Search

Ethylene, a plant hormone that significantly influences both plant growth and response to stress, plays a well-established role in stress signaling. However, its impact on stomatal opening and closure during dehydration and rehydration remains relatively unexplored and is still debated. Exogenous ethylene has been proven to induce stomatal closure through a series of signaling pathways, including the accumulation of reactive oxygen species, subsequent synthesis of nitric oxide and hydrogen sulfide, and SLOW ANION CHANNEL-ASSOCIATED 1 activation. Thus, it has been suggested that ethylene might function to induce stomatal closure synergistically with abscisic acid (ABA). Furthermore, it has also been shown that increased ethylene can inhibit ABA- and jasmonic acid-induced stomatal closure, thus hindering drought-induced closure during dehydration. Simultaneously, other stresses, such as chilling, ozone pollution, and K+ deficiency, inhibit drought- and ABA-induced stomatal closure in an ethylene synthesis-dependent manner. However, ethylene has been shown to take on an opposing role during rehydration, preventing stomatal opening in the absence of ABA through its own signaling pathway. These findings offer novel insights into the function of ethylene in stomatal regulation during dehydration and rehydration, giving a better understanding of the mechanisms underlying ethylene-induced stomatal movement in seed plants., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Parathyroid hormone (PTH) receptor agonists promote bone formation but also increase osteoclastogenesis, in part by increasing expression of the receptor activator of nuclear factor kappa-Β ligand (RANKL). In addition to activation of transcription, regulation of mRNA stability is another important molecular mechanism controlling mRNA abundance. PTH treatment for 6 h resulted in a 7.4-fold elevation in RANKL mRNA expression in UAMS-32P cells, despite prior inhibition of cellular transcription by thiophosphoryl (TPL). RANKL mRNA, like other TNF family members, contains AU-Rich Elements (AREs) in the 3' UTR. AU-Rich Element Binding Proteins (ABPs including KSRP, TTP, AUF1 and HuR) bind to AREs and regulate mRNA stability. There was significantly more KSRP bound to RANKL mRNA than any of the other ABPs. PTH did not increase the amount of ABPs bound to the RANKL transcript. However, the level of cellular phosphorylated KSRP was significantly increased in UAMS-32P cells pre-treated with TPL followed by PTH exposure, compared to cells treated with vehicle following TPL. The extent of phosphorylation of cellular AUF1, HuR, and TTP did not increase with PTH treatment. There were no significant changes in the cellular content of total Pin1 and phospho-Pin1 protein with PTH treatment. We conclude that increases in cellular phospho-KSRP following PTH treatment, together with fact that the total amount of the KSRP bound to the RANKL mRNA did not change with PTH-treatment, may indicate that phospho-KSRP plays some role in stabilizing the RANKL transcript., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier B.V.)

Determining the differences in flower hydraulic traits and structural resource allocation among closely related species adapted to low mean annual precipitation (MAP) can provide insight into plant adaptation to arid environments. Here, we measured the maximum flower hydraulic conductance (K max-flower ), water potential at induction 50% loss of K max-flower (P 50-flower ), flower pressure-volume parameters, dry mass of individual flowers and structural components (vexillum, wings, keels, stamens and sepals) of six Caragana species growing in regions ranging from 110 to 1400 mm MAP. Compared with species from high-MAP environments, those from low-MAP environments presented lower K max-flower , more negative P 50-flower , osmotic potential at full turgor (π o ) and turgor loss points (π tlp ), and a greater bulk modulus of elasticity (ε). Consequently, a negative correlation between K max-flower (hydraulic efficiency) and P 50-flower (hydraulic safety) was observed across Caragana species. Furthermore, the dry masses of individual flowers and structural components (vexillum, wings, keels, stamens and sepals) were greater in the species from the low-MAP environment than in those from the high-MAP environment. These findings suggest that greater flower hydraulic safety and drought tolerance combined with greater structural resource allocation promote drought adaptation in Caragana species to low-MAP environments., (© 2024 John Wiley & Sons Ltd.)

While variation in mean annual precipitation (MAP) of the native habitat of a species has been shown to determine the ability of a species to resist a hydraulic decrease during drought, it remains unknown whether these variations in MAP also influence the ability of a species to recover and survive drought. Leaf hydraulic and gas exchange recovery following drought and the underlying mechanisms of these responses in six Caragana species from habitats along a large precipitation gradient were investigated during rehydration in a common garden. The gas exchange of species from arid habitats recovered more rapidly during rehydration after mild, moderate and severe drought stress treatments than species from humid habitats. The recovery of gas exchange was not associated with foliar abscisic acid concentration, but tightly related to the recovery of leaf hydraulic conductance (K leaf ). The recovery of K leaf was associated with the loss of K leaf during dehydration under mild and moderate drought stress, and to leaf xylem embolism formation under severe drought stress. Results pointed to the different ability to recover in gas exchange in six Caragana species post-drought is associated with the MAP of the species in its native habitat., (© 2023 John Wiley & Sons Ltd.)

Clarifying the mechanisms underlying the recovery of gas exchange following drought is the key to providing insights into plant drought adaptation and habitat distribution. However, the mechanisms are still largely unknown. Targeting processes known to inhibit gas exchange during drought recovery, we measured leaf water potential, the leaf hydraulic conductance, stomatal reopening, abscisic acid (ABA) and the ethylene emission rate (EER) following moderate drought stress in seedlings of the globally pervasive woody tree Fraxinus chinensis. We found strong evidence that the slow stomatal reopening after rehydration is regulated by a slow decrease in EER, rather than changes in leaf hydraulics or foliar ABA levels. This was supported by evidence of rapid gas exchange recovery in plants after treatment with the ethylene antagonist 1-methylcyclopropene. These findings provide evidence to rigorously support ethylene as a key factor constraining stomatal reopening from moderate drought directly, thereby potentially opening new windows for understanding species drought adaptation., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Heat shock proteins (HSPs), which have a variety of functions, are one of the stress protein families. In recent years, They have been reported to play a dual role in hepatitis B virus (HBV) which as persistent infection which is associated with, cirrhosis and liver cancer. In this article, we have summarized the regulatory mechanisms between HSPs and viruses, especially HBV and associated diseases based on HSP biological functions of in response to viral infections. In view of their potential as broad-spectrum antiviral targets, we have also discuss current progress and challenges in drug development based on HSPs, as well as the potential applications of agents that have been evaluated clinically in HBV treatment., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Stomatal closure is regulated by plant hormones and some small molecules to reduce water loss under stress conditions. Both abscisic acid (ABA) and polyamines alone induce stomatal closure; however, whether the physiological functions of ABA and polyamines are synergistic or antagonistic with respect to inducing stomatal closure is still unknown. Here, stomatal movement in response to ABA and/or polyamines was tested in Vicia faba and Arabidopsis thaliana, and the change in the signaling components under stomatal closure was analyzed. We found that both polyamines and ABA could induce stomatal closure through similar signaling components, including the synthesis of hydrogen peroxide (H 2 O 2 ) and nitric oxide (NO) and the accumulation of Ca 2+ . However, polyamines partially inhibited ABA-induced stomatal closure both in epidermal peels and in planta by activating antioxidant enzymes, including superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT), to eliminate the ABA-induced increase in H 2 O 2 . These results strongly indicate that polyamines inhibit abscisic acid-induced stomatal closure, suggesting that polyamines could be used as potential plant growth regulators to increase photosynthesis under mild drought stress., (© 2023 Scandinavian Plant Physiology Society.)

Context: X-linked hypophosphatemia (XLH) is a genetic disease, causing life-long hypophosphatemia due to overproduction of fibroblast growth factor 23 (FGF23). XLH is associated with Chiari malformations, cranial synostosis, and syringomyelia. FGF23 signals through FGFR1c and requires a coreceptor, α-Klotho, which is expressed in the renal distal convoluted tubules and the choroid plexus (ChP). In the ChP, α-Klotho participates in regulating cerebrospinal fluid (CSF) production by shuttling the sodium/potassium adenosine triphosphatase (Na + /K + -ATPase) to the luminal membrane. The sodium/potassium/chloride cotransporter 1 (NKCC1) also makes a substantial contribution to CSF production., Objective: Since CSF production has not been studied in XLH, we sought to determine if there are changes in the expression of these molecules in the ChP of Hyp mice, the murine model of XLH, as a first step toward testing the hypothesis that altered CSF production contributes to the cranial and spinal malformations seen this disease., Methods: Semi-quantitative real-time PCR was used to analyze the level of expression of transcripts for Fgfr1c, and thee key regulators of CSF production, Klotho, Atp1a1 and Slc12a2. In situ hybridization was used to provide anatomical localization for the encoded proteins., Results: Real-time polymerase chain reaction (RT-PCR) demonstrated significant upregulation of Klotho transcripts in the fourth ventricle of Hyp mice compared to controls. Transcript levels for Fgfr1c were unchanged in Hyp mice. Atp1a1 transcripts encoding the alpha-1 subunit of Na + /K + -ATPase were significantly downregulated in the third and lateral ventricles (LV). Expression levels of the Slc12a2 transcript (which encodes NKCC1) were unchanged in Hyp mice compared to controls. In situ hybridization (ISH) confirmed the presence of all 4 transcripts in the LV ChP both of WT and Hyp mice., Conclusion: This is the first study to document a significant change in the level of expression of the molecular machinery required for CSF production in Hyp mice. Whether similar changes occur in patients with XLH, potentially contributing to the cranial and spinal cord abnormalities frequently seen in XLH, remains to be determined., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Resprouting plants are distributed in many vegetation communities worldwide. With increasing resprout age post-severe-disturbance, new stems grow rapidly at their early age, and decrease in their growth with gradually decreasing water status thereafter. However, there is little knowledge about how stem hydraulic strategies and anatomical traits vary post-disturbance. In this study, the stem water potential (Ψstem), maximum stem hydraulic conductivity (Kstem-max), water potential at 50% loss of hydraulic conductivity (Kstem  P50) and anatomical traits of Caragana korshinkii resprouts were measured during a 1- to 13-year post-disturbance period. We found that the Kstem-max decreased with resprout age from 1-year-old resprouts (84.2 mol m-1 s-1 MPa-1) to 13-year-old resprouts (54.2 mol m-1 s-1 MPa-1) as a result of decreases in the aperture fraction (Fap) and the sum of aperture area on per unit intervessel wall area (Aap). The Kstem  P50 of the resprouts decreased from 1-year-old resprouts (-1.8 MPa) to 13-year-old resprouts (-2.9 MPa) as a result of increases in vessel implosion resistance (t/b)2, wood density (WD), vessel grouping index (GI) and decreases in Fap and Aap. These shifts in hydraulic structure and function resulted in an age-based divergence in hydraulic strategies i.e., a change from an acquisitive strategy to a conservative strategy, with increasing resprout age post-disturbance., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Major depressive disorder (MDD) and generalized anxiety disorder (GAD) are frequently comorbid with each other, and both associated with substantial cognitive impairments; however, it is still unclear whether their impairments are neurobiologically similar or distinct. This study aims to investigate the cognitive functions of the prefrontal cortex (PFC) in patients with MDD and GAD during the verbal fluency task (VFT) using functional near-infrared spectroscopy (fNIRS). Fifty-two patients with MDD, fifty-one patients with GAD, fifty-two patients with the comorbidity of MDD and GAD (CMG), and forty-seven healthy controls (HC) participated in the study. Significant hypoactivation in the left ventrolateral and the left dorsolateral PFC was common in all patient groups when compared to HCs, suggesting a shared etiology. Furthermore,  MDD patients showed significant hypoactivation at the right frontal pole cortex (FPoC) when compared to HCs and significant hypoactivation at the middle FPoC when compared to the CMG patients. Our work is the first fNIRS study to reveal the shared and unique neurobiological profiles of MDD, GAD and their comorbidity under the same standard experimentation condition, suggesting fNIRS holds promise as an adjutant to assist clinical diagnosis., (Copyright © 2021. Published by Elsevier B.V.)

It has been suggested that a trade-off between hydraulic efficiency and safety is related to drought adaptation across species. However, whether leaf hydraulic efficiency is sacrificed for safety during woody resprout regrowth after crown removal is not well understood. We measured leaf water potential (ψ leaf ) at predawn (ψ pd ) and midday (ψ mid ), leaf maximum hydraulic conductance (K leaf-max ), ψ leaf at induction 50% loss of K leaf-max (K leaf P 50 ), leaf area-specific whole-plant hydraulic conductance (LSC), leaf vein structure and turgor loss point (π tlp ) in 1- to 13-year-old resprouts of the aridland shrub (Caragana korshinskii). ψ pd was similar, ψ mid and K leaf P 50 became more negative, and K leaf-max decreased in resprouts with the increasing age; thus, leaf hydraulic efficiency clearly traded off against safety. The difference between ψ mid and K leaf P 50 , leaf hydraulic safety margin, increased gradually with increasing resprout age. More negative ψ mid and K leaf P 50 were closely related to decreasing LSC and more negative π tlp , respectively, and the decreasing K leaf-max arose from the lower minor vein density and the narrower midrib xylem vessels. Our results showed that a clear trade-off between leaf hydraulic efficiency and safety helps C. korshinskii resprouts adapt to increasing water stress as they approach final size., (© 2021 John Wiley & Sons Ltd.)

Purpose: To identify factors associated with lymphoma in patients with prior Mycobacterium tuberculosis infection., Methods: A retrospective case-control analysis was performed in a highly tuberculosis (TB)-endemic area. Patients with a history of TB before the diagnosis of lymphoma were retrospectively identified. Inpatients with lymphoma (n=1,057) and pathologically confirmed benign diseases (n=12,916) were consecutively enrolled at Xinjiang Medical University Cancer Hospital between January 2016 and December 2019., Results: The proportion of TB infection in patients with lymphoma (n=148, 14.0%) was significantly higher than that in the control (benign diseases) group (n=175, 1.4%) (p<0.0001). The frequencies of TB infection in patients with Hodgkin lymphoma, B-cell non-Hodgkin lymphoma (NHL), and T/NK-cell NHL were 13.6%, 14.6%, and 11.9%, respectively. Relatively high proportions of TB infection were found in patients with chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL), marginal zone B-cell lymphoma (MZBL), and diffuse large B-cell lymphoma (DLBCL), at 20.6%, 18.6% and 15.3%, respectively, compared to other subtypes of B-cell NHL. For T/NK-cell NHL, the proportions of TB infection in patients with peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS), and anaplastic large cell lymphoma (ALCL) were 18.2% and 20%, respectively. The multivariate analysis revealed that male sex was an adverse risk factor for lymphoma after tubercular infection. In addition, male sex and older age (>60 years) were associated with B-cell NHL., Conclusion: A high proportion of TB infection was found in patients with lymphoma. In TB-infected patients, older age and male sex were associated with susceptibility to lymphoma, suggesting that screening programmes might be useful for the early detection of lymphoma. Keywords Lymphoma; tuberculosis; Burkitt's lymphoma; diffuse large B lymphoma; Hodgkin's disease., Competing Interests: Competing interests: The authors declare no conflict of Interest.

Investigating plant morphological traits can provide insights into plant drought tolerance. To date, many papers have focused on plant hydraulic responses to drought during dehydration, but atmospheric water absorption by trichomes to mitigate drought stress by influencing leaf hydraulics in plant species that inhabit arid environments has been largely ignored. The experiment in this study was designed to assess how dew absorbed by leaf trichomes helps Caragana korshinskii withstand drought. The results showed that under a drought stress and dew (DS & D) treatment, C. korshinskii displayed a strong capacity to absorb dew with trichomes; exhibited slow decreases in leaf water potential (Ψ leaf ), leaf hydraulic conductivity (K leaf ), and gas exchange; experienced 50% K leaf and gas exchange losses at lower relative soil water content levels than plants treated with drought stress and no dew (DS & ND); and experienced 50% K leaf loss (K leaf P 50 ) at similar Ψ leaf levels as DS & ND plants. Its congener C. sinica, which does not have leaf trichomes, displayed little ability to absorb dew under drought stress and did not show any remarkable improvement in the above parameters under the DS & D treatment. Our results indicated that leaf trichomes are important epidermal dew-uptake structures that assist in partially sustaining the leaf hydraulic assimilation system, mitigate the adverse effects of drought stress and contribute to the distribution of C. korshinskii in arid environments., (© 2021 Scandinavian Plant Physiology Society.)

Sphingosine-1-phosphate (S1P) is an anabolic clastokine. Sphingosine kinase (SPHK) is the rate-limiting enzyme in S1P production and has 2 isoforms. To evaluate the roles of SPHK1 and SPHK2 in bone, we examined the skeletal phenotype of mice with selective deletion of SPHK1 in osteoclasts (SPHK1-Oc-/-) and mice in which the SPHK2 gene was deleted in all tissues (SPHK2-/-). SPHK1-Oc-/- had normal bone mass. By contrast, SPHK2-/- female mice had a 14% lower spinal bone mineral density (BMD; P < 0.01) and males a 22% lower BMD at the same site (P < 0.001). SPHK2-/- and control mice were subsequently treated either with daily parathyroid hormone [PTH](1-34) or vehicle for 29 days. The response to PTH was significantly attenuated in the SPHK2-/-mice. The mean femoral bone volume to total volume fraction (BV/TV) increased by 24.8% in the PTH-treated female control animals vs 10.6% in the vehicle-treated female controls (P < 0.01). In contrast, in the SPHK2-/- female mice the difference in femoral trabecular BV/TV at the end of treatment was not significant (20.5 vs13.3%, PTH vs vehicle, P = NS). The anabolic response to PTH was significantly attenuated in the spine of male SPHK2-/- mice (29.7% vs 23.1%, PTH vs vehicle, in controls, P < 0.05; 26.9% vs 19.5% PTH vs vehicle in SPHK2-/- mice, P = NS). The spine responded normally in the SPHK2-/- female mice. Interestingly, suppression of sclerostin was blunted in the SPHK2-/- mice when those animals were treated with an anabolic PTH regimen. We conclude that SPHK2 has an important role in mediating both normal bone remodeling and the anabolic response to PTH., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Drought is a cyclical phenomenon in natural environments. During dehydration, stomatal closure is mainly regulated by abscisic acid (ABA) dynamics that limit transpiration in seed plants, but following rehydration, the mechanism of gas exchange recovery is still not clear. In this study, leaf water potential (ψ leaf ), stomatal conductance (g s ), leaf hydraulic conductance (K leaf ), foliar ABA level, ethylene emission rate in response to dehydration and rehydration were investigated in four Caragana species with isohydric (Caragana spinosa and C. pruinosa) and anisohydric (C. intermedia and C. microphylla) traits. Two isohydric species with ABA-induced stomatal closure exhibited more sensitive g s and K leaf to decreasing ψ leaf than two anisohydric species which exhibited a switch from ABA to water potential-driven stomatal closure during dehydration. Following rehydration, the recovery of gas exchange was not associated with a decrease in ABA level but was strongly limited by the degradation of the ethylene emission rate in all species. Furthermore, two anisohydric species with low drought-induced ethylene production exhibited more rapid recovery in gas exchange upon rehydration. Our results indicated that ethylene is a key factor regulating the drought-recovery ability in terms of gas exchange, which may shape species adaptation to drought and potential species distribution., (© 2020 John Wiley & Sons Ltd.)

Clarifying the coordination of leaf hydraulic traits with gas exchange across closely-related species adapted to varying rainfall can provide insights into plant habitat distribution and drought adaptation. The leaf hydraulic conductance (K leaf ), stomatal conductance (g s ), net assimilation (A), vein embolism and abscisic acid (ABA) concentration during dehydration were quantified, as well as pressure-volume curve traits and vein anatomy in 10 Caragana species adapted to a range of mean annual precipitation (MAP) conditions and growing in a common garden. We found a positive correlation between Ψ leaf at 50% loss of K leaf (K leaf P 50 ) and maximum K leaf (K leaf-max ) across species. Species from low-MAP environments exhibited more negative K leaf P 50 and turgor loss point, and higher K leaf-max and leaf-specific capacity at full turgor, along with higher vein density and midrib xylem per leaf area, and a higher ratio of K leaf-max : maximum g s . Tighter stomatal control mediated by higher ABA accumulation during dehydration in these species resulted in an increase in hydraulic safety and intrinsic water use efficiency (WUE i ) during drought. Our results suggest that high hydraulic safety and efficiency combined with greater stomatal sensitivity triggered by ABA production and leading to greater WUE i provides drought tolerance in Caragana species adapted to low-MAP environments., (© 2020 The Authors New Phytologist © 2020 New Phytologist Trust.)

Sphingosine-1-phosphate (S1P) is an anabolic clastokine. Colony Stimulating Factor 1 (CSF1) induces expression of the rate limiting enzyme required for S1P synthesis, sphingosine kinase 1 (SPHK1) in bone in vivo, and in osteoclasts in vitro. To study the mechanism of CSF1-induced SPHK1 gene expression, a 2608 bp fragment of the murine SPHK1 gene (- 2497 to + 111 bp relative to the transcription start site) was cloned and transfected into pZen cells (murine fibroblasts engineered to express c-fms). SPHK1 promoter activity was assessed using a dual-luciferase reporter assay system. By analyzing a series of 5'-deletions, a CSF1-responsive region was identified in the region - 1250 to - 1016 bp. To define putative DNA binding site(s) in this fragment, two biotin-labeled fragments that completely overlapped this region were generated, one 163 bp in length (- 1301 to - 1139) and one 169 bp in length (- 1157 to - 989). EMSAs revealed the 163 bp fragment as the target for protein binding. Using EMSAs, the nuclear protein binding region was further narrowed to an 85 bp fragment, (- 1223 to - 1139). Using a series of unlabeled DNA sequences as "cold competitors" in EMSAs, a 22 bp sequence is identified as the smallest fragment that could successfully compete away protein binding. The same 22 bp sequence also competed DNA binding in EMSAs using nuclear protein isolated from primary murine osteoclasts. A full-length wild-type SPHK1 promoter and an SPHK1 promoter in which the ATGGGGG motif was mutated were subsequently expressed in pZen cells. Mutating this ATGGGGG motif nearly completely abrogated the ability of CSF1 to activate the promoter. Although two transcription factors, KLF6 and Sp1 have been reported to bind to this sequence, supershift EMSAs failed to detect either among the proteins bound to the 85 bp DNA fragment.

Pharmacokinetic parameters can be significantly altered for acute kidney injury (AKI), extracorporeal membrane oxygenation (ECMO) and continuous veno-venous hemofiltration therapy (CVVH). Here we reported a case of individualized vancomycin dosing for a patient diagnosed as severe acute pancreatitis treated with concurrent ECMO and CVVH. A 65 kg 32-year-old woman was admitted to hospital presented with severe acute pancreatitis (SAP), respiratory failure, metabotropic acidosis and hyperkalemia. She was admitted to intensive care unit (ICU) on hospital day 1 and was initiated on CVVH. She progressed to multiple organ dysfunction syndrome (MODS) and acute respiratory distress syndrome (ARDS) on ICU day 2, and veno-venous ECMO was instituted. Several catheters were inserted into the body to support ECMO, CVVH and pulse indicator continuous cardiac output (PiCCO), so vancomycin was prescribed empirically on ICU day 3 for prevention of catheter-related infection. Given the residual renal function and continuous hemofiltration intensity on day 3, vancomycin bolus of 1 000 mg was prescribed, followed by a maintenance dose of 500 mg every 8 hours. On ICU day 4, a vancomycin trough serum concentration of 14.1 mg/L was obtained before the fourth dose, which was within the target range of 10-20 mg/L. By ICU day 7, vancomycin dosage was elevated to 1.0 g every 12 hours because of aggravated infection and improved kidney function. On ICU day 14, a vancomycin trough serum concentration of 17 mg/L was obtained. Her white blood cell (WBC) and neutrophil percentage (Neut%) dropped to the normal level by ICU day 19. This vancomycin regimen was successful in providing a target attainment of trough serum concentration ranging from 10-20 mg/L quickly and in controlling infection-related symptoms and signs properly. With the help of this case report we want to call attention to the clinically significant alteration in vancomycin pharmacokinetics among critically ill patients. Individualized vancomycin dosing regimens and therapeutic drug monitoring are necessary for critically ill patients receiving CVVH and ECMO to ensure that the target serum vancomycin levels are reached to adequately treat the infection and avoid nephrotoxicity.

Objective: To assess the nutritional status of severe malnutrition patients with anorexia nervosa by multi-frequency bioelectrical impedance technique, and to provide the basis for nutritional support therapy., Methods: A prospective study was conducted. Twenty-six severe malnutrition patients with anorexia nervosa, body mass index (BMI) ≤ 16 kg/m 2 admitted to intensive care unit (ICU) of Peking University Third Hospital and general three ward of Peking University Sixth Hospital from June 1st to September 30th, 2017 were enrolled. The extracellular water (ECW), intracellular water (ICW), ECW/ICW ratio, adipose tissue mass (ATM), lean tissue mass (LTM), total body water/body weight (TBW/WT), ATM/WT, and LTM/WT were measured by multi-frequency bioelectrical impedance meter. Thirty-eighty healthy volunteers with normal nutritional status (23.0 kg/m 2 > BMI > 18.5 kg/m 2 ) matched by gender and height were enrolled as healthy control group. The predictive value of main body composition for nutritional status were analyzed by receiver operating characteristic (ROC) curve., Results: All the patients were female. There was no significant difference in height between two groups, but WT and BMI in the severe malnutrition group were significantly higher than those in the healthy control group [WT (kg): 38.1±4.9 vs. 54.2±3.3, BMI (kg/m 2 ): 13.6±2.5 vs. 21.2±1.1, both P < 0.01]. Compared with the healthy control group, the ECW, ICW, ATM, LTM, ATM/WT and LTM/WT were significantly decreased in the severe malnutrition group [ECW (L): 9.02±0.42 vs. 10.19±0.77, ICW (L): 12.6±0.9 vs.19.1±1.3, ATM (kg): 9.3±1.1 vs. 16.6±1.9, LTM (kg): 16.5±1.5 vs. 26.1±1.7, ATM/WT: 0.26±0.02 vs. 0.30±0.02, LTM/WT: 0.22±0.02 vs. 0.26±0.01, all P < 0.01], the ECW/ICW and TBW/WT were significantly increased in the severe malnutrition group (ECW/ICW: 0.72±0.06 vs. 0.54±0.06, TBW/WT: 0.58±0.02 vs. 0.52±0.02, both P < 0.01). It was shown by ROC curve analysis that the area under ROC curve (AUC) of TBW/WT, ATM/WT, LTM/WT for evaluating severe malnutrition were 0.999, 0.919, 0.954 respectively; when the cut-off of TBW/WT, ATM/WT, LTM/WT were 0.58, 0.28, 0.24 respectively, the sensitivity were 100%, 85%, 80% respectively, and the specificity were 95%, 80%, 91% respectively., Conclusions: Main body composition of severe malnutrition patients with anorexia nervosa changed significantly. Bioelectrical impedance technology can be an effective assessment tool for the nutritional status of such patients.

Neutralizing CSF1 in vivo completely prevents ovariectomy (OVX)-induced bone loss in mice. There are two isoforms of CSF1, soluble (sCSF1), and membrane-bound (mCSF1), but their individual biological functions are unclear. It had been previously reported that mCSF1 knockout (K/O) and wild type (Wt) female mice experience the same degree of bone loss following OVX. In Wt mice the expression of sCSF1 was elevated fourfold in skeletal tissue following OVX while expression of mCSF1 was unchanged. To examine the role of sCSF1 in OVX-induced bone loss, mice were engineered in which sCSF1 was not expressed but expression of mCSF1 was unaffected (sCSF1 K/O). Isoform-specific reverse transcription PCR confirmed the absence of transcripts for sCSF1 in bone tissue isolated from these animals and no circulating CSF1 was detected by ELISA. Surprisingly, there were no significant differences in bone mineral density (BMD) between sCSF1 K/O mice and Wt controls as assessed by dual-energy X-ray absorptiometry and micro-CT. However, one month after OVX, femoral, spinal and total BMD had declined by 11.2%, 8.9%, and 8.7% respectively in OVX-Wt animals as compared to Sham-OVX. In contrast OVX sCSF1 K/O mice showed changes of +0.1%, -2.4%, and +2.3% at the same 3 sites compared to Sham-OVX sCSF1 K/O mice. These data indicate important non-redundant functions for the two isoforms of CSF1 and suggest that sCSF1, but not mCSF1, plays a key role in estrogen-deficiency bone loss., Competing Interests: The authors declare no conflict of interest.

Platelets in the primary tumor microenvironment play crucial roles in the regulation of tumor progression, but the mechanisms underlying are poorly understood. Here, we report that platelet releasates exerted a proliferative effect on hepatocellular carcinoma (HCC) cells both in vitro and in vivo. This effect depended on a reduction of KLF6 expression in HCC cells. After incubation with either platelets or platelet granule contents, SMMC.7721 and HepG2 cells exhibited significant increases in proliferation and decreases in apoptosis. However, no effect was observed when incubating cancer cells with resuspended activated platelet pellet which exhausted of releasates. Platelet releasates also increased the population of HCC cells in the S and G2/M phases of the cell cycle and reduced the cell population in the G0/G1 phase. Moreover, knocking down KLF6 expression significantly diminished the platelet-mediated enhancement of HCC growth. In addition, blocking TGF-β signaling with the TGF-β receptor inhibitor SB431542 counteracted the effect of platelets on KLF6 expression and proliferation of HCC cells. Based on these findings, we conclude that platelet releasates, especially TGF-β, promote the proliferation of SMMC.7721 and HepG2 cells by decreasing expression of KLF6. This discovery identifies a potential new therapeutic target for the prevention and treatment of hepatocellular carcinoma.

Scope: Propolis is thought to help prevent thrombotic and related cardiovascular diseases in humans. Chrysin, a bioflavonoids compound found in high levels in propolis and in honey, has been reported to possess antiplatelet activity. However, the mechanism by which it inhibits platelet function is unclear., Methods and Results: The effects of chrysin on agonist-activated platelet-aggregation, granule-secretion, and integrin αIIbβ3 activation were examined. Its effects on the phosphorylation of Akt, GSK3β, MAPKs, and several proteins of the glycoprotein VI (GPVI) signaling pathway were also studied on collaged-activated platelets. In addition, human platelet spreading on immobilized fibrinogen was also tested. We found that chrysin dose dependently inhibited platelet aggregation and granule secretion induced by collagen, as well as platelet aggregation induced by ADP, thrombin, and U46619. Chrysin also markedly reduced the number of adherent platelets and the single platelet spreading area on immobilized fibrinogen. Biochemical analysis revealed that chrysin inhibited collagen-induced activation of Syk, PLCγ2, PKC, as well as the phosphorylation of Akt and ERK1/2. Additionally, chrysin attenuated phosphorylation of molecules such as FcγRIIa, FAK, Akt, and GSK3β in platelet spreading on immobilized fibrinogen., Conclusions: Our findings indicate that chrysin suppresses not only integrin αIIbβ3-mediated "inside-out" signaling, but also the "outside-in" signal transmission. This implies that chrysin may represent a potential candidate for an antiplatelet agent., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The hypothalamus has been implicated in skeletal metabolism. Whether hunger-promoting neurons of the arcuate nucleus impact the bone is not known. We generated multiple lines of mice to affect AgRP neuronal circuit integrity. We found that mice with Ucp2 gene deletion, in which AgRP neuronal function was impaired, were osteopenic. This phenotype was rescued by cell-selective reactivation of Ucp2 in AgRP neurons. When the AgRP circuitry was impaired by early postnatal deletion of AgRP neurons or by cell autonomous deletion of Sirt1 (AgRP-Sirt1(-/-)), mice also developed reduced bone mass. No impact of leptin receptor deletion in AgRP neurons was found on bone homeostasis. Suppression of sympathetic tone in AgRP-Sirt1(-/-) mice reversed osteopenia in transgenic animals. Taken together, these observations establish a significant regulatory role for AgRP neurons in skeletal bone metabolism independent of leptin action., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Flavonoids exert both anti-oxidant and anti-platelet activities in vitro and in vivo. Pentamethylquercetin (PMQ), a polymethoxylated flavone derivative, has been screened for anti-carcinogenic and cardioprotective effects. However, it is unclear whether PMQ has anti-thrombotic effects. In the present study, PMQ (20 mg/kg) significantly inhibited thrombus formation in the collagen- epinephrine- induced acute pulmonary thrombosis mouse model and the ferric chloride-induced carotid injury model. To explore the mechanism, we evaluated the effects of PMQ on platelet function. We found that PMQ inhibited platelet aggregation and granule secretion induced by low dose agonists, including ADP, collagen, thrombin and U46619. Biochemical analysis revealed that PMQ inhibited collagen-, thrombin- and U46619-induced activation of Syk, PLCγ2, Akt, GSK3β and Erk1/2. Therefore, we provide the first report to show that PMQ possesses anti-thrombotic activity in vivo and inhibited platelet function in vitro, suggesting that PMQ may represent a potential therapeutic candidate for the prevention or treatment of thrombotic disorders.

Loureirin A is a flavonoid extracted from Dragon׳s Blood that has been used to promote blood circulation and remove stasis in Chinese traditional medicine. However, the mechanisms of these effects are not fully understood. We explored the anti-platelet activity and underlying mechanism of loureirin A in vitro. Our results indicated that loureirin A negatively affected agonist-induced platelet aggregation such as collagen, collagen-related peptide (CRP), ADP and thrombin. Loureirin A inhibited collagen-induced platelet ATP secretion and thrombin-stimulated P-selectin expression in a dose-dependent manner. Platelet spreading on immobilized fibrinogen was significantly impaired in the presence of loureirin A. Immunoblotting analysis indicated that 100μM of loureirin A almost completely eliminated collagen-induced Akt phosphorylation at Ser473. Interestingly, a submaximal dose (50μM) of loureirin A had an additive inhibitory effect with the phosphoinositide 3-kinase (PI3K) inhibitor Ly294002 on collage-induced Akt phosphorylation in platelets. Taken together, loureirin A had an inhibitory effect on platelet activation, perhaps through an impairment of PI3K/Akt signaling., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Colony-stimulating factor 1 (CSF1) is known to promote osteoclast progenitor survival, but its roles in osteoclast differentiation and mature osteoclast function are less well understood. In a microarray screen, Jun dimerization protein 2 (JDP2) was identified as significantly induced by CSF1. Recent reports indicate that JDP2 is required for normal osteoclastogenesis and skeletal metabolism. Because there are no reports on the transcriptional regulation of this gene, the DNA sequence from -2612 to +682 bp (relative to the transcription start site) of the JDP2 gene was cloned, and promoter activity was analyzed. The T box-binding element (TBE) between -191 and -141 bp was identified as the cis-element responsible for CSF1-dependent JDP2 expression. Using degenerate PCR, Tbx3 was identified as the major isoform binding the TBE. Overexpression of Tbx3 induced JDP2 promoter activity, whereas suppressing Tbx3 expression substantially attenuated CSF1-induced transcription. Suppressing Tbx3 in osteoclast precursors reduced JDP2 expression and significantly impaired RANKL/CSF1-induced osteoclastogenesis. A MEK1/2-specific inhibitor was found to block CSF1-induced JDP2 expression. Consistent with these data, JDP2(-/-) mice were found to have increased bone mass. In summary, CSF1 up-regulates JDP2 expression by inducing Tbx3 binding to the JDP2 promoter. The downstream signaling cascade from activated c-Fms involves the MEK1/2-ERK1/2 pathway. Tbx3 plays an important role in osteoclastogenesis at least in part by regulating CSF1-dependent expression of JDP2.

Objective: To describe the characteristics of acute pancreatitis during pregnancy and postpartum., Methods: From 1994 to 2012, 18 cases of gravida and postpartum women complicated with acute pancreatitis were treated at Peking University Third Hospital and retrospective analysis was performed., Results: The admission rate due to acute pancreatitis was 41.24 per 100 000 admission. The median age was 32.0 (28.0, 34.7) years, with the onset of acute pancreatitis on 35.0 (23.5, 37.0) weeks'gestation. Of all the cases, 13 (72.2%) were interstitial edematous acute pancreatitis, and 5 (27.8%) were necrotizing. Nine (50.0%) were caused by hyperlipidemia, of which 7 (38.9%) were caused by gallstones, and 2 (1.1%) were idiopathic. Stratified by severity, 6 (33.3%) were mild, 7 (38.9%) were moderately severe and 5 (27.8%) were severe, of which 8 were transferred to Intensive Care Unit. Compared with non-hyperlipidemic acute pancreatitis, cases caused by hyperlipidemia were more severe, however, the prognoses of mothers and infants were good., Conclusion: The incidence of acute pancreatitis during pregnancy and postpartum was similar to that of the regular population, and mostly caused by gallstones and hyperlipidemia. Although acute hyperlipidemic pancreatitis is more severe, the morbidity and mortality of maternal and perinatal could be decreased by aggressive therapy.

Aim: To investigate the efficacy and safety of ulinastatin for patients with acute lung injury (ALI) and those with acute respiratory distress syndrome (ARDS)., Methods: A systematic review of randomized controlled trials (RCTs) of ulinastatin for ALI/ARDS was conducted. Oxygenation index, mortality rate [intensive care unit (ICU) mortality rate, 28-d mortality rate] and length of ICU stay were compared between ulinastatin group and conventional therapy group. Meta-analysis was performed by using Rev Man 5.1., Results: Twenty-nine RCTs with 1726 participants were totally included, the basic conditions of which were similar. No studies discussed adverse effect. Oxygenation index was reported in twenty-six studies (1552 patients). Ulinastatin had a significant effect in improving oxygenation [standard mean difference (SMD) = 1.85, 95%CI: 1.42-2.29, P < 0.00001, I(2) = 92%]. ICU mortality and 28-d mortality were respectively reported in eighteen studies (987 patients) and three studies (196 patients). We found that ulinastatin significantly decreased the ICU mortality [I(2) = 0%, RR = 0.48, 95%CI: 0.38-0.59, number needed to treat (NNT) = 5.06, P < 0.00001], while the 28-d mortality was not significantly affected (I(2) = 0%, RR = 0.78, 95%CI: 0.51-1.19, NNT = 12.66, P = 0.24). The length of ICU stay (six studies, 364 patients) in the ulinastatin group was significantly lower than that in the control group (SMD = -0.97, 95%CI: -1.20--0.75, P < 0.00001, I(2) = 86%)., Conclusion: Ulinastatin seems to be effective for ALI and ARDS though most trials included were of poor quality and no information on safety was provided.

Background: The study aimed to investigate the analgesic effect of a combination of intravenous flurbiprofen axetil and opioids, and evaluate the relationship between refractory pain relief and plasma β-endorphin levels in cancer patients., Materials and Methods: A total of 120 cancer patients was randomly divided into two groups, 60 patients took orally morphine sulfate sustained-release tablets in group A, and another 60 patients receiving the combination treatment of intravenous flurbiprofen axetil and opioid drugs in group B. After 7 days, pain relief, quality of life improvement and side effects were evaluated. Furthermore, plasma β-endorphin levels were measured by radioimmunoassay., Results: With the combination treatment of intravenous intravenous flurbiprofen axetil and opioids, the total effective rate of pain relief rose to 91.4%, as compared to 82.1% when morphine sulfate sustained-release tablet was used alone. Compared with that of group A, the analgesic effect increased in group B (p=0.031). Moreover, satisfactory pain relief was associated with a significant increase in plasma β-endorphin levels. After the treatment, plasma β-endorphin level in group B was 62.4±13.5 pg/ml, which was higher than that in group A (45.8±11.2 pg/ml) (p<0.05)., Conclusions: Our results suggest the combination of intravenous flurbiprofen axetil and opioids can enhance the analgesic effect of opioid drugs by increasing plasma β-endorphin levels, which would offer a selected and reliable strategy for refractory cancer pain treatment.

To better define the biologic function of membrane-bound CSF1 (mCSF1) in vivo, we have generated mCSF1 knockout (k/o) mice. Spinal bone density (BMD) was 15.9% higher in k/o mice compared to wild-type (wt) controls (P < 0.01) and total BMD was increased by 6.8% (P < 0.05). A higher mean femur BMD was also observed but did not reach statistical significance (6.9% P = NS). The osteoclastogenic potential of bone marrow isolated from mCSF1 k/o mice was reduced compared to wt marrow. There were no defects in osteoblast number or function suggesting that the basis for the high bone mass phenotype was reduced resorption. In addition to a skeletal phenotype, k/o mice had significantly elevated serum triglyceride levels (123 ± 7 vs. 88 ± 3.2 mg/dl; k/o vs. wt, P < 0.001), while serum cholesterol levels were similar (122 ± 6 vs. 116 ± 6 mg/dl; k/o vs. wt, P = NS). One month after surgery, 5-month-old k/o and wt female mice experienced the same degree of bone loss following ovariectomy (OVX). OVX induced a significant fourfold increase in the expression of the soluble CSF1 isoform (sCSF1) in the bones of wt mice while expression of mCSF1 was unchanged. These findings indicate that mCSF1 is essential for normal bone remodeling since, in its absence, BMD is increased. Membrane-bound CSF1 does not appear to be required for estrogen-deficiency bone loss while in contrast; our data suggest that sCSF1 could play a key role in this pathologic process. The reasons why mCSF1 k/o mice have hypertriglyceridemia are currently under study.

Although recent investigations have identified that lymphangiogenesis is associated with regional lymph node metastasis and tumor prognosis in non-small cell lung cancer (NSCLC), peritumoral lymphatic microvessel density (LMVD) and its prognostic significance in lung adenocarcinoma remain unknown. In the present study, we assessed peritumoral LMVD in lung adenocarcinoma and investigated its correlation with patient prognosis. Using immunohistochemistry (SP method), the D2-40-positive peritumoral LMVD count in lung adenocarcinoma was found to be 11.56±10.73, which was higher than intratumoral LMVD (P<0.001), and was found to be associated with lymphatic metastasis (P=0.003) and pTNM staging (P=0.046). Furthermore, a significant difference in the patient overall survival time was demonstrated between tumors with a high peritumoral LMVD and those with a low peritumoral LMVD (P=0.005). Finally, using multivariate analysis, it was determined that peritumoral LMVD, lymphatic metastasis and pTNM staging were independent prognostic factors. In conclusion, the results suggest that D2-40-positive peritumoral LMVD may predict the prognosis of lung adenocarcinoma.

Objective: To demonstrate the pharmacokinetic profile of meropenem when administered by 3-hour infusion in patients undergoing continuous veno-venous hemofiltration (CVVH)., Methods: The study was conducted in 10 patients, who were treated with CVVH. Each subject received meropenem in 3-hour infusion of 500 mg every 6 hours. Blood samples were collected before infusion (0 hour) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6 hours (just before the infusion of the next dose) after the beginning of the fourth infusion. The concentrations of meropenem in plasma were measured by high-performance liquid chromatography method, and mean serum meropenem concentration-time curve was plotted., Results: Peak plasma drug concentrations measured 3 hours post-infusion were (25.05 ± 5.64) mg/L, and trough levels after 6 hours of infusion were (13.03 ± 3.01) mg/L. The area under the plasma concentration-time curve (AUC) was (118.42 ± 26.78) mg x h⁻¹ x L⁻². The elimination half-life (T1/2) was (3.74 ± 0.55) hours. The mean residence time (MRT) was (4.99 ± 0.84) hours. The volume of distribution (Vb) was (22.85 ± 9.85) L and clearance of meropenem (CL) was (4.49 ± 1.32) L/h. The percentage of time that the serum drug concentration was above the minimum inhibitory concentration (MIC) accounting for the interval time of infusion (%T>MIC) was 100% (MIC 8 mg/L) in all the 10 patients., Conclusion: Based on these data, we concluded that satisfactory pharmacodynamic parameters could be attained in CVVH patients treated with meropenem by a prolonged infusion time of 3 hours with a dosage of 500 mg for every 6 hours.

Objective: To determine the treatment effect of an optimized resuscitation strategy on prognosis of patients with septic shock., Methods: A systematic review of MEDLINE, the Cochrane Library, EMBASE, CBM, CNKI and other sources using a comprehensive strategy was conducted. All randomized controlled trials (RCTs) of treatment of severe sepsis and septic shock were included. The patients were randomized into treatment group and control group. Preplanned subgroup analysis required studies to be categorized based on early (goal-directed therapy accomplished within 6-24 hours) vs. late (initiated after 24 hours or unknown time of resuscitation implementation). Two authors independently extracted data and assessed study quality using standardized methods. Consensus was reached by conference. The Cochrance Collaboration's software RevMan 5.0 was used for data analysis., Results: Eleven studies were included in the final analysis, providing a sample of 2066 patients. The combined results demonstrated a decrease in mortality [odds ratio (OR) = 0.63, 95% confidence interval (95%CI) 0.48-0.84, P = 0.002]; however, there was statistically significant heterogeneity [P = 0.01, I(2) = 55%]. Among the early optimal resuscitation studies (n = 8) there was minimal heterogeneity [P = 0.44, I(2) = 0%] and a significant decrease in mortality (OR = 0.53, 95%CI 0.42-0.66, P < 0.00001) and incidence of multiple organ dysfunction syndrome (MODS, OR = 0.61, 95%CI 0.43-0.85, P = 0.004). For the late resuscitation studies (n = 3), there was statistically significant difference [P = 0.05, I (2)=66%], and there was no significant effect on mortality (OR = 0.89, 95%CI 0.52-1.54, P = 0.68) and incidence of MODS (OR = 0.43, 95%CI 0.17-1.08, P = 0.07)., Conclusion: This meta-analysis found that the application of an early optimal resuscitation strategy to patients with septic shock imparts a significant reduction in mortality and incidence of MODS.

Objective: To compare the effect of albumin as a resuscitation fluid with other fluids in lowering the mortality of patients with sepsis., Methods: By searching MEDLINE, Embase, Cochrane Central Registration of Controlled Trials databases, the metaRegister of Controlled Trials, the Medical Editors Trial Amnesty Register, and retrieval of the randomized controlled trial (RCT) literature to compare the result of resuscitation using albumin-containing fluid and other fluids. The study population included adult patients who were diagnosed to have sepsis, and the patients with sepsis who were studied as subgroup. The RevMan 5.0 software was used for Meta-analysis, and the main outcome was the mortality of the hospitalized patients., Results: In the 14 RCTs, 1729 patients received the albumin-containing fluid resuscitation or resuscitation with other fluids. It was found that the patients with sepsis were the only research objects in five studies, and in other nine studies patients with sepsis were studied as subgroup. P = 0.98, I (2)=0%, i.e. no heterogenicity, and the fixed effect model was used for combining results. There was no evident difference between the group of patients with sepsis resuscitated by albumin-containing fluids and other fluids [odds ratio (OR) was 0.87, 95% confidence interval (95%CI) 0.71-1.07, P = 0.18]. The pooled OR of resuscitation using high concentration albumin solution (20%) was 1.11, 95%CI 0.71-1.73, P = 0.65, the pooled OR of resuscitation using low concentration albumin solution (4%, 5%) was 0.82, 95%CI 0.65-1.03, P = 0.09. Resuscitation with different concentration of albumin-containing fluids was identical with the whole research results. After rejecting six articles of Boldt and other authors, and also saline versus albumin fluid evaluation (SAFE) study, the sensitivity analysis of the study was performed in order to check whether the data produced decisive significance to the whole research results or not. The whole results did not change after their rejection(Boldt studies were rejected:OR 0.82, 95%CI 0.65-1.02, P = 0.08; SAFE study was rejected: OR 1.05, 95%CI 0.71-1.55, P = 0.82). Therefore the analysis results were satisfactory., Conclusion: The Meta-analysis shows that by using albumin-containing fluids for resuscitation can not lower the mortality of sepsis as compared with other fluids.

Objective: To identify the risk factors of prolonged intensive care unit (ICU) stay of critically ill obstetric patients., Methods: A retrospective analysis of cases of critically ill obstetric patients admitted to the ICUs of Peking University Third Hospital, Capital Medical University Affiliated Beijing Chaoyang Hospital, and PLA 306 Hospital from January 1st 2006 to December 31st 2010 was made. Data included demographics, causes of critical illness or complications that prompted ICU admission, the acute physiology and chronic health evaluation II (APACHEII) scores, the time intervals between onset of acute symptoms and ICU admission, laboratory test results, treatment measures, length of ICU stay and the final maternal mortality. Data were used to identify univariate and multivariate predictors for prolonged ICU stay., Results: During the 5-year period there were 207 obstetric patients [mean age (31.74±2.32) years old, mean gestational age (34.86±4.72) weeks] were transferred to the ICU for critical care (42 ICU admissions per 10 000 deliveries), and among them 4 women died (mortality rate 1.93%). The pathogenesis of the cases could be divided into direct obstetric pathologies (n=138) and indirect or coincidental pathologies (n=69). The most common obstetric causes of admission were massive postpartum haemorrhage (n=42, 20.29%) and pregnancy associated hypertension (n=36, 17.39%), followed by acute fatty liver of pregnancy (AFLP, n=27, 13.04%), obstetric disseminated intravascular coagulation (DIC, n=23, 11.11%). The most common non obstetric causes of admission were acute heart failure (n=26, 12.56%) and acute respiratory failure (n=22, 10.63%), followed by severe acute pancreatitis (SAP, n=11, 5.31%). The incidence of prolonged ICU stay (ICU stay >3 days) was 52.66% (n=109). Univariate predictors of prolonged ICU stay included inadvertent antenatal care, high serum creatinine, abnormal international normalized ratio of prothrombin time (INR), abnormal oxygenation index (PaO(2)/FiO(2)), AFLP, obstetric DIC, SAP, use of mechanical ventilation, indications for inotropic support, and blood purification, and >24 hour interval between onset of acute symptoms and ICU admission. Multivariate modeling identified that inadvertent and irregular antenatal care [odds ratio (OR) 1.68, 95% confidence interval (95%CI) 1.14-2.69, P=0.011], PaO(2)/FiO(2) (OR 4.73, 95%CI 1.46-11.37, P=0.013), AFLP (OR3.21, 95%CI 1.13-4.76, P=0.026), DIC (OR 2.73, 95%CI 1.28-4.02, P=0.018), SAP (OR 4.78, 95%CI 1.83-7.42, P=0.021 ), indications for inotropic support (OR 1.96, 95%CI 1.24-3.15, P=0.001), blood purification (OR 11.02, 95%CI 3.04-58.02, P=0.015) and >24 hour interval between onset of acute symptoms and ICU admission (OR 2.04, 95%CI 1.21-4.25, P<0.001) were the independent predictors for prolonged ICU stay., Conclusion: The incidence of prolonged ICU stay is high for critically ill obstetric patients. Patients with identified multivariate predictors carry a high risk of prolonged ICU stay, they may benefit from enhanced regular antenatal care, prevention of critical obstetric and medical complications, shortening the interval between onset of acute symptoms and ICU admission and strengthening the support of organ function.

Parathyroid hormone (PTH) is a potent anabolic agent, but the cellular mechanisms by which it increases bone mass are not fully understood. Dickkopf 1 (Dkk1) is an endogenous inhibitor of Wnt signaling and suppresses bone formation in vivo. We sought to determine if Dkk1 and anabolic PTH treatment interact in regulating bone mass. PTH treatment of primary murine osteoblasts for 24 h reduced Dkk1 expression by 90% as quantified by real-time PCR, whereas PTH treatment in vivo reduced Dkk1 expression by 30% when given as a single daily subcutaneous dose. To directly determine whether Dkk1 modulates the anabolic response of PTH in vivo, we engineered transgenic (TG) mice expressing murine Dkk1 under the control of the 2.3-kb rat collagen alpha-1 promoter. TG mice had significantly reduced bone mass, which was accompanied by reduced histomorphometric parameters of bone formation (reduced OV/TV, ObS/OS, and NOb/TAR). Treatment of TG mice and wild-type (WT) littermates with 95 ng/g body weight of human (1-34) PTH daily for 34 days resulted in comparable increases in bone mass at all skeletal sites. Histomorphometric analyses indicated that PTH treatment increased the numbers of both osteoblasts and osteoclasts in WT mice but only increased the numbers of osteoblasts in TG mice. We conclude that overexpression of Dkk1 does not attenuate the anabolic response to PTH in vivo.

Background: Previous studies indicated that the time to positivity (TTP) of blood culture is a parameter correlating with degree of the bacteremia and outcome in patients with bloodstream infections caused by Escherichia coli (E. coli). The objective of this study was to further investigate the diagnostic and prognostic power of using TTP to predict E. coli bacteremia., Methods: A retrospective cohort study at two university hospitals was conducted. We retrieved all the medical records of those with E. coli bloodstream infection according to the records generated by their microbiology departments. Univariate and multivariate analyses were applied to identify clinical factors correlating with fast bacterial growth and significant prognostic factors for hospital mortality., Results: Medical records of 353 episodes of E. coli bacteremia diagnosed between January 1, 2007 and December 31, 2009 were retrieved in the investigation. Univariate analysis demonstrated that the TTP ≤ 7 hours group is associated with higher incidence of active malignancies (41.7% vs. 27.2%, P = 0.010), neutropenia (30% vs.14.3%, P = 0.007), primary bacteremia (55.0% vs. 33.4%, P = 0.002), and poorer outcome (hospital mortality 43.3% vs.11.9%, P = 0.000) than the TTP > 7 hours group. Multivariate analysis revealed that the significant predictors of hospital mortality, in rank order from high to low, were TTP (for TTP ≤ 7 hours, odds ratio (OR): 4.886; 95% confidence interval (CI): 2.572 - 9.283; P = 0.000), neutropenia (OR: 2.800; 95%CI: 1.428 - 5.490; P = 0.003), comedication of steroids or immunosuppressive agents (OR: 2.670; 95%CI: 0.971 - 7.342; P = 0.057)., Conclusions: Incidence of malignancies, neutropenia and primary bacteremia correlates with fast bacterial growth in patients with E. coli bacteremia. The parameter of TTP has been identified as a variable of highest correlation to hospital mortality and therefore can be potentially utilized as a mortality prognostic marker.

Objective: To identify the clinical and laboratory parameters correlating with speed of bacterial growth in culture and independent risk factors of in-hospital mortality in patients with Escherichia coli bacteremia., Methods: This retrospective study was conducted at Beijing University Third Hospital. The medical records and microbiological database of the patients diagnosed as Escherichia coli bacteremia between January 2007 and December 2009 were collected. The parameter of time to positivity (TTP) was used to be a surrogate marker of bacterial growth. Univariate analysis was used to identify relationship between clinical parameters and the speed of bacterial growth. Logistic multivariate analysis was used to identify risk factors of in-hospital mortality., Results: The medical records of 112 patients during the study period were collected, 25 patients died during hospital stay, the overall in-hospital mortality rate was 22.3%. Univariate analysis indicated the rapid-growth (TTP≤7 hours) group (n=20) had higher incidence of neutropenia (40.0% vs. 15.2%), higher incidence of primary bacteremia (40.0% vs. 18.5%) and higher in-hospital mortality rate (45.0% vs. 17.4%) than those with slow bacterial growth (TTP>7 hours) group (n =92, all P<0.05). The death group (n=25) was found to have a higher incidence of TTP≤7 hours (36.0% vs. 12.6%), higher incidence of active malignancies (44.0% vs. 24.1%), higher incidence of neutropenia (36.0% vs. 14.9%), higher rate of isolation of extended spectrum β lactamases (ESBL)-producing strains (48.0% vs. 24.1%) than the survival group (n=87, all P<0.05). Logistic multivariate analysis suggested the significant predictors of in-hospital mortality included TTP≤7 hours [odds ratio (OR)=3.412, 95% confidence interval (95% CI)=1.1819.856, P=0.023], ESBL-producing strains (OR=2.545, 95% CI=0.9776.625, P=0.056)., Conclusion: In vitro Escherichia coli growth speed in the blood culture correlates with the incidence of neutropenia and primary bacteremia, and TTP≤7 hours and ESBL-producing strains may be the strong, independent risk factors of a worse prognosis in patients with Escherichia coli bacteremia.

Objective: To explore the prognostic value of brain natriuretic peptide (BNP) level in patients with acute respiratory distress syndrome (ARDS)., Methods: Eighty-six patients with ARDS who had normal left ventricular ejection fraction (LVEF), from January 2004 to May 2009, were studied retrospectively. The baseline characteristics of the patients were recorded. The plasma concentration of BNP and Murray lung injury score (LIS) of the patients with their outcomes, and the relationship between the BNP concentration and LIS were analyzed. The prediction results of death and survival of patients using the cut off points of concentration of BNP and LIS were also analyzed., Results: Eighty-six patients were diagnosed as ARDS.Among those patients with ARDS, 55 patients were dead and 31 patients were survival in 14 days. The proportion of pulmonary hypertension (25.8% vs. 72.7%) and that of using large dose of intravenous norepinephrine (38.7% vs. 94.5%), the time without using mechanical ventilation in 14 days [(8.63+/-3.26) days vs. (0.38+/-0.02) days], BNP concentration [(179.5+/-84.5) ng/L vs. (550.8+/-337.1) ng/L] and LIS (1.37+/-0.65 vs. 2.29+/-0.46) differed significantly between the survivors and the nonsurvivors (P<0.05 or P<0.01). The plasma concentration of BNP had a significant correlation with LIS (r=0.786, P<0.001). By using the threshold value of 329.5 ng/L for BNP, the specificity for the prediction of mortality was 96.8%. The threshold value for LIS of 1.875 showed sensitivity of 80.0%., Conclusion: BNP concentration and LIS were significantly elevated in nonsurvivors than survivors in patients with ARDS who have normal LVEF. High BNP level can predict mortality.

The left ventricular apical systolic dysfunction syndrome was a rare acute cardiac syndrome. Its clinical presentation and electrocardiography were similar to acute myocardial infarction. The syndrome was characterized by transient ventricular wall-motion abnormalities involving the left ventricular apex and mid-ventricle in the absence of obstructive epicardial coronary disease. Cardiac enzyme was normal or minor elevation. At present, the cause of the syndrome is unknown. In this paper, we describe a 56-year-old female patient. She was admitted in hospital for acute appendititis and the transient left ventricular apical ballooning syndrome. She developed acute heart failure and septic shock in the hospital. The drainage of the appendiceal abscess was done and the heart failure and septic shock recovered completely in a few days.

Objective: To investigate the possible effects of recruitment maneuver (RM) imposing on extravascular lung water (EVLW) in patients with acute respiratory distress syndrome (ARDS)., Methods: Twenty patients with ARDS who were eligible for the study were randomized to two groups, one group of which received regular therapy+RM (RM group), and to the other group only regular therapy was given (control group). Mechanical ventilation of all the patients was performed on the principles of lung protective ventilation. RM was carried out in bi-level positive airway passage (BIPAP) mode, and repeated every 8 hours per day until on the 7th day or before weaning of mechanical ventilation. The treatment was same between the two groups except RM. Baseline data and the influencing factors of EVLW were all recorded, which included everyday EVLW, extravascular lung water index (EVLWI) after RM, respiratory mechanics, oxygenation parameters, central venous pressure (CVP), plasma colloid osmotic pressure (COP), dosage of corticosteroid and adrenergic drugs, 24-hour net fluid balance., Results: EVLW and EVLWI in RM and control group showed a tendency of decrease with passage of time, but the difference between both groups had no statistical significance (all P>0.05). The comparisons between the influencing factors of the groups, consisting of CVP, COP, noradrenaline and hydrocortisone, had no significant difference either (all P>0.05). Dopamine dosage in RM group on the 4th day was smaller than that of control group (P<0.05). Net fluid balance in RM group on the 7th day was negative, whereas it was positive in control group (P<0.05). Mean airway pressure [Pmean, RM group (18.8+/-3.2) cm H(2)O (1 cm H(2)O=0.098 kPa) vs. control group (16.6+/-3.9) cm H(2)O] and lung quasi-static compliance [Cstat, RM group (36.5+/-14.5) ml/cm H(2)O vs. control group (29.3+/-12.0) ml/cm H(2)O] in RM group were higher than those in control group (both P<0.05). Cstat on the 5th day was higher than that on the 2nd and 3rd day in RM group (both P<0.05). But oxygenation index (PaO(2)/FiO(2)) showed no distinct difference between the groups (all P>0.05)., Conclusion: RM for the patients with ARDS can merely improve lung mechanics without obvious effect on EVLW. Neither of the influencing factors involved in the study has impact on emergence and clearance of EVLW.

Colony-stimulating factor-1 (CSF1) is one of two cytokines required for normal osteoclastogenesis. There are two major isoforms of CSF1, the cell-surface or membrane-bound isoform (mCSF1) and soluble CSF1 (sCSF1). Whether these isoforms serve nonredundant functions in bone is unclear. To explore this question, we generated transgenic mice expressing human sCSF1, human mCSF1, or both (s/mCSF1) in osteoblasts using the 2.3-kb rat alphaI-collagen promoter. Bone density determined by peripheral quantitative computed tomography was significantly reduced in mCSF1, sCSF1, and s/mCSF1 transgenic mice compared with wild-type animals. When analyzed by sex, sCSF1, and s/mCSF1, female animals but not mCSF1 female mice were found to have greater bone loss than their male littermates (-20 vs. -9.2%; P<0.05 for sCSF1 and -21.6 vs. -11.2% for s/mCSF1; P<0.01). By breeding CSF1 isoform-selective transgenic mice to an op/op background, mice were generated in which a single CSF1 isoform was the only source of the cytokine (sCSF1op/op and mCSF1op/op). Unlike osteoblast-targeted overexpression of mCSF1, selective transgenic expression of sCSF1 did not completely correct the op/op phenotype in 5-mo-old animals. Interestingly, compared with sham-ovariectomized mice of the same genotype, ovariectomy in sCSF1op/op mice led to a greater loss of spinal bone mineral density (22.1%) than was seen in either mCSF1op/op mice (12.9%) or in wild-type animals (10.9%). Our findings support the conclusion that sCSF1 and mCSF1 serve nonredundant functions in bone and that sCSF1 may play a role in mediating estrogen-deficiency bone loss.

Objective: To assess the accuracy of indexes for predicting severe acute pancreatitis (SAP)., Methods: Thirty-nine patients suffering from acute pancreatitis (AP) were randomly selected, including 20 SAP cases and 19 mild acute pancreatitis (MAP) cases. The levels of polymorphonuclear leucocyte-elastase (PMN-E), serum phospholipase A2 (PLA2), pancreatic PLA2 (Pan-PLA2), PLA2 catalytic activity (CA-PLA2), amylase, as well as C-reactive protein (CRP) were determined Acute Physiology and chronic health evaluation II (APACHE II) was scored in every patient. Sensitivity and specificity of all the parameters were assessed, and receiver operator characteristic curve (ROC) was plotted. Positive predictive value, negative predictive value, and overall accuracy were then analyzed., Results: PMN-E, CRP and CA-PLA2 were obviously higher in SAP than in MAP, and were indicative of the severity of the disease (all P < 0.01). Pan-PLA2 and amylase of AP patients raised at the onset of the disease, and they showed no difference between the SAP groups and MAP groups. When SAP was predicted by PMN-E, sensitivity was 94.5%, specificity was 99.4%, positive predictive value was 97.8%, negative predictive value was 99.4%, overall accuracy was 98.7%, higher than other indexes. When SAP was Predicted by CRP, the overall accuracy was also high and reached 84.0%., Conclusion: PMN-E, CA-PLA2, CRP, and APACHE II are all indexes for the diagnosis of SAP. PMN-E is found to be the best index in predicting SAP.

Objective: To investigate incidence, causes and mortality of acute respiratory distress syndrome (ARDS) in intensive care units (ICU) in Beijing., Methods: Patients in ICU of eight general hospitals in Beijing from May 1998 to April 2003 were retrospectively studied. ARDS was diagnosed according to the 1994 American-European consensus conference criteria. Results Of 8 482 patients admitted to ICUs in the same period, there were 383 patients (4.5%) diagnosed as having ARDS. Major primary diseases for ARDS were sepsis (21.7%), pneumonia (16.2%), surgical operation (13.1%), acute pancreatitis (12.8%) and multiple severe trauma (10.7%). The mean interval between onset of the primary disease and onset of ARDS was (61.8 +/- 43.7) hours. The overall mortality of ARDS was 52.0%, the mortality adjusted for age (< or =39, 40-64, > or =65 years old) and gender (male) showed significant changes in each year (all P<0.05), but acute physiology and chronic health evaluation II (APACHE II, < or =12, 13-19, > or =20 scores) score showed no significant changes during the 5 years. Septic shock (36.2%) and heart failure (20.6%) were major lethal causes, while only 14.6% died of respiratory failure., Conclusion: ARDS was frequent in ICU in Beijing, the mortality remains high, and there is no tendency to decline in recent years.

The complete genetic absence of colony stimulating factor 1 (CSF1) in CSF1-deficient Csf1(op)/Csf1(op) mice leads to reproductive defects in males and females. Although the cell-surface or membrane-bound isoform of CSF1 (mCSF1) is biologically active in bone, little is known about its role in reproduction. Transgenic mice expressing mCSF1 under the control of the 2.4-kb rat collagen type I alpha promoter were developed [Tg(Col1a1-mCSF1)1Gqy] and bred onto a Csf1(op)/Csf1(op) background [Csf1(op)/Csf1(op); Tg(Col1a1-mCSF1)1Gqy] to examine the effects of the mCSF1 isoform in bone in vivo. Surprisingly, when interbred, these mice were fertile. The Csf1(op)/Csf1(op); Tg(Col1a1-mCSF1)1Gqy transgenic male mice have normal libido, sperm number and percent of motile sperm. In Csf1(op)/Csf1(op); Tg(Col1a1-mCSF1)1Gqy females, puberty and estrus cycles are at expected age and duration. Further, females are able to carry pregnancies to term and nurse their offspring. Crosses of Csf1(op)/Csf1(op); Tg(Col1a1-mCSF1)1Gqy males or females with their control littermates showed no significant differences in either number or viability of offspring. However, crossing Csf1(op)/Csf1(op); Tg(Col1a1-mCSF1)1Gqy males with Csf1(op); Tg(Col1a1-mCSF1)1Gqy females resulted in a decline in both the number and viability of offspring, suggesting that a subtle reproductive defect might persist in the transgenic animals that was only manifest when the animals were interbred. Although the gravid murine uterus expresses extremely high levels of CSF1 that are thought to be important for reproduction, uterine tissue levels of CSF1 remained low and unchanged during pregnancy in Csf1(op)/Csf1(op); Tg(Col1a1-mCSF1)1Gqy mice. Low levels of CSF1 protein were detected in serum and in lung and uterine tissue in Csf1(op)/Csf1(op); Tg(Col1a1-mCSF1)1Gqy mouse, which likely result from the known proteolytic shedding of mCSF1 from the cell surface. These data are consistent with the conclusion that mCSF1, when shed from the cell surface, can support reproduction and that high uterine tissue levels of CSF1 may not be required for mouse reproduction.