Infection control implications of heterogeneous resistance mechanisms in carbapenem-resistant Enterobacteriaceae (CRE)

The Centers for Disease Control and Prevention (CDC) defines carbapenem-resistant Enterobacteriaceae (CRE) based upon a phenotypic demonstration of carbapenem resistance. However, considerable heterogeneity exists within this definitional umbrella. CRE may mechanistically differ by whether they do or do not produce carbapenemases. Moreover, patients can acquire CRE through multiple pathways: endogenously through antibiotic selective pressure on intestinal microbiota, exogenously through horizontal transmission or through a combination of these factors. Some evidence suggests that non-carbapenemase-producing CRE may be more frequently acquired by antibiotic exposure and carbapenemase-producing CRE via horizontal transmission, but definitive data are lacking. This review examines types of CRE resistance mechanisms, antibiotic exposure and horizontal transmission pathways of CRE acquisition, and the implications of these heterogeneities to the development of evidence-based CRE healthcare epidemiology policies. In our Expert Commentary & Five-Year View, we outline specific nosocomial CRE knowledge gaps and potential methodological approaches for their resolution.     

Sub-chronic agmatine treatment modulates hippocampal neuroplasticity and cell survival signaling pathways in mice

Agmatine is an endogenous neuromodulator which, based on animal and human studies, is a putative novel antidepressant drug. In this study, we investigated the ability of sub-chronic (21 days) p.o. agmatine administration to produce an antidepressant-like effect in the tail suspension test and examined the hippocampal cell signaling pathways implicated in such an effect. Agmatine at doses of 0.01 and 0.1 mg/kg (p.o.) produced a significant antidepressant-like effect in the tail suspension test and no effect in the open-field test. Additionally, agmatine (0.001–0.1 mg/kg, p.o.) increased the phosphorylation of protein kinase A substrates (237–258% of control), protein kinase B/Akt (Ser⁴⁷³) (116–127% of control), glycogen synthase kinase-3β (Ser⁹) (110–113% of control), extracellular signal-regulated kinases 1/2 (119–137% and 121–138% of control, respectively) and cAMP response elements (Ser¹³³) (127–152% of control), and brain-derived-neurotrophic factor (137–175% of control) immunocontent in a dose-dependent manner in the hippocampus. Agmatine (0.001–0.1 mg/kg, p.o.) also reduced the c-jun N-terminal kinase 1/2 phosphorylation (77-71% and 65-51% of control, respectively). Neither protein kinase C nor p38^MAPK phosphorylation was altered under any experimental conditions. Taken together, the present study extends the available data on the mechanisms that underlie the antidepressant action of agmatine by showing an antidepressant-like effect following sub-chronic administration. In addition, our results are the first to demonstrate the ability of agmatine to elicit the activation of cellular signaling pathways associated with neuroplasticity/cell survival and the inhibition of signaling pathways associated with cell death in the hippocampus.     

床旁血滤联合BiPAP无创机械通气治疗难治性终末期心衰效果观察

目的探讨床旁血液滤过(CRRT)联合Bi PAP无创机械通气治疗顽固性心力衰竭的临床治疗效果。方法根据治疗方法不同将我院300例顽固性心力衰竭患者分为两组,均给予标准药物治疗,对照组143例加用Bi PAP无创机械通气治疗、研究组157例应用连续性CRRT联合Bi PAP无创机械通气治疗,观察治疗前后两组患者的生命体征、NT-pro-BNP、左室射血分数、血肌酐、动脉氧分压等指标的变化和治疗效果。结果对照组治疗前后NT-pro-BNP值分别为(1 996±63.7)pg/ml和(875±29.4)pg/ml,研究组分别为(2 096±62.8)pg/ml、(565±30.0)pg/ml;两组患者治疗后NT-pro-BNP值均明显降低,与治疗前比较差异均有统计学意义(P<0.01),研究组疗效更佳;对照组治疗前后血氧分压分别为(69.96±6.37)mm Hg和(87.5±2.94)mm Hg,研究组分别为(68.86±6.28)mm Hg和(92.5±3.00)mm Hg;两组患者治疗后血氧分压值均明显升高,与治疗前比较差异均有统计学意义(P<0.01);研究组患者治疗后血氧分压值明显低于对照组,且两组间比较差异有统计学意义(P<0.01);对照组治疗前后肌酐值分别为(199.6±63.7)μmol/L和(87.5±2.94)μmol/L,研究组分别为(198.6±62.8)μmol/L和(76.5±3.00)μmol/L,两组患者治疗后血肌酐值均明显降低,与治疗前比较差异均有统计学意义(P<0.01);研究组患者治疗后血肌酐值明显低于对照组,且两组间比较差异有统计学意义(P<0.05);研究组患者治疗后胸片渗出水肿改变及心脏彩超改变有效率为84.7%,对照组为71.3%,两组间比较差异有统计学意义(P<0.05);研究组患者治疗后呼吸困难症状及心功能分级及活动能力有效率为82.8%,对照组为69.9%,两组间比较差异有统计学意义(P<0.05);研究组患者生存率为86.0%,对照组为76.9%,两组患者生存率比较差异有统计学意义(P<0.05)。结论床旁血液滤过联合Bi PAP无创机械通气治疗能有效缓解顽固性心力衰竭的临床症状,改善心功能,提高了抢救成功率,是一种积极、安全、有效地新型治疗方法。     

Amphiregulin: an early trigger of liver regeneration in mice

BACKGROUND AND AIMS: Liver regeneration is a unique response directed to restore liver mass after resection or injury. The survival and proliferative signals triggered during this process are conveyed by a complex network of cytokines and growth factors acting in an orderly manner. Activation of the epidermal growth factor receptor is thought to play an important role in liver regeneration. Amphiregulin is a member of the epidermal growth factor family whose expression is not detectable in healthy liver. We have investigated the expression of amphiregulin in liver injury and its role during liver regeneration after partial hepatectomy. METHODS: Amphiregulin gene expression was examined in healthy and cirrhotic human and rat liver, in rodent liver regeneration after partial hepatectomy, and in primary hepatocytes. The proliferative effects and intracellular signaling of amphiregulin were studied in isolated hepatocytes. The in vivo role of amphiregulin in liver regeneration after partial hepatectomy was analyzed in amphiregulin-null mice. RESULTS: Amphiregulin gene expression is detected in chronically injured human and rat liver and is rapidly induced after partial hepatectomy in rodents. Amphiregulin expression is induced in isolated hepatocytes by interleukin 1beta and prostaglandin E(2), but not by hepatocyte growth factor, interleukin 6, or tumor necrosis factor alpha. We show that amphiregulin behaves as a primary mitogen for isolated hepatocytes, acting through the epidermal growth factor receptor. Finally, amphiregulin-null mice display impaired proliferative responses after partial liver resection. CONCLUSIONS: Our findings indicate that amphiregulin is an early-response growth factor that may contribute to the initial phases of liver regeneration.     

Multipotent progenitors resident in the skeletal muscle interstitium exhibit robust BMP-dependent osteogenic activity and mediate heterotopic ossification

Heterotopic ossification is a debilitating condition that can result from traumatic injury, surgery, or genetic disease. We investigated the cellular origins of heterotopic skeletogenesis in the mouse using lineage tracing and bioassays of heterotopic ossification based on intramuscular transplantation. We identified, characterized, and purified a tissue-resident stem/progenitor cell population that exhibits robust osteogenic potential and represents a major cell-of-origin for heterotopic ossification. These progenitors reside in the interstitium of skeletal muscle and other tissues, and are distinct from the endothelium, which does not exhibit osteogenic activity in response to bone morphogenetic protein 2 (BMP2) stimulation. Intramuscular transplantation, together with clonal analysis in culture, revealed that these progenitors are multipotent, exhibiting the capacity for both BMP-dependent skeletogenic differentiation and spontaneous adipogenic differentiation. Identifying the cells-of-origin responsible for heterotopic ossification provides a potential therapeutic target to treat, mitigate, or prevent this disabling condition.     

Changes in the prevalence of causative pathogens isolated from severe burn patients from 2012 to 2017

Infection is the leading cause of mortality in severe burn patients, benefitting from periodic monitoring of changes in bacterial prevalence and antibiotic resistance trends. This single facility retrospective study evaluated blood culture results for patients hospitalized in the burn intensive care unit (BICU) from January 2012 to December 2017. A total of 969 samples from 420 patients were reviewed. Isolated pathogens were recorded by year and the number of days of hospitalization. Results showed that Acinetobacter baumanni was the most predominant isolated pathogen, followed closely by Pseudomonas aeruginosa, Klebsiella spp., and Enterococcus spp. Throughout this 6-year study, several significant trends were noted; Klebsiella species increased, while P. aeruginosa decreased. Staphylococcus aureus and Klebsiella species gradually increased, and P. aeruginosa doubled as the length of hospital stay increased to 22 days. Interestingly, as the length of the hospital stay increased, the proportion of Carbapenem-resistant Enterobacteriaceae (CRE) significantly increased up to 45.0% at 22 days (P = 0.003). Conversely, the proportion of Acinetobacter baumannii gradually decreased as the days hospitalized increased. Overall, the rate of multidrug-resistant (MDR) bacteremia found in burn patients was substantially higher than that in other patients and appeared from the earliest phase of hospitalization. Therefore, early use of antibiotics targeting MDR Gram-negative bacteria in burn patients admitted to the BICU might be warranted. Further, since CRE infections increase in abundance over time, significant effort should be made to manage the initial CRE infections of burn patients before they can multiply into a life-threatening situation.     

IFT80 Is Required for Fracture Healing Through Controlling the Regulation of TGF-β Signaling in Chondrocyte Differentiation and Function

Primary cilia are essential cellular organelles that are anchored at the cell surface membrane to sense and transduce signaling. Intraflagellar transport (IFT) proteins are indispensable for cilia formation and function. Although major advances in understanding the roles of these proteins in bone development have been made, the mechanisms by which IFT proteins regulate bone repair have not been identified. We investigated the role of the IFT80 protein in chondrocytes during fracture healing by creating femoral fractures in mice with conditional deletion of IFT80 in chondrocytes utilizing tamoxifen inducible Col2α1-CreER mice. Col2α1^creIFT80^f/f mice had smaller fracture calluses than IFT80^f/f (control) mice. The max-width and max-callus area were 31% and 48% smaller than those of the control mice, respectively. Col2α1^creIFT80^f/f mice formed low-density/porous woven bony tissue with significantly lower ratio of bone volume, Trabecular (Tb) number and Tb thickness, and greater Tb spacing compared to control mice. IFT80 deletion significantly downregulated the expression of angiogenesis markers-VEGF, PDGF and angiopoietin and inhibited fracture callus vascularization. Mechanistically, loss of IFT80 in chondrocytes resulted in a decrease in cilia formation and chondrocyte proliferation rate in fracture callus compared to the control mice. Meanwhile, IFT80 deletion downregulated the TGF-β signaling pathway by inhibiting the expression of TGF-βI, TGF-βR, and phosphorylation of Smad2/3 in the fracture callus. In primary chondrocyte cultures in vitro, IFT80 deletion dramatically reduced chondrocyte proliferation, cilia assembly, and chondrogenic gene expression and differentiation. Collectively, our findings demonstrate that IFT80 and primary cilia play an essential role in fracture healing, likely through controlling chondrocyte proliferation and differentiation, and the TGF-β signaling pathway. © 2019 American Society for Bone and Mineral Research.     

Dullard/Ctdnep1 Regulates Endochondral Ossification via Suppression of TGF‐β Signaling

Transforming growth factor (TGF)‐β signaling plays critical roles during skeletal development and its excessive signaling causes genetic diseases of connective tissues including Marfan syndrome and acromelic dysplasia. However, the mechanisms underlying prevention of excessive TGF‐β signaling in skeletogenesis remain unclear. We previously reported that Dullard/Ctdnep1 encoding a small phosphatase is required for nephron maintenance after birth through suppression of bone morphogenetic protein (BMP) signaling. Unexpectedly, we found that Dullard is involved in suppression of TGF‐β signaling during endochondral ossification. Conditional Dullard‐deficient mice in the limb and sternum mesenchyme by Prx1‐Cre displayed the impaired growth and ossification of skeletal elements leading to postnatal lethality. Dullard was expressed in early cartilage condensations and later in growth plate chondrocytes. The tibia growth plate of newborn Dullard mutant mice showed reduction of the proliferative and hypertrophic chondrocyte layers. The sternum showed deformity of cartilage primordia and delayed hypertrophy. Micromass culture experiments revealed that Dullard deficiency enhanced early cartilage condensation and differentiation, but suppressed mineralized hypertrophic chondrocyte differentiation, which was reversed by treatment with TGF‐β type I receptor kinase blocker LY‐364947. Dullard deficiency induced upregulation of protein levels of both phospho‐Smad2/3 and total Smad2/3 in micromass cultures without increase of Smad2/3 mRNA levels, suggesting that Dullard may affect Smad2/3 protein stability. The phospho‐Smad2/3 level was also upregulated in perichondrium and hypertrophic chondrocytes in Dullard‐deficient embryos. Response to TGF‐β signaling was enhanced in Dullard‐deficient primary chondrocyte cultures at late, but not early, time point. Moreover, perinatal administration of LY‐364947 ameliorated the sternum deformity in vivo. Thus, we identified Dullard as a new negative regulator of TGF‐β signaling in endochondral ossification. © 2014 American Society for Bone and Mineral Research.