that Fn functionalized HA coatings applied to transdermal implants may promote and sustain the skin‐implant interface and assist in preventing infection long term.
Nanostructured Complexes of Polyelectrolytes and Charged Polypeptides
Authors: Müller Martin , Ouyang Wuye , Bohata Karolina , Keßler Bernd
Published: August 2010

Nanoparticles and films of complexes between polyelectrolytes (PELs) and oppositely charged polypeptides emphasizing the influence of PEL molecular stiffness on the generated nanostructures are reported. Homopolypeptides like cationic poly(L‐lysine) (PLL) and anionic poly(L‐glutamic acid) (PLG) were used, whose conformations can be changed from random coil to α‐helix by salt type or pH value. PLL and PLG were complexed with standard commercial polyanions (PA) like poly(vinylsulfate) (PVS) or poly(methacrylic acid) (PMAC) and polycations (PC) like poly(diallyldimethylammoniumchloride) (PDADMAC), respectively. In situ attenuated total reflection infrared (ATR‐IR), circular dichroism (CD), and atomic force microscopy (AFM) were used for surface and bulk characterization. Randomly coiled PLL caused spherical PEC particles and isotropically structured PEM films. Whereas, α‐helical PLL resulted in needle‐like or worm‐like PEC particles and anisotropic PEM films. For PEM films consisting of PDADMAC/PLG PLG terminating PEM‐6 was proteininert, while PDADMAC terminating PEM‐7 was proteinactive. PEM films consisting of PDL/PSS showed higher enantiospecific adsorption of α‐helical myoglobin compared to PLL/PSS. These nanoparticles and films are envisioned as bioinert and bioactive material substrates, unidirectional cell growth, polymer/cell scaffolds, and nanocarriers.
Atomically Defined Rare‐Earth Scandate Crystal Surfaces
Authors: Kleibeuker Josée E. , Koster Gertjan , Siemons Wolter , Dubbink David , Kuiper Bouwe , Blok Jeroen L. , Yang Chan‐Ho , Ravichandran Jayakanth , Ramesh Ramamoorthy , ten Elshof Johan E. , Blank Dave H. A. , Rijnders Guus
Published: August 2010

The fabrication of well‐defined, atomically sharp substrate surfaces over a wide range of lattice parameters is reported, which is crucial for atomically regulated epitaxial growth of complex oxide heterostructures. By applying a framework for controlled selective wet etching of complex oxides on the stable rare‐earth scandates (REScO3), apseudocubic = 0.394 – 0.404 nm, the large chemical sensitivity of REScO3 to basic solutions is exploited, which results in reproducible, single‐terminated surfaces. Time‐of‐flight mass‐spectroscopy measurements show that after wet etching the surfaces are predominantly ScO2 ‐terminated. Moreover, the morphology study of SrRuO3 thin‐film growth gives no evidence for mixed termination. Therefore, it is concluded that the REScO3 surfaces are completely ScO2 ‐terminated.
Ultrasensitive and Selective Detection of a Prognostic Indicator in Early‐Stage Cancer Using Graphene Oxide and Carbon Nanotubes
Authors: Wang Xiaohui , Wang Chunyan , Qu Konggang , Song Yujun , Ren Jinsong , Miyoshi Daisuke , Sugimoto Naoki , Qu Xiaogang
Published: August 2010

Cyclin A2 is a prognostic indicator in early‐stage cancer. However, since most of peptide‐protein bindings do not produce an easily measurable output signal, this severely hinders homogeneous detection of protein using peptide as detection probe. Cyclin A2 can be detected as low as 0.6 μM using a well‐known p21(WAF‐1) consensus senquence for a specific cyclin A2 binding motif, which is incorporated into a Tb3+ chelating macrocycle by chemical modification at the N‐terminus of CMB. Herein, a simple, ultra‐sensitive, and selective signal‐on fluorescence assay is developed for detection of a prognostic indicator in early‐stage cancer, cyclin A2. Graphene oxide (GO) is even superior to SWNTs for cyclin A2 detection. The direct detection limit using graphene oxide is 0.5 nM, 10‐fold better than using SWNTs, and 1200‐fold better than the latest reported value of 0.6 μM using the Tb3+ chelating macrocycle modified p21(WAF‐1) peptide.
Dry Autoclaving for the Nanofabrication of Sulfides, Selenides, Borides, Phosphides, Nitrides, Carbides, and Oxides
Authors: Pol Vilas G. , Pol Swati V. , Gedanken Aharon
Published: August 2010

This review compiles various nanostructures fabricated by a distinct “dry autoclaving” approach, where the chemical reactions are carried out without solvents; above the dissociation temperature of the chemical precursor(s) at elevated temperature in a closed reactor. The diversity to fabricate carbides (SiC, Mo2C, WC), oxides (VOx‐C, ZnO, Eu2O3, Fe3O4, MoO2), hexaborides (LaB6, CeB6, NdB6, SmB6, EuB6, GdB6), nitrides (TiN, NbN, TaN), phosphides (PtP2, WP), sulfides (ZnS, FeS/C, SnS/C, WS2, WS2/C), and selenides (Zn1‐xMnxSe/C, Cd1‐xMnxSe/C), with various shapes and sizes is accounted with plausible applications. This unique single‐step, solvent‐free synthetic process opens up a new route in the growing nanomaterials science; owing to its considerable advantages on the existing approaches.
Endoscopic and heat transfer effects on the peristaltic flow of a third‐order fluid with chemical reactions
Authors: Nadeem S. , Akbar Noreen Sher
Published: August 2010

This article analyzes the peristaltic pumping characteristics of a third‐order fluid in an endoscope. The governing momentum energy and concentration equations are simplified by using low Reynold's number and long wavelength approximations. The resulting, highly nonlinear equations are solved by (1) perturbation method and (2) shooting method. The solutions obtained by using both the methods are presented graphically to interpret physical behavior of the various parameters appearing in the problem. Trapping phenomena are also discussed at the end of the article. Copyright © 2010 Curtin University of Technology and John Wiley & Sons, Ltd.
Structure effect of benzofuranone on the anti‐oxidation kinetics in polypropylene
Authors: Cai Zhi , Meng Xin , Shen Benxian , Xin Zhong
Published: August 2010

Benzofuranone compounds are used as chain‐breaking antioxidants in the melt processing of polymers owing to their strong hydrogen donating ability. In this article, the structural effects of benzofuranone compounds on anti‐oxidation in polypropylene (PP) were evaluated using oxidation onset temperature (OOT) of PP stabilised by the compounds in oxygen and the oxidation kinetics of the PP was studied using Ozawa and Kissinger methods, respectively. The results show that benzofuranone compounds inhibit the oxidative degradation of PP by increasing the oxidation activation energy, and the higher the oxidation activation energy of PP, the better the anti‐oxidation activity of benzofuranone in PP. Furthermore, the anti‐oxidation activity of benzofuranone compounds in PP is weakened by the methyl group in the 2′‐position. Compared to benzofuranone compounds OXBF1 and TBF1 without 2′‐position methyl group, PP stabilised by benzofuranone compound MXBF1 with 2′‐position methyl group has lower OOT values and smaller oxidation activation energy. Copyright © 2010 Curtin University of Technology and John Wiley & Sons, Ltd.
Relationship between nitrogenous species in coals and volatile nitrogen‐containing yields during pyrolysis
Authors: Wang Zonghua , Zhang Junying , Zhao Yongchun , Zheng Chuguang
Published: August 2010

Nitrogen in coal is a major pollutant that inhibits the effective and extensive utilization of coal, and hence, nitrogen removal during and after coal combustion is of great importance. Future utilization of coal requires accurate knowledge of its structure and properties. Datong coal (DT, bituminous coal), Huolinhe coal (NM, brown coal) and Fushun coal (FS, brown coal) were pyrolyzed in a fixed‐bed reactor under argon atmosphere with a heating rate of 15 °C/min. X‐ray photoelectron spectroscopy (XPS) was used to investigate the presence of nitrogen in the coals and their chars obtained from pyrolysis. The nitrogenous components in the product gases were analyzed by Fourier transform infrared (FT‐IR) spectrometer. The results indicate that N‐5 is the main nitrogen‐bearing compound in DT coal and NM coal, whereas in FS coal N‐6 is the main nitrogen‐bearing compound. After pyrolysis at 600 °C, the quantity of N‐6 in the char rises for DT coal, and drops for NM coal and FS coal. After pyrolysis at 1000 °C, the quantity of N‐6 decreases significantly for FS coal, and considerable quantity of N‐Q is detected. NH3, HCN, and NO were identified among the gases resulting from pyrolysis, with the HCN and NO yields being lower than the NH3 yields. In coal pyrolysis, the initial formation temperature of NH3 is approximately the same as that of HCN. The temperatures are almost identical when the concentrations of NH3 and HCN reach their maxima for DT coal and FS coal. The formation of HCN starts at a temperature of about 400 °C, and below 700 °C, considerable amounts of HCN and NH3 are produced. The amount of nitrogen released increases with the temperature at which pyrolysis takes place, the maximum release rate being 81.28% at 1000 °C. Copyright © 2010 Curtin University of Technology and John Wiley & Sons, Ltd.