bluuebunny/crossref_metadata_2025 huggingface dataset:
Cortical spreading depression as a target for anti-migraine agents
Authors: Costa Cinzia , Tozzi Alessandro , Rainero Innocenzo , Cupini Letizia Maria , Calabresi Paolo , Ayata Cenk , Sarchielli Paola
Published: July 2013

Spreading depression (SD) is a slowly propagating wave of neuronal and glial depolarization lasting a few minutes, that can develop within the cerebral cortex or other brain areas after electrical, mechanical or chemical depolarizing stimulations. Cortical SD (CSD) is considered the neurophysiological correlate of migraine aura. It is characterized by massive increases in both extracellular K+and glutamate, as well as rises in intracellular Na+and Ca2+. These ionic shifts produce slow direct current (DC) potential shifts that can be recorded extracellularly. Moreover, CSD is associated with changes in cortical parenchymal blood flow.

CSD has been shown to be a common therapeutic target for currently prescribed migraine prophylactic drugs. Yet, no effects have been observed for the antiepileptic drugs carbamazepine and oxcarbazepine, consistent with their lack of efficacy on migraine. Some molecules of interest for migraine have been tested for their effect on CSD. Specifically, blocking CSD may play an enabling role for novel benzopyran derivative tonabersat in preventing migraine with aura. Additionally, calcitonin gene-related peptide (CGRP) antagonists have been recently reported to inhibit CSD, suggesting the contribution of CGRP receptor activation to the initiation and maintenance of CSD not only at the classic vascular sites, but also at a central neuronal level. Understanding what may be lying behind this contribution, would add further insights into the mechanisms of actions for “gepants”, which may be pivotal for the effectiveness of these drugs as anti-migraine agents.

CSD models are useful tools for testing current and novel prophylactic drugs, providing knowledge on mechanisms of action relevant for migraine.
White matter disintegration in cluster headache
Authors: Szabó Nikoletta , Kincses Zsigmond Tamás , Párdutz Árpád , Tóth Eszter , Szok Délia , Csete Gergő , Vécsei László
Published: July 2013

Background

Previous studies in primary headache disorders showed microstructural alterations in the white matter as measured by diffusion imaging. However these investigations are not in full agreement and some of those, especially in cluster headache, restricted the analysis to only a limited number of diffusion parameters. Therefore, in the current study we examined white matter microstructure in cluster headache patients.

Methods

Diffusion weighted MRI images with 60 directions were acquired from thirteen patients with cluster headache and sixteen age-matched healthy controls. Tract based spatial statistics were used to compare white matter integrity in the core of the fibre bundles. Correlation of the diffusion parameters with cumulative number of headache days was examined.

Results

There was a significant increment of the mean, axial and perpendicular diffusivity in widespread white matter regions in the frontal, parietal, temporal and occipital lobes. Reduced fractional anisotropy was found in the corpus callosum and some frontal and parietal white matter tracts mainly in the contralateral side of the pain. Axial diffusivity showed negative correlation to the number of the headache attacks.

Conclusions

The in vivo analysis of microstructural alterations in cluster headache provides important features of the disease, which might offer a deeper insight into the pathomechanism of the disease.
Evidence of antimicrobial resistance-conferring genetic elements among pneumococci isolated prior to 1974
Authors: Wyres Kelly L , van Tonder Andries , Lambertsen Lotte M , Hakenbeck Regine , Parkhill Julian , Bentley Stephen D , Brueggemann Angela B
Published: July 2013

Background

Antimicrobial resistance among pneumococci has greatly increased over the past two to three decades. Resistance to tetracycline (tet(M)), chloramphenicol (cat) and macrolides (erm(B) and/or mef(A/E)) is generally conferred by acquisition of specific genes that are associated with mobile genetic elements, including those of the Tn916 and Tn5252 families. The first tetracycline-, chloramphenicol- and macrolide-resistant pneumococci were detected between 1962 and 1970; however, until now the oldest pneumococcus shown to harbour Tn916 and/or Tn5252 was isolated in 1974. In this study the genomes of 38 pneumococci isolated prior to 1974 were probed for the presence of tet(M), cat, erm(B), mef(A/E) and int (integrase) to indicate the presence of Tn916/ Tn5252-like elements.

Results

Two Tn916-like, tet(M)-containing, elements were identified among pneumococci dated 1967 and 1968. The former element was highly similar to that of the PMEN1 multidrug-resistant, globally-distributed pneumococcal reference strain, which was isolated in 1984. The latter element was associated with a streptococcal phage. A third, novel genetic element, designated ICESp PN1, was identified in the genome of an isolate dated 1972. ICESp PN1 contained a region of similarity to Tn5252, a region of similarity to a pneumococcal pathogenicity island and novel lantibiotic synthesis/export-associated genes.

Conclusions

These data confirm the existence of pneumococcal Tn916 elements in the first decade within which pneumococcal tetracycline resistance was described. Furthermore, the discovery of ICESp PN1 demonstrates the dynamic variability of pneumococcal genetic elements and is contrasted with the evidence for Tn916 stability.
Socio-demographic and behavioural correlates of physical activity perception in individuals with recently diagnosed diabetes: results from a cross-sectional study
Authors: Long Gráinne H , Brage Søren , Wareham Nicholas J , van Sluijs Esther MF , Sutton Stephen , Griffin Simon J , Simmons Rebecca K
Published: July 2013

Background

Physical activity (PA) levels in type 2 diabetes mellitus (T2DM) patients are generally low. Poor PA perception may impede healthy behaviour change in this high risk group. We describe (i) objective PA levels, (ii) the difference between objective and self-reported PA (‘PA disparity’) and the correlates of (iii) PA disparity and (iv) overestimation in recently diagnosed T2DM patients.

Methods

Cross-sectional analysis of 425 recently diagnosed T2DM patients aged 42 to 71, participating in the ADDITION-Plus study in Eastern England, UK. We define ‘PA disparity’ as the non-negative value of the difference (in mathematical terms the absolute difference) between objective and self-reported physical activity energy expenditure (PAEE in kJ · kg-1 · day-1). ‘Overestimators’ comprised those whose self-reported- exceeded objective-PAEE by 4.91 kJ · kg-1 · day-1(the equivalent of 30 minutes moderate activity per day). Multivariable linear regression examined the association between PA disparity (continuous) and socio-demographic, clinical, health behaviour, quality of life and psychological characteristics. Logistic regression examined the association between PA overestimation and individual characteristics.

Results

Mean objective and self-reported PAEE levels ± SD were 34.4 ± 17.0 and 22.6 ± 19.4 kJ · kg-1 · day-1, respectively (difference in means =11.8; 95% CI = 9.7 to 13.9 kJ · kg-1 · day-1). Higher PA disparity was associated with male sex, younger age, lower socio-economic status and lower BMI. PA overestimators comprised 19% (n = 80), with those in routine/manual occupations more likely to be overestimators than those in managerial/professional occupations.

Conclusions

T2DM patients with poor physical activity perception are more likely to be male, younger, from a lower socio-economic class and to have a lower BMI. PA overestimators were more likely to be in lower socio-economic categories. Self-monitoring and targeted feedback, particularly to those in lower socio-economic categories, may improve PA perceptions and optimise interventions in T2DM patients. Our findings suggest that strategies for enabling realistic assessment of physical activity levels, through self-monitoring or feedback, warrant further investigation and may help refine and improve physical activity interventions.
Multidrug-resistant bacterial isolates in infected wounds at Jimma University Specialized Hospital, Ethiopia
Authors: Godebo Girma , Kibru Gebre , Tassew Himanot
Published: July 2013

Background

The term ’Multidrug-resistant’ (MDR) applies to a bacterium that is simultaneously resistant to a number of antimicrobials belonging to different chemical classes. The effectiveness of currently available antmicrobial drugs is decreasing due to the increasing number of resistant strains causing infections so that available therapeutic options for such organisms are severely limited.

Objective

The aim of this study was to determine multidrug-resistance rate of bacterial isolates that caused wound infections.

Methods

A Hospital based cross-sectional study was conducted on 322 wound samples taken from consecutive patients seen at inpatient and outpatient department of Jimma University Specialized Hospital from June to December 2011. Swabs from surgical incisions, burns, abscess and traumatic wounds were collected aseptically using Levine’s technique. Bacteriological culture and examination was done following standard microbiological techniques. Multidrug-resistance test was performed by disk diffusion method against 10 classes of antimicrobials. The data was analyzed for descriptive statistics using SPSS version 16 and Microsoft Excel.

Results

The overall MDR among gram positive and gram negative bacterial isolates were (77%) and (59.3%) respectively. About, 86.2% S.aureus and 28.6% of Coagulase negative Staphylococci became MDR. Nearly 30.1% of S.aureus was resistant to six classes of antimicrobials. The average MDR rate of Proteus, Klebsiella, and Providencia species was 74.8%, 69.6% and 75% in that order. Nearly, 30.8% of Proteus sp, 32.6% of Klebsiella sp and 61% of Citrobacter sp were resistance to 4 classes each. Surprisingly, the average MDR rate for Citrobacter sp was 100%. About (76.7%) of S.aureus was Oxacillin/Methicillin resistant while (16.4%) were Vancomycin resistant. Proteus species was the predominant isolates (27.9%) followed by P.aeruginosa and S.aureus (19.3%) and (19%) respectively.

Conclusion

This study indicated that, the overall rate of MDR bacterial pathogens that caused wound infection was very high and many of the isolates were also identified as resistant to three or more classes of antimicrobials. Such widespread resistance to antimicrobial classes is something serious because a few treatment options remain for patients with wound infections. Periodic monitoring of etiology and antimicrobial susceptibility in areas where there is no culture facility is essential to assists physician in selection of chemotherapy.
Association of ADRB2 polymorphism with triglyceride levels in Tongans
Authors: Naka Izumi , Ohashi Jun , Kimura Ryosuke , Inaoka Tsukasa , Matsumura Yasuhiro
Published: July 2013

Background

Our previous study demonstrated that the A-allele of the single nucleotide polymorphism (SNP) rs34623097 located in the upstream region of the β2 adrenergic receptor gene (ADRB2) is significantly associated with risk for obesity in Oceanic populations.

Methods

To investigate whether the ADRB2 polymorphisms explain part of the individual differences in lipid mobilization, energy expenditure and glycogen breakdown, the associations of 10 ADRB2 SNPs with total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol and triglyceride levels were examined in 128 adults in Tonga.

Results

A multiple linear regression analysis adjusted for age, sex, and body mass index revealed that rs34623097 was significantly associated with triglyceride levels (P-value = 0.037). A copy of the rs34623097-A allele increased serum triglyceride levels by 70.1 mg/dL (0.791 mmol/L). None of the ADRB2 SNPs showed a significant association with total-cholesterol, high-density lipoprotein cholesterol, or low-density lipoprotein cholesterol.

Conclusions

In a Tongan population, a SNP located in the upstream region of ADRB2 is associated with triglyceride levels independent of body mass index.
InAs-mediated growth of vertical InSb nanowires on Si substrates
Authors: Li Tianfeng , Gao Lizhen , Lei Wen , Guo Lijun , Pan Huayong , Yang Tao , Chen Yonghai , Wang Zhanguo
Published: July 2013

In this work, InSb nanowires are grown vertically on Si (111) with metal organic chemical vapor deposition using InAs as seed layer, instead of external metal catalyst. Two groups of InSb nanowires are fabricated and characterized: one group presents Indium droplets at the nanowire's free end, while the other, in contrast, ends without Indium droplet but with pyramid-shaped InSb. The indium-droplet-ended nanowires are longer than the other group of nanowires. For both groups of InSb nanowires, InAs layers play an important role in their formation by serving as a template for growing InSb nanowires. The results presented in this work suggest a useful approach to grow catalyst-free InSb nanowires on Si substrates, which is significant for their device applications.
A new co-ultramicronized composite including palmitoylethanolamide and luteolin to prevent neuroinflammation in spinal cord injury
Authors: Paterniti Irene , Impellizzeri Daniela , Di Paola Rosanna , Navarra Michele , Cuzzocrea Salvatore , Esposito Emanuela
Published: July 2013

Background

It has recently been demonstrated that palmitoylethanolamide (PEA), an endogenous lipid amide belonging to the N-acylethanolamine family, exerts neuroprotection in central nervous system (CNS) pathologies. In recent studies, we have demonstrated that treatment with PEA significantly reduced inflammatory secondary events associated with spinal cord injury (SCI). Since oxidative stress is considered to play an important role in neuroinflammatory disorders, in the present work we studied a new composite, a formulation including PEA and the antioxidant compound luteolin (Lut), subjected to an ultramicronization process, co-ultraPEALut. We investigated the effect of co-ultraPEALut (in the respective fixed doses of 10:1 in mass) in both an ex vivo organotypic spinal cord culture model and an in vivo model of SCI.

Methods

For the organotypic cultures, spinal cords were prepared from mice at postnatal day 6 and were cut into transverse slices of 400 μm thickness to generate the lumbar organotypic slice cultures. After 7 days of culturing, the slices were mechanically injured onto the center of the slice and the co-ultraPEALut was applied at different concentrations (0.00009, 0.0009 and 0.009 g/l) 1 hour before damage. For in vivo studies, SCI was induced in mice through spinal cord compression by the application of vascular clips (force of 24 g) to the dura via a four-level T5 to T8 laminectomy, and co-ultraPEALut (1 mg/kg ip) was administered at 1 and 6 hours after SCI. At 24 hours after SCI, mice were sacrificed and the spinal cords were collected for further evaluation. Additional animals were treated similarly and sacrificed 10 days after SCI.

Results

Pretreatment with co-ultraPEALut significantly reduced cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression in a concentration-dependent manner, restored neuronal nitric oxide synthase (nNOS) expression at all three tested concentrations, and protected cells by cell death (MTT assay) in spinal cord organotypic cultures. Moreover, we demonstrated in vivo that co-ultraPEALut 1 mg/kg reduced the severity of trauma induced by compression and improved the motor activity evaluated at 10 days post-injury.

Conclusion

The present study demonstrates that the protective effect of PEA on SCI-associated neuroinflammation could be improved by co-ultramicronization with Lut possibly due to its antioxidant properties.
Glycemic variability in relation to oral disposition index in the subjects with different stages of glucose tolerance
Authors: Chen Tong , Xu Feng , Su Jian-bin , Wang Xue-qin , Chen Jin-feng , Wu Gang , Jin Yan , Wang Xiao-hua
Published: July 2013

Background

Glucose variability could be an independent risk factor for diabetes complications in addition to average glucose. The deficiency in islet β cell secretion and insulin sensitivity, the two important pathophysiological mechanisms of diabetes, are responsible for glycemic disorders. The oral disposition index evaluated by product of insulin secretion and sensitivity is a useful marker of islet β cell function. The aim of the study is to investigate glycemic variability in relation to oral disposition index in the subjects across a range of glucose tolerance from the normal to overt type 2 diabetes.

Methods

75-g oral glucose tolerance test (OGTT) was performed in total 220 subjects: 47 with normal glucose regulation (NGR), 52 with impaired glucose metabolism (IGM, 8 with isolated impaired fasting glucose [IFG], 18 with isolated impaired glucose tolerance [IGT] and 26 with combined IFG and IGT), 61 screen-diagnosed diabetes by isolated 2-h glucose (DM2h) and 60 newly diagnosed diabetes by both fasting and 2-h glucose (DM). Insulin sensitivity index (Matsuda index, ISI), insulin secretion index (ΔI30/ΔG30), and integrated β cell function measured by the oral disposition index (ΔI30/ΔG30 multiplied by the ISI) were derived from OGTT. All subjects were monitored using the continuous glucose monitoring system for consecutive 72 hours. The multiple parameters of glycemic variability included the standard deviation of blood glucose (SD), mean of blood glucose (MBG), high blood glucose index (HBGI), continuous overlapping net glycemic action calculated every 1 h (CONGA1), mean of daily differences (MODD) and mean amplitude of glycemic excursions (MAGE).

Results

From the NGR to IGM to DM2h to DM group, the respective values of SD (mean ± SD) (0.9 ± 0.3, 1.5 ± 0.5, 1.9 ± 0.6 and 2.2 ± 0.6 mmol/), MBG (5.9 ± 0.5, 6.7 ± 0.7, 7.7 ± 1.0 and 8.7 ± 1.5 mmol/L), HGBI [median(Q1–Q3)][0.8(0.2–1.2), 2.0(1.2–3.7), 3.8(2.4–5.6) and 6.4(3.2–9.5)], CONGA1 (1.0 ± 0.2, 1.3 ± 0.2, 1.5 ± 0.3 and 1.8 ± 0.4 mmol/L), MODD (0.9 ± 0.3, 1.4 ± 0.4, 1.8 ± 0.7 and 2.1 ± 0.7 mmol/L) and MAGE (2.1 ± 0.6, 3.3 ± 1.0, 4.3 ± 1.4 and 4.8 ± 1.6 mmol/L) were all increased progressively (all p < 0.05), while their oral disposition indices [745(546–947), 362(271–475), 203(134–274) and 91(70–139)] were decreased progressively (p < 0.05). In addition, SD, MBG, HGBI, CONGA1, MODD and MAGE were all negatively associated with the oral disposition index in each group (all p < 0.05) and in the entire data set (r = −0.66, –0.66, –0.72, –0.59, –0.61 and −0.65, respectively, p < 0.05).

Conclusions

Increased glycemic variability parameters are consistently associated with decreased oral disposition index in subjects across the range of glucose tolerance from the NGR to IGM to DM2h to DM group.
Polycomblike protein PHF1b: a transcriptional sensor for GABA receptor activity
Authors: Saha Shamol , Hu Yinghui , Martin Stella C , Bandyopadhyay Sabita , Russek Shelley J , Farb David H
Published: July 2013

Background

The γ-aminobutyric acid (GABA) type A receptor (GABAAR) contains the recognition sites for a variety of agents used in the treatment of brain disorders, including anxiety and epilepsy. A better understanding of how receptor expression is regulated in individual neurons may provide novel opportunities for therapeutic intervention. Towards this goal we have studied transcription of a GABAAR subunit gene (GABRB1) whose activity is autologously regulated by GABA via a 10 base pair initiator-like element (β1-INR).

Methods

By screening a human cDNA brain library with a yeast one-hybrid assay, the Polycomblike (PCL) gene product PHD finger protein transcript b (PHF1b) was identified as a β1-INR associated protein. Promoter/reporter assays in primary rat cortical cells demonstrate that PHF1b is an activator at GABRB1, and chromatin immunoprecipitation assays reveal that presence of PHF1 at endogenous Gabrb1 is regulated by GABAAR activation.

Results

PCL is a member of the Polycomb group required for correct spatial expression of homeotic genes in Drosophila. We now show that PHF1b recognition of β1-INR is dependent on a plant homeodomain, an adjacent helix-loop-helix, and short glycine rich motif. In neurons, it co-immunoprecipitates with SUZ12, a key component of the Polycomb Repressive Complex 2 (PRC2) that regulates a number of important cellular processes, including gene silencing via histone H3 lysine 27 trimethylation (H3K27me3).

Conclusions

The observation that chronic exposure to GABA reduces PHF1 binding and H3K27 monomethylation, which is associated with transcriptional activation, strongly suggests that PHF1b may be a molecular transducer of GABAAR function and thus GABA-mediated neurotransmission in the central nervous system.
Linked decreases in liver kinase B1 and AMP-activated protein kinase activity modulate matrix catabolic responses to biomechanical injury in chondrocytes
Authors: Petursson Freyr , Husa Matt , June Ron , Lotz Martin , Terkeltaub Robert , Liu-Bryan Ru
Published: July 2013

Introduction

AMP-activated protein kinase (AMPK) maintains cultured chondrocyte matrix homeostasis in response to inflammatory cytokines. AMPK activity is decreased in human knee osteoarthritis (OA) chondrocytes. Liver kinase B1 (LKB1) is one of the upstream activators of AMPK. Hence, we examined the relationship between LKB1 and AMPK activity in OA and aging cartilages, and in chondrocytes subjected to inflammatory cytokine treatment and biomechanical compression injury, and performed translational studies of AMPK pharmacologic activation.

Methods

We assessed activity (phosphorylation) of LKB1 and AMPKα in mouse knee OA cartilage, in aging mouse cartilage (6 to 24 months), and in chondrocytes after mechanical injury by dynamic compression, via immunohistochemistry or western blot. We knocked down LKB1 by siRNA transfection. Nitric oxide, matrix metalloproteinase (MMP)-3, and MMP-13 release were measured by Griess reaction and ELISA, respectively.

Results

Knockdown of LKB1 attenuated chondrocyte AMPK activity, and increased nitric oxide, MMP-3 and MMP-13 release (P <0.05) in response to IL-1β and TNFα. Both LKB1 and AMPK activity were decreased in mouse knee OA and aged knee cartilage, and in bovine chondrocytes after biomechanical injury. Pretreatment of bovine chondrocytes with AMPK activators AICAR and A-769662 inhibited both AMPKα dephosphorylation and catabolic responses after biomechanical injury.

Conclusion

LKB1 is required for chondrocyte AMPK activity, thereby inhibiting matrix catabolic responses to inflammatory cytokines. Concurrent loss of LKB1 and AMPK activity in articular chondrocytes is associated with OA, aging and biomechanical injury. Conversely, pharmacologic AMPK activation attenuates catabolic responses to biomechanical injury, suggesting a potentially novel approach to inhibit OA development and progression.
Development of a screen to identify selective small molecules active against patient-derived metastatic and chemoresistant breast cancer cells
Authors: Gligorich Keith M , Vaden Rachel M , Shelton Dawne N , Wang Guoying , Matsen Cindy B , Looper Ryan E , Sigman Matthew S , Welm Bryan E
Published: July 2013

Introduction

High failure rates of new investigational drugs have impaired the development of breast cancer therapies. One challenge is that excellent activity in preclinical models, such as established cancer cell lines, does not always translate into improved clinical outcomes for patients. New preclinical models, which better replicate clinically-relevant attributes of cancer, such as chemoresistance, metastasis and cellular heterogeneity, may identify novel anti-cancer mechanisms and increase the success of drug development.

Methods

Metastatic breast cancer cells were obtained from pleural effusions of consented patients whose disease had progressed. Normal primary human breast cells were collected from a reduction mammoplasty and immortalized with human telomerase. The patient-derived cells were characterized to determine their cellular heterogeneity and proliferation rate by flow cytometry, while dose response curves were performed for chemotherapies to assess resistance. A screen was developed to measure the differential activity of small molecules on the growth and survival of patient-derived normal breast and metastatic, chemoresistant tumor cells to identify selective anti-cancer compounds. Several hits were identified and validated in dose response assays. One compound, C-6, was further characterized for its effect on cell cycle and cell death in cancer cells.

Results

Patient-derived cells were found to be more heterogeneous, with reduced proliferation rates and enhanced resistance to chemotherapy compared to established cell lines. A screen was subsequently developed that utilized both tumor and normal patient-derived cells. Several compounds were identified, which selectively targeted tumor cells, but not normal cells. Compound C-6 was found to inhibit proliferation and induce cell death in tumor cells via a caspase-independent mechanism.

Conclusions

Short-term culture of patient-derived cells retained more clinically relevant features of breast cancer compared to established cell lines. The low proliferation rate and chemoresistance make patient-derived cells an excellent tool in preclinical drug development.
Anemia is an independent prognostic factor in intracerebral hemorrhage: an observational cohort study
Authors: Kuramatsu Joji B , Gerner Stefan T , Lücking Hannes , Kloska Stephan P , Schellinger Peter D , Köhrmann Martin , Huttner Hagen B
Published: July 2013

Introduction

To date only two studies have evaluated anemia status in acute intracerebral hemorrhage (ICH) reporting that on admission anemia (OAA) was associated with larger hematoma volume, and lower hemoglobin levels during hospital stay, which related to poorer outcome. The question remains whether anemia influences outcome through related volume-effects or itself has an independent impact?

Methods

This single-center investigation included 435 consecutive patients with spontaneous ICH admitted to the Department of Neurology over five years. Functional short- and long-term outcome (3 months and 1 year) were analyzed for anemia status. Multivariate logistic and graphical regression analyses were calculated for associations of anemia and to determine independent effects on functional outcome. It was decided to perform a separate analysis for patients with ICH-volume <30cm3 (minor-volume-ICH).

Results

Overall short-term-outcome was worse in anemic patients (mRS[4-6] OAA = 93.3% vs. non-OAA = 61.2%, P < 0.01), and there was a further shift towards an increased long-term mortality (P = 0.02). The probability of unfavorable long-term-outcome (mRS[4-6]) in OAA was elevated 7-fold (OR:7.5; P < 0.01). Receiver operating characteristics curve (ROC) analysis revealed a positive but poor association of ICH-volume and anemia (AUC = 0.67) suggesting volume-undriven outcome-effects of anemia (AUC = 0.75). Multivariate regression analyses revealed that anemia, besides established parameters, has the strongest relation to unfavorable outcome (OR:3.0; P < 0.01). This is even more pronounced in minor-volume-ICH (OR:5.6; P < 0.01).

Conclusions

Anemia seems to be a previously unrecognized significant predictor of unfavorable functional outcome with independent effects beyond its association with larger hemorrhage volumes. The recognition of anemia and its treatment may possibly influence outcome after ICH and as such prospective interventional studies are warranted.
Plasma gelsolin levels and outcomes after aneurysmal subarachnoid hemorrhage
Authors: Pan Jian-Wei , He Ling-Na , Xiao Feng , Shen Jian , Zhan Ren-Ya
Published: July 2013

Introduction

Lower gelsolin levels have been associated with the severity and poor outcome of critical illness. Nevertheless, their link with clinical outcomes of aneurysmal subarachnoid hemorrhage is unknown. Therefore, we aimed to investigate the relationship between plasma gelsolin levels and clinical outcomes in patients with aneurysmal subarachnoid hemorrhage.

Methods

A total of 262 consecutive patients and 150 healthy subjects were included. Plasma gelsolin levels were measured by enzyme-linked immunosorbent assay. Mortality and poor long-term outcome (Glasgow Outcome Scale score of 1-3) at 6 months were recorded.

Results

Plasma gelsolin levels on admission were substantially lower in patients than in healthy controls (66.9 (26.4) mg/L vs. 126.4 (35.4) mg/L, P < 0.001), and negatively associated with World Federation of Neurological Surgeons score (r = -0.554, P < 0.001) and Fisher score (r = -0.538, P < 0.001), and identified as an independent predictor of poor functional outcome (odds ratio, 0.957; 95% confidence interval (CI), 0.933-0.983; P = 0.001) and death (odds ratio, 0.953; 95% CI, 0.917-0.990; P = 0.003) after 6 months. The areas under the ROC curve of gelsolin for functional outcome and mortality were similar to those of World Federation of Neurological Surgeons score and Fisher score (all P > 0.05). Gelsolin improved the predictive values of World Federation of Neurological Surgeons score and Fisher score for functional outcome (both P < 0.05), but not for mortality (both P > 0.05).

Conclusions

Gelsolin levels are a useful, complementary tool to predict functional outcome and mortality 6 months after aneurysmal subarachnoid hemorrhage.
Etiologies, diagnostic strategies, and outcomes of diffuse pulmonary infiltrates causing acute respiratory failure in cancer patients: a retrospective observational study
Authors: Yoo Hongseok , Suh Gee Young , Jeong Byeong-Ho , Lim So Yeon , Chung Man Pyo , Jung Kwon O , Jeon Kyeongman
Published: July 2013

Introduction

Although previous studies have reported etiologies, diagnostic strategies, and outcomes of acute respiratory failure (ARF) in cancer patients, few studies investigated ARF in cancer patients presenting with diffuse pulmonary infiltrates.

Methods

This was a retrospective observational study of 214 consecutive cancer patients with diffuse pulmonary infiltrates on chest radiography admitted to the oncology medical intensive care unit for acute respiratory failure between July 2009 and June 2011.

Results

After diagnostic investigations including bronchoalveolar lavage in 160 (75%) patients, transbronchial lung biopsy in 75 (35%), and surgical lung biopsy in 6 (3%), the etiologies of diffuse pulmonary infiltrates causing ARF were identified in 187 (87%) patients. The most common etiology was infection (138, 64%), followed by drug-induced pneumonitis (13, 6%) and metastasis (12, 6%). Based on the etiologic diagnoses, therapies for diffuse pulmonary infiltrates were subsequently modified in 99 (46%) patients. Diagnostic yield (46%, 62%, 85%, and 100%; P for trend < 0.001) and frequency of therapeutic modifications (14%, 37%, 52%, and 100%; P for trend < 0.001) were significantly increased with additional invasive tests. Patients with therapeutic modification had a 34% lower in-hospital mortality rate than patients without therapeutic modification (38% versus 58%, P = 0.004) and a similar difference in mortality rate was observed up to 90 days (55% versus 73%, Log-rank P = 0.004). After adjusting for potential confounding factors, therapeutic modification was still significantly associated with reduced in-hospital mortality (adjusted OR 0.509, 95% CI 0.281-0.920).

Conclusions

Invasive diagnostic tests, including lung biopsy, increased diagnostic yield and caused therapeutic modification that was significantly associated with better outcomes for diffuse pulmonary infiltrates causing ARF in cancer patients.
Increased plasma levels of heparin-binding protein in patients with acute respiratory distress syndrome
Authors: Lin Qionghua , Shen Jie , Shen Lihua , Zhang Zhongwei , Fu Fengming
Published: July 2013

Introduction

Heparin-binding protein (HBP) is an antimicrobial protein stored in neutrophil granules and plays a role in endothelial permeability regulation. The aim was to assess the diagnostic and prognostic value of measuring HBP in patients with acute lung injury (ALI)/acute respiratory distress syndrome (ARDS).

Methods

Plasma HBP was collected from 78 patients with ALI/ARDS, 28 patients with cardiogenic pulmonary edema (CPE) and 20 healthy volunteers at enrollment. Levels of HBP were measured by ELISA.

Results

Patients with ALI/ARDS had significantly higher median levels of HBP compared with patients with CPE (17.15 (11.95 to 24.07) ng/ml vs. 9.50 (7.98 to 12.18) ng/ml, P <0.001) at enrollment. There was no significant difference between CPE patients and healthy subjects in terms of HBP value (P = 0.372). The HBP levels of nonsurvivors was significantly higher than that of survivors (23.90 (14.81 to 32.45) ng/ml vs. 16.01 (10.97 to 21.06) ng/ml, P = 0.012) and multivariate logistic regression showed HBP (odds ratio =1.52, P = 0.034) was the independent predictor for 30-day mortality in patients with ALI/ARDS.

Conclusions

Plasma HBP levels of ALI/ARDS patients were significantly higher than that of CPE patients. HBP was a strong prognostic marker for short-term mortality in ALI/ARDS.
Exercise rehabilitation for patients with critical illness: a randomized controlled trial with 12 months of follow-up
Authors: Denehy Linda , Skinner Elizabeth H , Edbrooke Lara , Haines Kimberley , Warrillow Stephen , Hawthorne Graeme , Gough Karla , Hoorn Steven Vander , Morris Meg E , Berney Sue
Published: July 2013

Introduction

The purpose of this trial was to investigate the effectiveness of an exercise rehabilitation program commencing during ICU admission and continuing into the outpatient setting compared with usual care on physical function and health-related quality of life in ICU survivors.

Methods

We conducted a single-center, assessor-blinded, randomized controlled trial. One hundred and fifty participants were stratified and randomized to receive usual care or intervention if they were in the ICU for 5 days or more and had no permanent neurological insult. The intervention group received intensive exercises in the ICU and the ward and as outpatients. Participants were assessed at recruitment, ICU admission, hospital discharge and at 3-, 6- and 12-month follow-up. Physical function was evaluated using the Six-Minute Walk Test (6MWT) (primary outcome), the Timed Up and Go Test and the Physical Function in ICU Test. Patient-reported outcomes were measured using the Short Form 36 Health Survey, version 2 (SF-36v2) and Assessment of Quality of Life (AQoL) Instrument. Data were analyzed using mixed models.

Results

The a priori enrollment goal was not reached. There were no between-group differences in demographic and hospital data, including acuity and length of acute hospital stay (LOS) (Acute Physiology and Chronic Health Evaluation II score: 21 vs 19; hospital LOS: 20 vs 24 days). No significant differences were found for the primary outcome of 6MWT or any other outcomes at 12 months after ICU discharge. However, exploratory analyses showed the rate of change over time and mean between-group differences in 6MWT from first assessment were greater in the intervention group.

Conclusions

Further research examining the trajectory of improvement with rehabilitation is warranted in this population.

Trial registration

The trial was registered with the Australian New Zealand Clinical Trials Registry ACTRN12605000776606.
CD8+T-cell counts: an early predictor of risk and mortality in critically ill immunocompromised patients with invasive pulmonary aspergillosis
Authors: Cui Na , Wang Hao , Long Yun , Liu Dawei
Published: July 2013

Introduction

Critically ill immunocompromised (CIIC) patients with pulmonary infection are a population at high risk for invasive pulmonary aspergillosis (IPA). The host defenses are important factors to consider in determining the risk and outcome of infection. Quantification of changes in the status of host immunity could be valuable for clinical diagnosis and outcome prediction.

Methods

We evaluated the quantitative changes in key humoral and cellular parameters in CIIC patients with pulmonary infection and their potential influence on the risk and prognosis of IPA. We monitored the evolution of these parameters in 150 CIIC patients with pulmonary infection on days 1, 3 and 10 (D1, D3 and D10) following ICU admission. The primary outcome was 28-day mortality. Follow-up included 60- and 90-day mortality.

Results

Among the 150 CIIC patients included in this study, 62 (41.3%) had microbiological evidence of IPA. Compared with patients without IPA, CD3+, CD8+, CD28+CD4+ and CD28+CD8+ CD28+CD8+ T-cell counts (D1, D3 and D10) and B-cell counts (D1 and D3) were significantly reduced in patients with IPA (P < 0.05). Multivariate regression analysis revealed that CD8+ (D3 and D10) (odds ratio (OR) 0.34, 95% confidence interval (CI) 0.23 to 0.46; OR 0.68, 95% CI 0.56 to 0.80), CD28+CD8+ (D3) (OR 0.73, 95% CI 0.61 to 0.86) and CD3+ (D10) (OR 0.81, 95% CI 0.63 to 0.98) T-cell counts were independent predictors of IPA in CIIC patients. Receiver operating characteristic analysis of immune parameters predicting 28-day mortality revealed area under the curve values of 0.82 (95% CI 0.71 to 0.92), 0.94 (95% CI 0.87 to 0.99), and 0.94 (95% CI 0.85 to 0.99) for CD8+ T-cell counts (D1, D3 and D10, respectively) and 0.84 (95% CI 0.75 to 0.94), 0.92 (95% CI 0.85 to 0.99) and 0.90 (95% CI 0.79 to 0.99) for CD28+CD8+ T-cell counts (D1, D3 and D10, respectively). Kaplan-Meier survival analysis provided evidence that CD8+ and CD28+CD8+ T-cell counts (<149.5 cells/mm3 and <75 cells/mm3, respectively) were associated with early mortality in CIIC patients with IPA (logrank test; P < 0.001).

Conclusions

CD8+ and CD28+CD8+ T-cell counts were significantly lower in CIIC patients with IPA than in non-IPA patients. Lower CD8+ and CD28+CD8+ T-cell counts in CIIC patients with pulmonary infection were associated with higher risk and early mortality in IPA and may be valuable for clinical diagnosis and outcome prediction.
Whole body protein kinetics during hypocaloric and normocaloric feeding in critically ill patients
Authors: Berg Agneta , Rooyackers Olav , Bellander Bo-Michael , Wernerman Jan
Published: July 2013

Introduction

Optimal feeding of critically ill patients in the ICU is controversial. Existing guidelines rest on rather weak evidence. Whole body protein kinetics may be an attractive technique for assessing optimal protein intake. In this study, critically ill patients were investigated during hypocaloric and normocaloric IV nutrition.

Methods

Neurosurgical patients on mechanical ventilation (n = 16) were studied during a 48-hour period. In random order 50% and 100% of measured energy expenditure was given as IV nutrition during 24 hours, corresponding to hypocaloric and normocaloric nutrition, respectively. At the end of each period, whole body protein turnover was measured using d5-phenylalanine and 13C-leucine tracers.

Results

The phenylalanine tracer indicated that whole-body protein synthesis was lower during hypocaloric feeding, while whole-body protein degradation and amino acid oxidation were unaltered, which resulted in a more negative protein balance, namely −1.9 ± 2.1 versus −0.7 ± 1.3 mg phenylalanine/kg/h (P = 0.014). The leucine tracer indicated that whole body protein synthesis and degradation and amino acid oxidation were unaltered, but the protein balance was negative during hypocaloric feeding, namely −0.3 ± 0.5 versus 0.6 ± 0.5 mg leucine/kg/h (P < 0.001).

Conclusion

In the patient group studied, hypocaloric feeding was associated with a more negative protein balance, but the amino acid oxidation was not different. The protein kinetics measurements and the study’s investigational protocol were useful for assessing the efficacy of nutrition support on protein metabolism in critically ill patients.
Feasibility of fully automated closed-loop glucose control using continuous subcutaneous glucose measurements in critical illness: a randomized controlled trial
Authors: Leelarathna Lalantha , English Shane W , Thabit Hood , Caldwell Karen , Allen Janet M , Kumareswaran Kavita , Wilinska Malgorzata E , Nodale Marianna , Mangat Jasdip , Evans Mark L , Burnstein Rowan , Hovorka Roman
Published: July 2013

Introduction

Closed-loop (CL) systems modulate insulin delivery according to glucose levels without nurse input. In a prospective randomized controlled trial, we evaluated the feasibility of an automated closed-loop approach based on subcutaneous glucose measurements in comparison with a local sliding-scale insulin-therapy protocol.

Methods

Twenty-four critically ill adults (predominantly trauma and neuroscience patients) with hyperglycemia (glucose, ≥10 mM) or already receiving insulin therapy, were randomized to receive either fully automated closed-loop therapy (model predictive control algorithm directing insulin and 20% dextrose infusion based on FreeStyle Navigator continuous subcutaneous glucose values, n = 12) or a local protocol (n = 12) with intravenous sliding-scale insulin, over a 48-hour period. The primary end point was percentage of time when arterial blood glucose was between 6.0 and 8.0 mM.

Results

The time when glucose was in the target range was significantly increased during closed-loop therapy (54.3% (44.1 to 72.8) versus 18.5% (0.1 to 39.9), P = 0.001; median (interquartile range)), and so was time in wider targets, 5.6 to 10.0 mM and 4.0 to 10.0 mM (P ≤ 0.002), reflecting a reduced glucose exposure >8 and >10 mM (P ≤ 0.002). Mean glucose was significantly lower during CL (7.8 (7.4 to 8.2) versus 9.1 (8.3 to 13.0] mM; P = 0.001) without hypoglycemia (<4 mM) during either therapy.

Conclusions

Fully automated closed-loop control based on subcutaneous glucose measurements is feasible and may provide efficacious and hypoglycemia-free glucose control in critically ill adults.

Trial Registration

ClinicalTrials.gov Identifier, NCT01440842.
Pupillary reflex measurement predicts insufficient analgesia before endotracheal suctioning in critically ill patients
Authors: Paulus Jerome , Roquilly Antoine , Beloeil Hélène , Théraud Julien , Asehnoune Karim , Lejus Corinne
Published: July 2013

Introduction

This study aimed to evaluate the pupillary dilatation reflex (PDR) during a tetanic stimulation to predict insufficient analgesia before nociceptive stimulation in the intensive care unit (ICU).

Methods

In this prospective non-interventional study in a surgical ICU of a university hospital, PDR was assessed during tetanic stimulation (of 10, 20 or 40 mA) immediately before 40 endotracheal suctionings in 34 deeply sedated patients. An insufficient analgesia during endotracheal suction was defined by an increase of ≥1 point on the Behavioral Pain Scale (BPS).

Results

A total of 27 (68%) patients had insufficient analgesia. PDR with 10 mA, 20 mA and 40 mA stimulation was higher in patients with insufficient analgesia (P <0.01). The threshold values of the pupil diameter variation during a 10, 20 and 40 mA tetanic stimulation to predict insufficient analgesia during an endotracheal suctioning were 1, 5 and 13% respectively. The areas (95% confidence interval) under the receiver operating curve were 0.70 (0.54 to 0.85), 0.78 (0.61 to 0.91) and 0.85 (0.721 to 0.954) with 10, 20 and 40 mA tetanic stimulations respectively. A sensitivity analysis using the Richmond Agitation Sedation Scale (RASS) confirmed the results. The 40 mA stimulation was poorly tolerated.

Conclusions

In deeply sedated mechanically ventilated patients, a pupil diameter variation ≥5% during a 20 mA tetanic stimulation was highly predictable of insufficient analgesia during endotracheal suction. A 40 mA tetanic stimulation is painful and should not be used.
Noninvasive intracranial pressure estimation by orbital subarachnoid space measurement: the Beijing Intracranial and Intraocular Pressure (iCOP) study
Authors: Xie Xiaobin , Zhang Xiaojun , Fu Jidi , Wang Huaizhou , Jonas Jost B , Peng Xiaoxia , Tian Guohong , Xian Junfang , Ritch Robert , Li Lei , Kang Zefeng , Zhang Shoukang , Yang Diya , Wang Ningli ,   Beijing iCOP Study Group
Published: July 2013

Introduction

The orbital subarachnoid space surrounding the optic nerve is continuous with the circulation system for cerebrospinal fluid (CSF) and can be visualized by using magnetic resonance imaging (MRI). We hypothesized that the orbital subarachnoid space width (OSASW) is correlated with and can serve as a surrogate for intracranial pressure (ICP). Our aim was to develop a method for a noninvasive measurement of the intracranial CSF-pressure (CSF-P) based on MRI-assisted OSASW.

Methods

The prospective observational comparative study included neurology patients who underwent lumbar CSF-P measurement and 3.0-Tesla orbital magnetic resonance imaging (MRI) for other clinical reasons. The width of the orbital subarachnoid space (OSASW) around the optic nerve was measured with MRI at 3, 9, and 15 mm behind the globe. The study population was randomly divided into a training group and a test group. After adjusting for body mass index (BMI) and mean arterial blood pressure (MABP), algorithms for the associations between CSF-P and OSASW were calculated in the training group. The algorithms were subsequently verified in the test group. Main outcome measures were the width of the orbital subarachnoid space (OSASW) and the lumbar cerebrospinal fluid pressure (CSF-P).

Results

Seventy-two patients were included in the study. In the training group, the algorithms for the associations between CSF-P and OSASW were as follows: (a) CSF-P = 9.31 × OSASW (at 3 mm) + 0.48 × BMI + 0.14 × MABP-19.94; (b) CSF-P = 16.95 × OSASW (at 9 mm) + 0.39 × BMI + 0.14 × MABP-20.90; and (c) CSF-P = 17.54 × OSASW (at 15 mm) + 0.47 × BMI + 0.13 × MABP-21.52. Applying these algorithms in the independent test group, the measured lumbar CSF-P (13.6 ± 5.1 mm Hg) did not differ significantly from the calculated MRI-derived CSF-P (OSASW at 3 mm: 12.7 ± 4.2 mm Hg (P = 0.07); at 9 mm: 13.4 ± 5.1 mm Hg (P = 0.35); and at 15 mm: 14.0 ± 4.9 mm Hg (P = 0.87)). Intraclass correlation coefficients (ICCs) were higher for the CSF-P assessment based on OSASW at 9 mm and at 15 mm behind the globe (all ICCs, 0.87) than for OSASW measurements at 3 mm (ICC, 0.80).

Conclusions

In patients with normal, moderately decreased or elevated ICP, MRI-assisted measurement of the OSASW appears to be useful for the noninvasive quantitative estimation of ICP, if BMI and MABP as contributing parameters are taken into account.

Trial registration

Clinical trial registered with the Chinese Clinical Trial Registry: ChiCTR-OCC-11001271