bluuebunny/crossref_metadata_2025_split huggingface dataset:
HSV-1-induced chemokine expression via IFI16-dependent and IFI16-independent pathways in human monocyte-derived macrophages
Authors: Søby Stine , Laursen Rune R , Østergaard Lars , Melchjorsen Jesper 
Published: October 2012

AbstractBackgroundInnate recognition is essential in the antiviral response against infection by herpes simplex virus (HSV). Chemokines are important for control of HSV via recruitment of natural killer cells, T lymphocytes, and antigen-presenting cells. We previously found that early HSV-1-mediated chemokine responses are not dependent on TLR2 and TLR9 in human macrophages. Here, we investigated the role of the recently identified innate IFN-inducible DNA receptor IFI16 during HSV-1 infection in human macrophages.MethodsPeripheral blood mononuclear cells were purified from buffy coats and monocytes were differentiated to macrophages. Macrophages infected with HSV-1 were analyzed using siRNA-mediated knock-down of IFI16 by real-time PCR, ELISA, and Western blotting.ResultsWe determined that both CXCL10 and CCL3 are induced independent of HSV-1 replication. IFI16 mediates CCL3 mRNA accumulation during early HSV-1 infection. In contrast, CXCL10 was induced independently of IFI16.ConclusionsOur data provide the first evidence of HSV-1-induced innate immune responses via IFI16 in human primary macrophages. In addition, the data suggest that at least one additional unidentified receptor or innate sensing mechanism is involved in recognizing HSV-1 prior to viral replication.
Gender, anthropometric factors and risk of colorectal cancer with particular reference to tumour location and TNM stage: a cohort study
Authors: Brändstedt Jenny , Wangefjord Sakarias , Nodin Björn , Gaber Alexander , Manjer Jonas , Jirström Karin 
Published: October 2012

AbstractBackgroundIt remains unclear whether the increased risk of colorectal cancer (CRC) associated with obesity differs by gender, distribution of fat, tumour location and clinical (TNM) stage. The primary aim of this study was to examine these associations in 584 incident colorectal cancer cases from a Swedish prospective population-based cohort including 28098 men and women.MethodsSeven anthropometric factors; height, weight, bodyfat percentage, hip circumference, waist circumference, BMI and waist-hip ratio (WHR) were categorized into quartiles of baseline anthropometric measurements. Relative risks of CRC, total risk as well as risk of different TNM stages, and risk of tumours located to the colon or rectum, were calculated for all cases, women and men, respectively, using multivariate Cox regression models.ResultsObesity, as defined by all anthropometric variables, was significantly associated with an overall increased risk of CRC in both women and men. While none of the anthropometric measures was significantly associated with risk of tumour (T)-stage 1 and 2 tumours, all anthropometric variables were significantly associated with an increased risk of T-stage 3 and 4, in particular in men. In men, increasing quartiles of weight, hip, waist, BMI and WHR were significantly associated with an increased risk of lymph node positive (N1 and N2) disease, and risk of both non-metastatic (M0) and metastatic (M1) disease. In women, there were no or weak associations between obesity and risk of node-positive disease, but statistically significant associations between increased weight, bodyfat percentage, hip, BMI and M0 disease. Interestingly, there was an increased risk of colon but not rectal cancer in men, and rectal but not colon cancer in women, by increased measures of weight, hip-, waist circumference and bodyfat percentage.ConclusionsThis study is the first to show a relationship between obesity, measured as several different anthropometric factors, and an increased risk of colorectal cancer of more advanced clinical stage, in particular in men. These findings suggest that risk of CRC differs according to the method of characterising obesity, and also according to gender, location, and tumour stage.
Treatment of splenic marginal zone lymphoma of the CNS with high-dose therapy and allogeneic stem cell transplantation
Authors: Busemann Christoph , Gudzuhn Andrej , Hirt Carsten , Kirsch Michael , Vogelgesang Silke , Schmidt Christian A , Dölken Gottfried , Krüger William H 
Published: October 2012

Abstract
Therapy of indolent lymphomas with involvement of the central nervous system (CNS) has not been standardized so far. A 42-year old male patient presented with neurological signs because of leukemic splenic marginal zone lymphoma (SMZL) manifested in bone marrow, lymph nodes and CNS. Due to the aggressiveness of the disease and the young age of the patient, an intensive immunochemotherapy followed by high-dose therapy with busulfan, thiotepa and fludarabine and subsequent unrelated allogeneic stem cell transplantation (alloSCT) was performed. The haemopoietic stem cells engrafted in time and the patient is doing well (ECOG 0) without evidence for active lymphoma three years after transplantation. Highly sensitive tests by specific quantitative real-time polymerase chain reaction for presence of lymphoma cells in blood and bone marrow indicated also a molecular remission. The reported case shows the feasibility of high-dose therapy and allogeneic stem cell transplantation in high-risk patients with CNS-involvement of indolent non-Hodgkin’s lymphoma. In addition, the case supports the hypothesis that the graft-versus lymphoma effect after alloSCT is also active within the CNS.
Pharmacokinetic modeling of P-glycoprotein function at the rat and human blood–brain barriers studied with (R)-[11C]verapamil positron emission tomography
Authors: Müllauer Julia , Kuntner Claudia , Bauer Martin , Bankstahl Jens P , Müller Markus , Voskuyl Rob A , Langer Oliver , Syvänen Stina 
Published: October 2012

Abstract

Background
This study investigated the influence of P-glycoprotein (P-gp) inhibitor tariquidar on the pharmacokinetics of P-gp substrate radiotracer (R)-[11C]verapamil in plasma and brain of rats and humans by means of positron emission tomography (PET).

Methods
Data obtained from a preclinical and clinical study, in which paired (R)-[11C]verapamil PET scans were performed before, during, and after tariquidar administration, were analyzed using nonlinear mixed effects (NLME) modeling. Administration of tariquidar was included as a covariate on the influx and efflux parameters (Q
in and Q
out) in order to investigate if tariquidar increased influx or decreased outflux of radiotracer across the blood–brain barrier (BBB). Additionally, the influence of pilocarpine-induced status epilepticus (SE) was tested on all model parameters, and the brain-to-plasma partition coefficient (V
T-NLME) was calculated.

Results
Our model indicated that tariquidar enhances brain uptake of (R)-[11C]verapamil by decreasing Q
out. The reduction in Q
out in rats during and immediately after tariquidar administration (sevenfold) was more pronounced than in the second PET scan acquired 2 h after tariquidar administration (fivefold). The effect of tariquidar on Q
out in humans was apparent during and immediately after tariquidar administration (twofold reduction in Q
out) but was negligible in the second PET scan. SE was found to influence the pharmacological volume of distribution of the central brain compartment V
br1. Tariquidar treatment lead to an increase in V
T-NLME, and pilocarpine-induced SE lead to increased (R)-[11C]verapamil distribution to the peripheral brain compartment.

Conclusions
Using NLME modeling, we were able to provide mechanistic insight into the effects of tariquidar and SE on (R)-[11C]verapamil transport across the BBB in control and 48 h post SE rats as well as in humans.
Late pharmacologic conditioning with volatile anesthetics after cardiac surgery
Authors: Steurer Marc P , Steurer Martina A , Baulig Werner , Piegeler Tobias , Schläpfer Martin , Spahn Donat R , Falk Volkmar , Dreessen Pamela , Theusinger Oliver M , Schmid Edith R , Schwartz David , Neff Thomas A , Beck-Schimmer Beatrice 
Published: October 2012

Abstract
Introduction
The aim of this randomized controlled trial was to investigate whether volatile anesthetics used for postoperative sedation have any beneficial effects on myocardial injury in cardiac surgery patients after on-pump valve replacement.

Methods
Anesthesia was performed with propofol. After arrival in the intensive care unit (ICU), 117 patients were randomized to be sedated for at least 4 hours with either propofol or sevoflurane. Sevoflurane was administered by using the anesthetic-conserving device. Troponin T, creatine kinase, creatine kinase from heart muscle tissue, myoglobin, and oxygenation index were determined on arrival at the ICU, 4 hours after sedation, and in the morning of the first postoperative day (POD1). Primary end points were cardiac injury markers on POD1. As secondary end points oxygenation, postoperative pulmonary complications, and ICU and hospital stay were documented.

Results
Fifty-six patients were analyzed in the propofol arm, and 46 patients in the sevoflurane arm. Treatment groups were comparable with regard to patient demographics and intraoperative characteristics. Concentration of troponin T as the most sensitive marker for myocardial injury at POD1 was significantly lower in the sevoflurane group compared with the propofol group (unadjusted difference, -0.4; 95% CI, -0.7 to -0.1; P < 0.01; adjusted difference, -0.2; 95% CI, -0.4 to -0.02; P = 0.03, respectively).

Conclusions
The data presented in this investigation indicate that late postconditioning with the volatile anesthetic sevoflurane might mediate cardiac protection, even with a late, brief, and low-dose application.

Trial registration
ClinicalTrials.gov: NCT00924222.
Complication rates as a trauma care performance indicator: a systematic review
Authors: Moore Lynne , Stelfox Henry Thomas , Turgeon Alexis F 
Published: October 2012

Abstract
Introduction
Information on complication rates is essential to trauma quality improvement efforts. However, it is unclear which complications are the most clinically relevant. The objective of this study was to evaluate whether there is consensus on the complications that should be used to evaluate the performance of acute care trauma hospitals.

Methods
We searched the Medline, EMBASE, Cochrane Central, CINAHL, BIOSIS, TRIP and ProQuest databases and included studies using at least one nonfatal outcome to evaluate the performance of acute care trauma hospitals. Data were extracted in duplicate using a piloted electronic data abstraction form. Consensus was considered to be reached if a specific complication was used in ≥ 70% of studies (strong recommendation) or in ≥ 50% of studies (weak recommendation).

Results
Of 14,521 citations identified, 22 were eligible for inclusion. We observed important heterogeneity in the complications used to evaluate trauma care. Seventy-nine specific complications were identified but none were used in ≥ 70% of studies and only three (pulmonary embolism, deep vein thrombosis, and pneumonia) were used in ≥ 50% of studies. Only one study provided evidence for the clinical relevance of complications used and only five studies (23%) were considered of high methodological quality.

Conclusion
Based on the results of this review, we can make a weak recommendation on three complications that should be used to evaluate acute care trauma hospitals; pulmonary embolism, deep vein thrombosis, and pneumonia. However, considering the observed disparity in definitions, the lack of clinical justification for the complications used, and the low methodological quality of studies, further research is needed to develop a valid and reliable performance indicator based on complications that can be used to improve the quality and efficiency of trauma care.
Probability of Metachronous Testicular Cancer in Patients With Biopsy-Proven Intratubular Germ Cell Neoplasia Depends on First-Time Treatment of Germ Cell Cancer
Authors: Brabrand Sigmund , Fosså Sophie D. , Cvancarova Milada , Axcrona Ulrika , Lehne Gustav 
Published: October 2012

Purpose To evaluate the probability of subsequent testicular cancer (STC) in patients with intratubular germ cell neoplasia unclassified (IGCNU) treated for first-time invasive germ cell cancer. Patients and Methods Sixty-one patients with germ cell testicular cancer or extragonadal germ cell cancer received follow-up from diagnosis of IGCNU to development of STC, initiation of IGCNU-definitive treatment (orchiectomy/radiotherapy), emigration, death, or end of follow-up. The probability of STC was assessed in subgroups according to chemotherapy burden. Results The probability of STC in the nonexposed patients was significantly increased compared with those exposed to chemotherapy (P = .05; 5-year probability of 54% [95% CI, 33% to 78%] and 23% [95% CI, 11% to 45%], respectively). In the group of patients treated with one to three cycles or no chemotherapy, the probability of STC was significantly increased compared with those exposed to four or more cycles (P = .03; 5-year probability of 42% [95% CI, 27% to 62%] and 22% [95% CI, 8% to 54%], respectively). Twenty-two of 22 patients were tumor-free and alive at a median of 56 months (range, 2 to 184 months) after diagnosis of STC. Conclusion Platinum-based chemotherapy may reduce the probability of STC in patients with IGCNU, particularly in those treated with four or more cycles of chemotherapy. A watch-and-wait strategy for patients with IGCNU may be justified in selected patients with future plans for paternity.
Phase I Trial and Pharmacokinetic Study of Lexatumumab in Pediatric Patients With Solid Tumors
Authors: Merchant Melinda S. , Geller James I. , Baird Kristin , Chou Alexander J. , Galli Susana , Charles Ava , Amaoko Martha , Rhee Eunice H. , Price Anita , Wexler Leonard H. , Meyers Paul A. , Widemann Brigitte C. , Tsokos Maria , Mackall Crystal L. 
Published: October 2012

Purpose Lexatumumab is an agonistic, fully human monoclonal antibody against tumor necrosis factor–related apoptosis-inducing ligand receptor 2 with preclinical evidence of activity in pediatric solid tumors. Patients and Methods This phase I dose-escalation study examined the safety, tolerability, pharmacokinetics, and immunogenicity of lexatumumab at doses up to, but not exceeding, the adult maximum-tolerated dose (3, 5, 8, and 10 mg/kg), administered once every 2 weeks to patients age ≤ 21 years with recurrent or progressive solid tumors. Results Twenty-four patients received a total of 56 cycles of lexatumumab over all four planned dose levels. One patient had grade 2 pericarditis consistent with radiation recall, and one patient developed grade 3 pneumonia with hypoxia during the second cycle. Five patients experienced stable disease for three to 24 cycles. No patients experienced complete or partial response, but several showed evidence of antitumor activity, including one patient with recurrent progressive osteosarcoma who experienced resolution of clinical symptoms and positron emission tomography activity, ongoing more than 1 year off therapy. One patient with hepatoblastoma showed a dramatic biomarker response. Conclusion Pediatric patients tolerate 10 mg/kg of lexatumumab administered once every 14 days, the maximum-tolerated dose identified in adults. The drug seems to mediate some clinical activity in pediatric solid tumors and may work with radiation to enhance antitumor effects.
TNF-α Up-Regulates Protein Level and Cell Surface Expression of the Leptin Receptor by Stimulating Its Export via a PKC-Dependent Mechanism
Authors: Gan Lixia , Guo Kaiying , Cremona Maria Laura , McGraw Timothy E. , Leibel Rudolph L. , Zhang Yiying 
Published: October 2012

Abstract
Increasing evidence suggests that inflammation/cytokines may modulate hypothalamic responses to leptin, which is a key regulator of energy homeostasis and inflammatory/stress responses. We investigated a possible role of TNF-α, a key early mediator of inflammation, in regulating the expression and trafficking of the long-isoform leptin receptor (LEPRb), the primary mediator of leptin signaling, in cultured cells. We found that TNF-α in a wide range of concentrations up-regulated LEPRb protein level and soluble LEPR (sLEPR) release via ectodomain shedding of LEPRb in multiple cell types, including neuronal cells. TNF-α also acutely increased LEPRb cell surface expression and leptin-induced STAT3 phosphorylation. In contrast, TNF-α had no significant effects on the protein level or cell surface expression of several other transmembrane proteins, including the transferrin receptor and cadherin. The stimulatory effects of TNF-α on LEPRb cell surface expression and sLEPR release were not dependent on de novo protein synthesis or functional lysosomes but were blocked by brefeldin A, suggesting that an intact Golgi or continuous endoplasmic reticulum to Golgi transport of newly synthesized proteins is required for these effects. However, TNF-α did not increase the half-life of cell surface LEPRb. Protein kinase C (PKC) inhibitor GF109203X abrogated the effects of TNF-α, whereas the pan-PKC activator phorbol 12-myristate 13-acetate mimicked the TNF-α effects. Taken together, our results suggest that TNF-α, via activation of PKC, regulates anterograde trafficking and/or degradation of LEPRb in the biosynthetic pathway, leading to concomitant increases in LEPRb protein level, cell surface expression, and sLEPR production. The finding that LEPRb cell surface expression and sLEPR production, key modulators of leptin sensitivity and bioavailability, are direct targets of TNF-α signaling could have a potentially important implication in the regulation of leptin signaling activity in different pathophysiological conditions as diverse as obesity and sepsis.
Large Conductance Ca2+-Activated and Voltage-Activated K+ Channels Contribute to the Rise and Maintenance of Estrogen-Induced Uterine Vasodilation and Maintenance of Blood Pressure
Authors: Rosenfeld Charles R. , Roy Timothy 
Published: October 2012

Abstract
Uterine blood flow (UBF) increases greater than 4-fold 90 min after systemic estradiol-17β (E2β) in nonpregnant sheep and remains elevated longer than 6–8 h; mean arterial pressure (MAP) is unchanged. Large-conductance Ca+2-activated (BKCa) and voltage-activated (KV) K+ channels contribute to the acute rise in UBF; their role in maintaining UBF and MAP longer than 90 min is unknown. We examined this in five nonpregnant, ovariectomized ewes with uterine artery (UA) flow probes and catheters in a UA for infusion of K+ channel inhibitors and uterine vein to sample venous effluent. Animals received systemic E2β (1.0 μg/kg; control), E2β+UA tetraethylammonium (TEA; 0.4–0.8 mm, n = 4), and E2β+UA 4-aminopyridine (4-AP; 0.01–0.08 mm, n = 4) to block BKCa and KV, respectively, while monitoring MAP, heart rate, and UBF. Uterine cGMP synthesis was measured. Ninety minutes after E2β, UBF rose 4.5-fold, uterine vascular resistance (UVR) fell greater than 5-fold and MAP was unchanged [78 ± 0.8 (sem) vs. 77 ± 1.5 mm Hg] in control studies and before UA inhibition with TEA and 4-AP. Between 90 and 120min, UBF, UVR, and MAP were unchanged after E2β alone. E2β+TEA dose dependently decreased ipsilateral UBF and increased UVR (24 ± 8.9 and 38 ± 16%, respectively, at 0.8 mm; P &lt; 0.03); MAP was unchanged. Contralateral UBF/UVR were unaffected. E2β+4-AP also dose dependently decreased ipsilateral UBF and increased UVR (27 ± 5.3 and 76 ± 18%, respectively, at 0.08 mm; P &lt; 0.001); however, MAP rose 27 ± 6.9% (P ≤ 0.006). E2β increased uterine cGMP synthesis greater than 3.5-fold and was unaffected by local K+ channel inhibition. BKCa and KV contribute to the rise and maintenance of E2β-induced uterine vasodilation, which is partially cGMP dependent. Systemic vascular KV also contributes to maintaining MAP after systemic E2β.
An Approach to Pyrazoline-Fused Chlorins by Dipolar [3 + 2]-Cycloaddition of Iminonitriles to meso-Tetrakis(pentafluorophenyl)porphyrin: Synthesis of New PDT Photosensitizers
Authors: Wyrebek Przemysaw , Ostrowski Stanisaw 
Published: October 2012

Abstract
meso-Tetrakis(pentafluorophenyl)porphyrin reacts at higher temperature with unstable iminonitriles (R–C≡N+–N−–Ar), affording pyrazoline-fused chlorins, according to dipolar [3 + 2]-cycloaddition pathway. The respective iminonitriles were in situ generated from the corresponding functionalized α-halogenohydrazine derivatives by 1,3-elimination of HX in the presence of base (NEt3, DABCO). This method allows synthesis of very attractive moieties which may be of potential use as sensitizers in photodynamic therapy (PDT).
Reference intervals for plasma free metanephrines with an age adjustment for normetanephrine for optimized laboratory testing of phaeochromocytoma
Authors: Eisenhofer Graeme , Lattke Peter , Herberg Maria , Siegert Gabriele , Qin Nan , Därr Roland , Hoyer Jana , Villringer Arno , Prejbisz Aleksander , Januszewicz Andrzej , Remaley Alan , Martucci Victoria , Pacak Karel , Ross H Alec , Sweep Fred C G J , Lenders Jacques W M 
Published: October 2012

Background Measurements of plasma normetanephrine and metanephrine provide a useful diagnostic test for phaeochro-mocytoma, but this depends on appropriate reference intervals. Upper cut-offs set too high compromise diagnostic sensitivity, whereas set too low, false-positives are a problem. This study aimed to establish optimal reference intervals for plasma normetanephrine and metanephrine. Methods Blood samples were collected in the supine position from 1226 subjects, aged 5-84 y, including 116 children, 575 normotensive and hypertensive adults and 535 patients in whom phaeochromocytoma was ruled out. Reference intervals were examined according to age and gender. Various models were examined to optimize upper cut-offs according to estimates of diagnostic sensitivity and specificity in a separate validation group of 3888 patients tested for phaeochromocytoma, including 558 with confirmed disease. Results Plasma metanephrine, but not normetanephrine, was higher (P < 0.001) in men than in women, but reference intervals did not differ. Age showed a positive relationship (P < 0.0001) with plasma normetanephrine and a weaker relationship (P = 0.021) with metanephrine. Upper cut-offs of reference intervals for normetanephrine increased from 0.47 nmol/L in children to 1.05 nmol/L in subjects over 60 y. A curvilinear model for age-adjusted compared with fixed upper cut-offs for normetanephrine, together with a higher cut-off for metanephrine (0.45 versus 0.32 nmol/L), resulted in a substantial gain in diagnostic specificity from 88.3% to 96.0% with minimal loss in diagnostic sensitivity from 93.9% to 93.6%. Conclusions These data establish age-adjusted cut-offs of reference intervals for plasma normetanephrine and optimized cut-offs for metanephrine useful for minimizing false-positive results.