Tina Mele

Early mobilization in the critical care unit: A review of adult and pediatric literature.

Early mobilization of critically ill patients is beneficial, suggesting that it should be incorporated into daily clinical practice. Early passive, active, and combined progressive mobilizations can be safely initiated in intensive care units (ICUs). Adult patients receiving early mobilization have fewer ventilator-dependent days, shorter ICU and hospital stays, and better functional outcomes. Pediatric ICU data are limited, but recent studies also suggest that early mobilization is achievable without increasing patient risk. In this review, we provide a current and comprehensive appraisal of ICU mobilization techniques in both adult and pediatric critically ill patients. Contraindications and perceived barriers to early mobilization, including cost and health care provider views, are identified. Methods of overcoming barriers to early mobilization and enhancing sustainability of mobilization programs are discussed. Optimization of patient outcomes will require further studies on mobilization timing and intensity, particularly within specific ICU populations.

TLR2 signalling: At the crossroads of commensalism, invasive infections and toxic shock syndrome by Staphylococcus aureus.

Although up to 60% of the population at any one time carry Staphylococcus aureus (S. aureus) without significant clinical consequences, infections by S. aureus are a major health care threat in the Western world. The underlying mechanisms that determine this two-sided interaction between S. aureus and the human immune system are unknown. Work on the pathogenesis of S. aureus infections and toxic shock syndrome may provide unexpected clues to understand the duality of such an interaction. Recent evidence suggests that the cell wall of S. aureus contains peptidoglycan-embedded TLR2 ligands that not only act as pathogen-associated molecular patterns, which trigger pro-inflammatory innate immune responses, but also can act as anti-inflammatory modulators of the pathogenicity by this microbe and its toxins. Here, we discuss this theme in the context of staphylococcal toxic shock syndrome and explore its implications on the development of therapeutic strategies to prevent and treat S. aureus infections.

Cardiac fibroblasts contribute to myocardial dysfunction in mice with sepsis: the role of NLRP3 inflammasome activation.

Myocardial contractile dysfunction in sepsis is associated with the increased morbidity and mortality. Although the underlying mechanisms of the cardiac depression have not been fully elucidated, an exaggerated inflammatory response is believed to be responsible. Nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome is an intracellular platform that is involved in the maturation and release of interleukin (IL)-1β. The aim of the present study is to evaluate whether sepsis activates NLRP3 inflammasome/caspase-1/IL-1β pathway in cardiac fibroblasts (CFs) and whether this cytokine can subsequently impact the function of cardiomyocytes (cardiac fibroblast-myocyte cross-talk). We show that treatment of CFs with lipopolysaccharide (LPS) induces upregulation of NLRP3, activation of caspase-1, as well as the maturation (activation) and release of IL-1β. In addition, the genetic (small interfering ribonucleic acid [siRNA]) and pharmacological (glyburide) inhibition of the NLRP3 inflammasome in CFs can block this signaling pathway. Furthermore, the inhibition of the NLRP3 inflammasome in cardiac fibroblasts ameliorated the ability of LPS-chalenged CFs to impact cardiomyocyte function as assessed by intracellular cyclic adenosine monophosphate (cAMP) responses in cardiomyocytes. Salient features of this the NLP3 inflammasome/ caspase-1 pathway were confirmed in in vivo models of endotoxemia/sepsis. We found that inhibition of the NLRP3 inflammasome attenuated myocardial dysfunction in mice with LPS and increased the survival rate in mice with feces-induced peritonitis. Our results indicate that the activation of the NLRP3 inflammasome in cardiac fibroblasts is pivotal in the induction of myocardial dysfunction in sepsis.

Intestinal obstruction as a complication of Kawasaki disease.

Kawasaki disease is a syndrome characterized by multiple organ system inflammation and diffuse arteritis. Although gastrointestinal complications have been described, bowel obstruction rarely has been reported. The authors describe the case of a 1-year-old girl with Kawasaki disease who, after her acute illness, returned with mechanical bowel obstruction. During laparotomy, complete obstruction was found at the level of the jejunum, and resection was performed. Pathological examination of the resected specimen confirmed complete luminal obstruction with proliferation of granulation tissue, findings compatible with ischemic enteritis.

Establishment of duodenojejunal bypass surgery in mice: A model designed for diabetic research

We have developed a mouse duodenojejunal bypass (DJB) surgical model that is for studying the effects of bariatric surgery on glucose homeostasis and has potential to impact clinical therapy of diabetes. The operation consists of using the majority of the duodenum and proximal part of the jejunum for biliopancreatic diversion. The distal end of the jejunum is anastomosed in an end‐to‐end fashion to the remaining proximal end of the duodenum just distal to the pylorus. The biliopancreatic secretions are diverted into the distal jejunum through an end‐to‐side anastomosis. We performed 10 DJB operations in C57BL/6 mice, with a 100% survival rate. The surgery had no effect on the growth or feeding patterns of the animals. The intestinal mucosa showed normal histology and function. This study confirms that it is technically possible to perform DJB surgery in mice. This mouse model can be used in the study of surgical treatment for type II diabetes.

Induction of acute lung inflammation in mice with hemorrhagic shock and resuscitation: role of HMGB1

BackgroundHemorrhagic shock and resuscitation (HS/R) can induce multiple organ failure which is associated with high mortality. The lung is an organ commonly affected by the HS/R. Acute lung injury is a major cause of dysfunction in other organ systems. The objective of this study is to test the hypothesis that HS/R causes increased gut permeability which results in induction of high mobility group box1 protein (HMGB1) and further leads to the development of acute lung inflammation.Materials and methodsA mouse model of HS/R was employed in this study. Gut permeability and bacterial translocation were assessed with circulating FD4 and lipopolysaccharide (LPS). Circulating HMGB1 was determined with ELISA. Acute lung inflammation (ALI) was determined with lung myeloperoxidase (MPO) activity and pulmonary protein leakage.ResultsHS/R induced intestinal barrier dysfunction as evidenced by increased circulating FD4 and LPS at 30 min and 2 hrs after resuscitation, respectively. In addition, circulating HMGB1 levels were increased in mice with HS/R as compared with sham animals (p < 0.05). HS/R resulted in ALI (increased lung MPO activity and pulmonary protein leakage in mice with HS/R compared with sham mice, p < 0.05). Inhibition of HMGB1 (A-box and TLR4-/-) attenuated the ALI in mice with HS/R. However, inhibition of HMGB1 did not show protective effect on gut injury in early phase of HS/R in mice.ConclusionsOur results suggest that induction of HMGB1 is important in hemorrhagic shock and resuscitation-induced acute lung inflammation.

Mucosa-associated invariant T cells infiltrate hepatic metastases in patients with colorectal carcinoma but are rendered dysfunctional within and adjacent to tumor microenvironment.

Mucosa-associated invariant T (MAIT) cells are innate-like T lymphocytes that are unusually abundant in the human liver, a common site of colorectal carcinoma (CRC) metastasis. However, whether they contribute to immune surveillance against colorectal liver metastasis (CRLM) is essentially unexplored. In addition, whether MAIT cell functions can be impacted by chemotherapy is unclear. These are important questions given MAIT cells’ potent immunomodulatory and inflammatory properties. Herein, we examined the frequencies and functions of peripheral blood, healthy liver tissue, tumor-margin and tumor-infiltrating MAIT cells in 21 CRLM patients who received no chemotherapy, FOLFOX, or a combination of FOLFOX and Avastin before they underwent liver resection. We found that MAIT cells, defined as CD3ε+Vα7.2+CD161++ or CD3ε+MR1 tetramer+ cells, were present within both healthy and tumor-afflicted hepatic tissues. Paired and grouped analyses of samples revealed the physical proximity of MAIT cells to metastatic lesions to drastically influence their functional competence. Accordingly, unlike those residing in the healthy liver compartment, tumor-infiltrating MAIT cells failed to produce IFN-γ in response to a panel of TCR and cytokine receptor ligands, and tumor-margin MAIT cells were only partially active. Furthermore, chemotherapy did not account for intratumoral MAIT cell insufficiencies. Our findings demonstrate for the first time that CRLM-penetrating MAIT cells exhibit wide-ranging functional impairments, which are dictated by their physical location but not by preoperative chemotherapy. Therefore, we propose that MAIT cells may provide an attractive therapeutic target in CRC and that their ligands may be combined with chemotherapeutic agents to treat CRLM.

Growth Differentiation Factor-15 Deficiency Augments Inflammatory Response and Exacerbates Septic Heart and Renal Injury Induced by Lipopolysaccharide

Septic acute kidney injury (AKI) and myocardial dysfunction are leading causes of mortality with no accepted method of therapy. In this study we demonstrate the role of growth differentiating factor 15 (GDF15) in septic AKI and myocardial dysfunction using a murine lipopolysaccharide (LPS)-induced sepsis model and an in vitro cell culture system. Data show that GDF15 deficiency augments inflammatory response and exacerbates renal and cardiac injury induced by LPS, while over-expression of GDF15 protects the kidney and heart from LPS-induced organ dysfunction. Therefore, this study highlights the therapeutic potential of GDF15 in the treatment of endotoxin-induced sepsis.

Acute care surgery: a means for providing cost-effective, quality care for gallstone pancreatitis

BackgroundModern practice guidelines recommend index cholecystectomy (IC) for patients admitted with gallstone pancreatitis (GSP). However, this benchmark has been difficult to widely achieve. Previous work has demonstrated that dedicated acute care surgery (ACS) services can facilitate IC. However, the associated financial costs and economic effectiveness of this intervention are unknown and represent potential barriers to ACS adoption. We investigated the impact of an ACS service at two hospitals before and after implementation on cost effectiveness, patient quality-adjusted life years (QALY) and impact on rates of IC.MethodsAll patients admitted with non-severe GSP to two tertiary care teaching hospitals from January 2008–May 2015 were reviewed. The diagnosis of GSP was confirmed upon review of clinical, biochemical and radiographic criteria. Patients were divided into three time periods based on the presence of ACS (none, at one hospital, at both hospitals). Data were collected regarding demographics, cholecystectomy timing, resource utilization, and associated costs. QALY analyses were performed and incremental cost effectiveness ratios were calculated comparing pre-ACS to post-ACS periods.ResultsIn 435 patients admitted for GSP, IC increased from 16 to 76% after implementing an ACS service at both hospitals. There was a significant reduction in admissions and emergency room visits for GSP after introduction of ACS services (p < 0.001). There was no difference in length of stay or conversion to an open operation. The implementation of the ACS service was associated with a decrease in cost of

Over-expression of growth differentiation factor 15 (GDF15) preventing cold ischemia reperfusion (I/R) injury in heart transplantation through Foxo3a signaling

1162 per patient undergoing cholecystectomy, representing a 12.6% savings.The time period with both hospitals having established ACS services resulted in a highly favorable cost to quality-adjusted life year ratio (QALY gained and financial costs decreased).ConclusionsACS services facilitate cost-effective management of GSP. The result is improved and timelier patient care with decreased healthcare costs. Hospitals without a dedicated ACS service should strongly consider adopting this model of care.