bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adiponectin is a potential catabolic mediator in osteoarthritis cartilage
Authors: Kang Eun Ha , Lee Yun Jong , Kim Tae Kyun , Chang Chong Bum , Chung Jin-Haeng , Shin Kichul , Lee Eun Young , Lee Eun Bong , Song Yeong Wook 
Published: January 2011

Abstract
Introduction
Adiponectin has been implicated in the pathogenesis of osteoarthritis (OA). We studied the effects of adiponectin on the OA cartilage homeostasis.

Methods
Immunohistochemical analysis was performed to evaluate differential expression of adiponectin receptors (AdipoRs) in nonlesional and lesional areas of OA cartilage. Cartilage and chondrocytes from the knee joints of primary OA patients were cultured in the presence of adiponectin (0~30 μg/ml). The levels of total nitric oxide (NO), matrix metalloproteinase (MMP)-1, -3, and -13, and tissue inhibitor of metalloproteinase (TIMP)-1 were measured in the conditioned media. The levels of inducible NO synthase (iNOS) and MMPs were determined with the quantitative real-time reverse transcription-polymerase chain reaction. The concentrations of collagenase-cleaved type II collagen neoepitope (C1-2C) were determined in the supernatant of adiponectin-stimulated OA cartilage explants. The effects of kinase and NOS inhibitors were evaluated in the adiponectin-stimulated chondrocytes.

Results
The expression levels of both AdipoR1 and AdipoR2 were significantly higher in lesional than in nonlesional areas of OA cartilage. The increased rate of AdipoR1-positive chondrocytes was twice that of AdipoR2-positive chondrocytes when compared between nonlesional and lesional areas. Adiponectin-stimulated OA chondrocytes showed increased total NO and MMP-1, -3, and -13 levels compared with nonstimulated cells. The TIMP-1 level was not affected. The C1-2C levels were increased by adiponectin in OA cartilage explant culture. AMP-activated protein kinase (AMPK) and c-Jun N-terminal kinase (JNK) inhibitors (compound C and SP600125) significantly suppressed adiponectin-induced production of total NO and MMP-1, -3, and -13. Inducible NOS inhibitors enhanced the expression of the adiponectin-induced MMPs.

Conclusions
Adiponectin causes matrix degradation in OA cartilage and increases MMPs and iNOS expression via the AMPK and JNK pathways in human OA chondrocytes. The catabolic effects of adiponectin may be counteracted by NO.
Inhibition of breast cancer cell invasion by melatonin is mediated through regulation of the p38 mitogen-activated protein kinase signaling pathway
Authors: Mao Lulu , Yuan Lin , Slakey Lauren M , Jones Frank E , Burow Matthew E , Hill Steven M 
Published: January 2011

Abstract
Introduction
The pineal gland hormone, melatonin, has been shown by numerous studies to inhibit the proliferation of estrogen receptor α (ERα)-positive breast cancer cell lines. Here, we investigated the role of melatonin in the regulation of breast cancer cell invasion.

Methods
Three invasive MCF-7 breast cancer cell clones - MCF-7/6, MCF-7/Her2.1, and MCF-7/CXCR4 cells - were employed in these studies. All three cell lines exhibited elevated phosphorylation of the ERK1/2 and p38 mitogen-activated protein kinase (MAPK) as determined by Western blot analysis. The effect of melatonin on the invasive potential of these human breast cancer cells was examined by matrigel invasion chamber assays. The expression and proteinase activity of two matrix metalloproteinases (MMPs), MMP-2 and MMP-9, were analyzed by Western blot analysis and gelatin zymography, respectively.

Results
Melatonin (10-9 M) significantly suppressed the invasive potential of MCF-7/6 and MCF-7/Her2.1 cells as measured by matrigel invasion chamber assays, and significantly repressed the proteinase activity of MMP-2 and MMP-9. In MCF-7/CXCR4 cells, melatonin significantly inhibited stromal-derived factor-1 (SDF-1/CXCL12) induced cell invasion and activity of MMP-9. Elevated expression of the MT1 melatonin receptor further enhanced, while luzindole, an MT1/MT2 antagonist, abrogated melatonin's anti-invasive effect, suggesting that melatonin's effect on invasion is mediated, principally, through the MT1 receptor. Furthermore, melatonin repressed the phosphorylation of p38 MAPK in MCF-7/Her2.1 cells and blocked stromal-derived factor-1 (SDF-1) induced p38 phosphorylation in MCF-7/CXCR4 cells. SB230580, a p38 inhibitor, was able to mimic, while transfection of the cells with a constitutively-active MKK6b construct blocked melatonin's effect on cell invasion, suggesting that the anti-invasive action of melatonin is mediated through the p38 pathway.

Conclusions
Melatonin exerts an inhibitory effect on breast cancer cell invasion through down-regulation of the p38 pathway, and inhibition of MMP-2 and MMP-9 expression and activity.
Differences in organ dysfunctions between neonates and older children: a prospective, observational, multicenter study
Authors: Bestati Nawar , Leteurtre Stéphane , Duhamel Alain , Proulx François , Grandbastien Bruno , Lacroix Jacques , Leclerc Francis 
Published: January 2011

Abstract
Introduction
The multiple organ dysfunction syndrome (MODS) is a major cause of death for patients admitted to pediatric intensive care units (PICU). The Pediatric Logistic Organ Dysfunction (PELOD) score has been validated in order to describe and quantify the severity of organ dysfunction (OD). There are several physiological differences between neonates and older children. The objective of the study was to determine whether there are differences in incidence of ODs and mortality rate between full-term neonates (age <28 days) and older children.

Methods
In a prospective, observational study, 1806 patients, admitted to seven PICUs between September 1998 and February 2000 were included. The PELOD score, which includes six organ dysfunctions and 12 variables, was recorded daily. For each variable, the most abnormal value was used to define the daily OD. For each OD, the most abnormal value each day and that during the entire stay were used in calculating the daily PELOD and PELOD scores, respectively. The relationships between OD, daily OD, PELOD, daily PELOD and mortality were compared between the two strata (neonates, older children) based on the discrimination power, logistic and multiple regression analyses.

Results
Of the 1806 enrolled patients 171 (9.5%) were neonates. Incidence of MODS and mortality rate were higher among neonates than in older children (14.6% vs. 5.5%, P < 10-7; 75.4%, vs. 50.9%, P < 10-4; respectively). Daily PELOD scores were significantly higher in neonates from day 1 to day 4. Daily cardiovascular, respiratory and renal dysfunction scores from day 1 to day 4 as well as the PELOD score for the entire pediatric intensive care unit stay were also significantly higher in neonates. Neurological, cardiovascular, and hepatic dysfunctions were independent predictors of death among neonates while all ODs significantly contributed to the risk of mortality in older children.

Conclusions
Our data demonstrate that incidence of MODS and mortality rate are higher among neonates compared to older children. Neurological, cardiovascular, and hepatic dysfunctions were the only significant contributors to neonatal mortality. Stratification for neonates versus older children might be useful in clinical trials where MODS is considered as an outcome measure.
Recombinant human activated protein C attenuates cardiovascular and microcirculatory dysfunction in acute lung injury and septic shock
Authors: Maybauer Marc O , Maybauer Dirk M , Fraser John F , Szabo Csaba , Westphal Martin , Kiss Levente , Horvath Eszter M , Nakano Yoshimitsu , Herndon David N , Traber Lillian D , Traber Daniel L 
Published: January 2011

Abstract
Introduction
This prospective, randomized, controlled, experimental animal study looks at the effects of recombinant human activated protein C (rhAPC) on global hemodynamics and microcirculation in ovine acute lung injury (ALI) and septic shock, resulting from smoke inhalation injury.

Methods
Twenty-one sheep (37 ± 2 kg) were operatively prepared for chronic study and randomly allocated to either the sham, control, or rhAPC group (n = 7 each). The control and rhAPC groups were subjected to insufflation of four sets of 12 breaths of cotton smoke followed by instillation of live Pseudomonas aeruginosa into both lung lobes, according to an established protocol. Healthy sham animals were not subjected to the injury and received only four sets of 12 breaths of room air and instillation of the vehicle (normal saline). rhAPC (24 μg/kg/hour) was intravenously administered from 1 hour post injury until the end of the 24-hour experiment. Regional microvascular blood flow was analyzed using colored microspheres. All sheep were mechanically ventilated with 100% oxygen, and fluid resuscitated with lactated Ringer's solution to maintain hematocrit at baseline levels.

Results
The rhAPC-associated reduction in heart malondialdehyde (MDA) and heart 3-nitrotyrosine (a reliable indicator of tissue injury) levels occurred parallel to a significant increase in mean arterial pressure and to a significant reduction in heart rate and cardiac output compared with untreated controls that showed a typical hypotensive, hyperdynamic response to the injury (P < 0.05). In addition, rhAPC significantly attenuated the changes in microvascular blood flow to the trachea, kidney, and spleen compared with untreated controls (P < 0.05 each). Blood flow to the ileum and pancreas, however, remained similar between groups. The cerebral blood flow as measured in cerebral cortex, cerebellum, thalamus, pons, and hypothalamus, was significantly increased in untreated controls, due to a loss of cerebral autoregulation in septic shock. rhAPC stabilized cerebral blood flow at baseline levels, as in the sham group.

Conclusions
We conclude that rhAPC stabilized cardiovascular functions and attenuated the changes in visceral and cerebral microcirculation in sheep suffering from ALI and septic shock by reduction of cardiac MDA and 3-nitrotyrosine.
Mean glucose during ICU admission is related to mortality by a U-shaped curve in surgical and medical patients: a retrospective cohort study
Authors: Siegelaar Sarah E , Hermanides Jeroen , Oudemans-van Straaten Heleen M , van der Voort Peter HJ , Bosman Robert J , Zandstra Durk F , DeVries J Hans 
Published: January 2011

Abstract
Introduction
Lowering of hyperglycemia in the intensive care unit (ICU) is widely practiced. We investigated in which way glucose regulation, defined as mean glucose concentration during admission, is associated with ICU mortality in a medical and a surgical cohort.

Methods
Retrospective database cohort study including patients admitted between January 2004 and December 2007 in a 20-bed medical/surgical ICU in a teaching hospital. Hyperglycemia was treated using a computerized algorithm targeting for glucose levels of 4.0-7.0 mmol/l. Five thousand eight hundred twenty-eight patients were eligible for analyses, of whom 1,339 patients had a medical and 4,489 had a surgical admission diagnosis.

Results
The cohorts were subdivided in quintiles of increasing mean glucose. We examined the relation between these mean glucose strata and mortality. In both cohorts we observed the highest mortality in the lowest and highest strata. Logistic regression analysis adjusted for age, sex, Acute Physiology and Chronic Health Evaluation II (APACHE II) score, admission duration and occurrence of severe hypoglycemia showed that in the medical cohort mean glucose levels <6.7 mmol/l and >8.4 mmol/l and in the surgical cohort mean glucose levels < 7.0 mmol/l and >9.4 mmol/l were associated with significantly increased ICU mortality (OR 2.4-3.0 and 4.9-6.2, respectively). Limitations of the study were its retrospective design and possible incomplete correction for severity of disease.

Conclusions
Mean overall glucose during ICU admission is related to mortality by a U-shaped curve in medical and surgical patients. In this cohort of patients a 'safe range' of mean glucose regulation might be defined approximately between 7.0 and 9.0 mmol/l.
Common NFKBIL2 polymorphisms and susceptibility to pneumococcal disease: a genetic association study
Authors: Chapman Stephen J , Khor Chiea C , Vannberg Fredrik O , Rautanen Anna , Walley Andrew , Segal Shelley , Moore Catrin E , Davies Robert JO , Day Nicholas P , Peshu Norbert , Crook Derrick W , Berkley James A , Williams Thomas N , Scott J Anthony , Hill Adrian VS 
Published: January 2011

Abstract
Introduction
Streptococcus pneumoniae remains a major global health problem and a leading cause of death in children worldwide. The factors that influence development of pneumococcal sepsis remain poorly understood, although increasing evidence points towards a role for genetic variation in the host's immune response. Recent insights from the study of animal models, rare human primary immunodeficiency states, and population-based genetic epidemiology have focused attention on the role of the proinflammatory transcription factor NF-κB in pneumococcal disease pathogenesis. The possible role of genetic variation in the atypical NF-κB inhibitor IκB-R, encoded by NFKBIL2, in susceptibility to invasive pneumococcal disease has not, to our knowledge, previously been reported upon.

Methods
An association study was performed examining the frequencies of nine common NFKBIL2 polymorphisms in two invasive pneumococcal disease case-control groups: European individuals from hospitals in Oxfordshire, UK (275 patients and 733 controls), and African individuals from Kilifi District Hospital, Kenya (687 patients with bacteraemia, of which 173 patients had pneumococcal disease, together with 550 controls).

Results
Five polymorphisms significantly associated with invasive pneumococcal disease susceptibility in the European study, of which two polymorphisms also associated with disease in African individuals. Heterozygosity at these loci was associated with protection from invasive pneumococcal disease (rs760477, Mantel-Haenszel 2 × 2 χ2 = 11.797, P = 0.0006, odds ratio = 0.67, 95% confidence interval = 0.53 to 0.84; rs4925858, Mantel-Haenszel 2 × 2 χ2 = 9.104, P = 0.003, odds ratio = 0.70, 95% confidence interval = 0.55 to 0.88). Linkage disequilibrium was more extensive in European individuals than in Kenyans.

Conclusions
Common NFKBIL2 polymorphisms are associated with susceptibility to invasive pneumococcal disease in European and African populations. These findings further highlight the importance of control of NF-κB in host defence against pneumococcal disease.
End-of-life decisions in Greek intensive care units: a multicenter cohort study
Authors: Kranidiotis Georgios , Gerovasili Vasiliki , Tasoulis Athanasios , Tripodaki Elli , Vasileiadis Ioannis , Magira Eleni , Markaki Vasiliki , Routsi Christina , Prekates Athanasios , Kyprianou Theodoros , Clouva-Molyvdas Phyllis-Maria , Georgiadis Georgios , Floros Ioannis , Karabinis Andreas , Nanas Serafim 
Published: January 2011

Abstract
Introduction
Intensive care may prolong the dying process in patients who have been unresponsive to the treatment already provided. Limitation of life-sustaining therapy, by either withholding or withdrawing support, is an ethically acceptable and common worldwide practice. The purpose of the present study was to examine the frequency, types, and rationale of limiting life support in Greek intensive care units (ICUs), the clinical and demographic parameters associated with it, and the participation of relatives in decision making.

Methods
This was a prospective observational study conducted in eight Greek multidisciplinary ICUs. We studied all consecutive ICU patients who died, excluding those who stayed in the ICU less than 48 hours or were brain dead.

Results
Three hundred six patients composed the study population, with a mean age of 64 years and a mean APACHE II score on admission of 21. Of study patients, 41% received full support, including unsuccessful cardiopulmonary resuscitation (CPR); 48% died after withholding of CPR; 8%, after withholding of other treatment modalities besides CPR; and 3%, after withdrawal of treatment. Patients in whom therapy was limited had a longer ICU (P < 0.01) and hospital (P = 0.01) length of stay, a lower Glasgow Coma Scale score (GCS) on admission (P < 0.01), a higher APACHE II score 24 hours before death (P < 0.01), and were more likely to be admitted with a neurologic diagnosis (P < 0.01). Patients who received full support were more likely to be admitted with either a cardiovascular (P = 0.02) or trauma diagnosis (P = 0.05) and to be surgical rather than medical (P = 0.05). The main factors that influenced the physician's decision were, when providing full support, reversibility of illness and prognostic uncertainty, whereas, when limiting therapy, unresponsiveness to treatment already offered, prognosis of underlying chronic disease, and prognosis of acute disorder. Relatives' participation in decision making occurred in 20% of cases and was more frequent when a decision to provide full support was made (P < 0.01). Advance directives were rare (1%).

Conclusions
Limitation of life-sustaining treatment is a common phenomenon in the Greek ICUs studied. However, in a large majority of cases, it is equivalent to the withholding of CPR alone. Withholding of other therapies besides CPR and withdrawal of support are infrequent. Medical paternalism predominates in decision making.
Levosimendan for resuscitating the microcirculation in patients with septic shock: a randomized controlled study
Authors: Morelli Andrea , Donati Abele , Ertmer Christian , Rehberg Sebastian , Lange Matthias , Orecchioni Alessandra , Cecchini Valeria , Landoni Giovanni , Pelaia Paolo , Pietropaoli Paolo , Van Aken Hugo , Teboul Jean-Louis , Ince Can , Westphal Martin 
Published: January 2011

Abstract
Introduction
The purpose of the present study was to investigate microcirculatory blood flow in patients with septic shock treated with levosimendan as compared to an active comparator drug (i.e. dobutamine). The primary end point was a difference of ≥ 20% in the microvascular flow index of small vessels (MFIs) among groups.

Methods
The study was designed as a prospective, randomized, double-blind clinical trial and performed in a multidisciplinary intensive care unit. After achieving normovolemia and a mean arterial pressure of at least 65 mmHg, 40 septic shock patients were randomized to receive either levosimendan 0.2 μg·kg-1·min-1 (n = 20) or an active comparator (dobutamine 5 μg·kg-1·min-1; control; n = 20) for 24 hours. Sublingual microcirculatory blood flow of small and medium vessels was assessed by sidestream dark-field imaging. Microcirculatory variables and data from right heart catheterization were obtained at baseline and 24 hours after randomization. Baseline and demographic data were compared by means of Mann-Whitney rank sum test or chi-square test, as appropriate. Microvascular and hemodynamic variables were analyzed using the Mann-Whitney rank sum test.

Results
Microcirculatory flow indices of small and medium vessels increased over time and were significantly higher in the levosimendan group as compared to the control group (24 hrs: MFIm 3.0 (3.0; 3.0) vs. 2.9 (2.8; 3.0); P = .02; MFIs 2.9 (2.9; 3.0) vs. 2.7 (2.3; 2.8); P < .001). The relative increase of perfused vessel density vs. baseline was significantly higher in the levosimendan group than in the control group (dMFIm 10 (3; 23)% vs. 0 (-1; 9)%; P = .007; dMFIs 47 (26; 83)% vs. 10 (-3; 27); P < .001). In addition, the heterogeneity index decreased only in the levosimendan group (dHI -93 (-100; -84)% vs. 0 (-78; 57)%; P < .001). There was no statistically significant correlation between systemic and microcirculatory flow variables within each group (each P > .05).

Conclusions
Compared to a standard dose of 5 μg·kg-1·min-1 of dobutamine, levosimendan at 0.2 μg·kg-1·min-1 improved sublingual microcirculatory blood flow in patients with septic shock, as reflected by changes in microcirculatory flow indices of small and medium vessels.

Trial registration
NCT00800306.
Hydrogen inhalation ameliorates ventilator-induced lung injury
Authors: Huang Chien-Sheng , Kawamura Tomohiro , Lee Sungsoo , Tochigi Naobumi , Shigemura Norihisa , Buchholz Bettina M , Kloke John D , Billiar Timothy R , Toyoda Yoshiya , Nakao Atsunori 
Published: January 2011

Abstract
Introduction
Mechanical ventilation (MV) can provoke oxidative stress and an inflammatory response, and subsequently cause ventilator-induced lung injury (VILI), a major cause of mortality and morbidity of patients in the intensive care unit. Inhaled hydrogen can act as an antioxidant and may be useful as a novel therapeutic gas. We hypothesized that, owing to its antioxidant and anti-inflammatory properties, inhaled hydrogen therapy could ameliorate VILI.

Methods
VILI was generated in male C57BL6 mice by performing a tracheostomy and placing the mice on a mechanical ventilator (tidal volume of 30 ml/kg without positive end-expiratory pressure, FiO2 0.21). The mice were randomly assigned to treatment groups and subjected to VILI with delivery of either 2% nitrogen or 2% hydrogen in air. Sham animals were given same gas treatments for two hours (n = 8 for each group). The effects of VILI induced by less invasive and longer exposure to MV (tidal volume of 10 ml/kg, 5 hours, FiO2 0.21) were also investigated (n = 6 for each group). Lung injury score, wet/dry ratio, arterial oxygen tension, oxidative injury, and expression of pro-inflammatory mediators and apoptotic genes were assessed at the endpoint of two hours using the high-tidal volume protocol. Gas exchange and apoptosis were assessed at the endpoint of five hours using the low-tidal volume protocol.

Results
Ventilation (30 ml/kg) with 2% nitrogen in air for 2 hours resulted in deterioration of lung function, increased lung edema, and infiltration of inflammatory cells. In contrast, ventilation with 2% hydrogen in air significantly ameliorated these acute lung injuries. Hydrogen treatment significantly inhibited upregulation of the mRNAs for pro-inflammatory mediators and induced antiapoptotic genes. In the lungs treated with hydrogen, there was less malondialdehyde compared with lungs treated with nitrogen. Similarly, longer exposure to mechanical ventilation within lower tidal volume (10 mg/kg, five hours) caused lung injury including bronchial epithelial apoptosis. Hydrogen improved gas exchange and reduced VILI-induced apoptosis.

Conclusions
Inhaled hydrogen gas effectively reduced VILI-associated inflammatory responses, at both a local and systemic level, via its antioxidant, anti-inflammatory and antiapoptotic effects.