Reduction of Venous Thromboembolism in Surgical Patients Using a Mandatory Risk-Scoring System: 5-Year Follow-Up of an American College of Surgeons National Surgical Quality Improvement Program.

BACKGROUND: Sheikh Khalifa Medical City's (SKMC) surgery institute was identified as a high outlier in the incidence of venous thromboembolism (VTE; deep vein thrombosis [DVT] and pulmonary embolism [PE]) based on the semiannual report of the American College of Surgeon's National Surgical Quality Improvement Program (ACS NSQIP) in June 2010. AIM: To report our rates of VTE at SKMC, the results, and 5-year follow-up after an ACS NSQIP quality improvement program. METHODS: A multidisciplinary VTE task force was established in June 2010. We instituted a compulsory risk assessment for VTE and utilized the ACS NSQIP best practice guidelines to review cases of VTE. We prospectively evaluated the observed/expected (O/E) ratio for DVT/PE after implementing the action plan. RESULTS: The O/E ratio for PE/DVT in general and general/vascular (GV) surgery was 6.00 and 4.86 in June 2010. Our compliance with ordering antithrombotic prophylactic measures was as low and it improved to 100% and our O/E ratio decreased to 1.18 and 1.5 in July 2011 and stabilized for the next 4 years. Currently, our compliance with ordering antithrombotic prophylactic measures is 100%, and our last 2 O/E ratio for DVT/PE are 0.74 and 0.75 in GV surgery and 0.82 and 0.78 in the entire surgery institute, respectively, and we are considered an exemplary site of the ACS NSQIP in GV surgery. CONCLUSION: A compulsory risk assessment for VTE has led to an overall improvement in DVT/PE rates in the surgery institute and for GV surgery to become an exemplary site for the ACS NSQIP.

Screening colonoscopy in the initial workup of bariatric surgery patients: guidelines are needed.

BACKGROUND: Cancer is one of the most common causes of death among morbidly obese individuals. Obese individuals have a well-documented increased risk of colon cancer. No guidelines are available for the workup of bariatric surgery patients in relation to colon cancer. METHODS: The indications for screening colonoscopy at the Bariatric and Metabolic Institute Abu Dhabi (BMI Abu Dhabi) include all patients older than 50 years [40 years if patients are United Arab Emirates (UAE) nationals] with unexplained abdominal symptoms, anemia of unknown cause, or a family or personal history of colonic pathology. This study retrospectively reviewed the charts of all the patients who had colonoscopy during the period January 2009 to January 2013. The patients were divided into two groups: group A [patients with a body mass index (BMI) > 30 kg/m(2)] and group B (patients with a BMI < 30 kg/m(2)). The demographics and the prevalence of polyps and cancer in the two groups were compared. RESULTS: During the study period, 341 colonoscopies were performed: 137 for patients with a BMI higher than 30 kg/m(2) (mean age, 44 years) and 204 for patients with a BMI lower than 30 kg/m(2) (mean age, 46 years) (P > 0.05). The overall prevalence of adenomatous polyps was 6.74 % and that of cancer was 1.75 %. Further analysis showed that the prevalences of adenomatous polyps and cancer were respectively 12.4 and 2.1 % for the patients with a BMI higher than 30 kg/m(2), whereas the prevalences were respectively 2.9 and 0.9 % for the patients with BMI lower than 30 kg/m(2) (P < 0.001). CONCLUSION: The risk for the development of colonic adenomatous polyps and cancer is high among young obese individuals in the Middle East. Guidelines are needed to establish criteria for screening in this group of individuals.

Are results of bariatric surgery different in the Middle East? Early experience of an international bariatric surgery program and an ACS NSQIP outcomes comparison.

BACKGROUND: Bariatric operations performed at the Bariatric and Metabolic Institute Abu Dhabi are submitted randomly from the entire surgery volume at Sheikh Khalifa Medical City to the American College of Surgeons (ACS) NSQIP. Our aim is to report our early experience and compare our bariatric surgery outcomes with ACS NSQIP hospitals of similar size. STUDY DESIGN: We queried the ACS NSQIP database for bariatric surgery codes between August 2009 and August 2012 for hospitals with >500 beds. Statistical analysis was performed (p < 0.05). RESULTS: We performed 275 bariatric operations compared with a total of 29,715 at other NSQIP hospitals. The ACS NSQIP bariatric surgery cohort at the Bariatric and Metabolic Institute Abu Dhabi represents 275 of 312 (89.3%) of our entire bariatric surgery volume. Our patients were statistically significantly younger (mean age 36 vs 44.8 years), healthier (American Society of Anesthesiologists scores 1 to 2 in 78.6% vs 35.7%), and heavier (body mass index 47.4 vs 45.5). In addition, we had fewer diabetic (18.5% vs 27.3%) and hypertensive (21.1% vs 52.2%) patients. We performed more Roux-en-Y gastric bypass (69.8% vs 54.5%) and sleeve gastrectomy (24.8% vs 17.2%) and fewer laparoscopic adjustable gastric banding (0.8% vs 22.7%). Outcomes were similar with regard to rates of reoperation, wounds, urinary tract infection, bleeding, thromboembolic, respiratory, and overall complications. We had lower septic, cardiac, and renal failure complications; lower mortality, and longer hospital stay by 0.4 days. We achieved 94.9% 30-day follow-up compared with 90.7% at other ACS NSQIP hospitals. CONCLUSIONS: This is the first report comparing outcomes of an international bariatric surgery program (Bariatric and Metabolic Institute Abu Dhabi) with ACS NSQIP bariatric surgery programs. Our outcomes are equivalent to ACS NSQIP bariatric surgery programs.

Central nervous system Toll-like receptor expression in response to Theiler's murine encephalomyelitis virus-induced demyelination disease in resistant and susceptible mouse strains.

BACKGROUND: In immunopathological diseases, such as multiple sclerosis (MS), genetic and environmental factors that contribute to the initiation and progression of the disease are often discussed. The Theiler murine encephalomyelitis virus-induced demyelination disease (TMEV-IDD) model used to study MS reflects this: genetically susceptible mice infected intra-cerebrally with TMEV develop a chronic demyelination disease. TMEV-IDD can be induced in resistant mouse strains by inducing innate immunity with lipopolysaccharide (LPS). Interestingly, Toll-like receptor 4 (TLR4) is the cognate receptor for LPS and its activation can induces up-regulation of other TLRs, such as TLR7 (the receptor for TMEV) and 9, known to be involved in autoimmunity. Up-regulation of TLRs could be involved in precipitating an autoimmune susceptible state. Consequently, we looked at TLR expression in the susceptible (SJL/J) and resistant (C57BL/6) strains of mice infected with TMEV. The resistant mice were induced to develop TMEV-IDD by two LPS injections following TMEV infection. RESULTS: Both strains were found to up-regulate multiple TLRs (TLR2, 7 and 9) following the TMEV infection. Expression of these TLRs and of viral mRNA was significantly greater in infected SJL/J mice. The susceptible SJL/J mice showed up-regulation of TLR3, 6 and 8, which was not seen in C57BL/6 mice. CONCLUSION: Expression of TLRs by susceptible mice and the up-regulation of the TLRs in resistant mice could participate in priming the mice toward an autoimmune state and develop TMEV-IDD. This could have implications on therapies that target TLRs to prevent the emergence of conditions such as MS in patients at risk for the disease.

Irradiation does not compromise or exacerbate the innate immune response in the brains of mice that were transplanted with bone marrow stem cells.

Microglia and invading macrophages play key roles in the brain immune response. The contributions of these two populations of cells in health and diseases have yet to be clearly established. The use of chimeric mice receiving bone marrow-derived stem cell grafts from green fluorescent protein (GFP)-expressing mice has provided an invaluable tool to distinguish between local and blood-derived monocytic populations. The validity of the method is questioned because of the possible immune alterations caused by the irradiation of the recipient mouse. In this experiment, we compared the brain expression of innate immune markers Toll-like receptor 2, interleukin-1 beta, tumor necrosis factor-alpha, and monocyte chemoattractant protein-1 in C57BL/6, GFP, and chimeric mice following an intracerebral injection of lipopolysaccharide. The endotoxin caused a marked transcriptional activation of all these innate immune genes in microglial cells across the ipsilateral side of injection. The expression patterns and signal intensity were similar in the brains of the three groups of mice. Consequently, the chimera technique is appropriate to study the role of infiltrating and resident immune cells in the brain without having immune compromised hosts. Disclosure of potential conflicts of interest is found at the end of this article.

Tumor necrosis factor alpha but not interleukin 1 beta mediates neuroprotection in response to acute nitric oxide excitotoxicity.

Neurodegenerative processes in the brain are accompanied by activation of innate immunity, which involves the release of proinflammatory cytokines by microglia and infiltrating macrophages. The beneficial or detrimental roles of these cytokines, including interleukin 1beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha), remain to be clarified. These cytokines have numerous overlapping activities that make it difficult to interpret data generated by mice that have a mutation in the gene encoding either TNF-alpha or IL-1beta. To remediate the problem, we generated a mouse that bears a mutation in both genes and exposed them to an acute neurotoxic insult. Intracerebral infusion with the nitric oxide donor sodium nitroprusside (SNP) caused neurodegeneration and demyelination that were markedly increased in the brain of TNF-alpha- and IL-1beta/TNF-alpha-deficient mice compared with IL-1beta-deficient and wild-type mice. Surprisingly, TNF and double mutants exhibited an early (6 h after SNP injections) blunted microglial activation followed by an exaggerated response later on (4 d later). No differences were found in the brain of the IL-1beta knock-out and wild-type groups. This suggests a crucial role for TNF-alpha in mediating microglial reactivity to acute injury. An immediate response clearly helps eliminate cell debris, restrict subsequent damages, and restore homeostasis. These findings may have direct implications for the use anti-inflammatory drugs in acute neurodegenerative and demyelinating disorders.

Molecular and cellular immune mediators of neuroprotection.

Our view of the immune privileged status of the brain has dramatically changed during the past two decades. Even though systemic immune stimuli have the ability to activate different populations of neurons, cells of monocytic lineage also have access to the neuronal tissue and populate it as microglia. Although such a phenomenon is limited in intact brains, it is greatly increased during neurodegenerative processes associated with innate immunity and the release of pro-inflammatory molecules by either resident microglia or those derived from the bone marrow stem cells. The role of these events is currently a matter of great debate and controversy, especially as it relates to brain protection, repair, or further injury. In recent years, accumulating data have supported the notion that when immune molecules are timely released by microglia, they limit neuronal injury in the presence of pathogens and toxic agents, help clear debris from degenerated cells, and restore the cerebral environment for repair. It has been shown that alteration of the natural innate immune response by microglia has direct consequences in exacerbating the damages following acute injury to neurons. This article presents and discusses these data, supporting a powerful neuroprotective role for microglia and their innate immune reactions in response to pathogens and central nervous system insults.

Cyclooxygenase 2 (COX-2) inhibition increases the inflammatory response in the brain during systemic immune stimuli.

Non-steroidal anti-inflammatory drugs (NSAIDs) and inhibitors of the cyclooxygenase (COX) pathways are currently recommended for the prevention and treatment of several inflammatory diseases, including neurodegenerative disorders. However non-selective blockade of COX was found to have pro-inflammatory properties, because they have the ability to alter the plasma glucocorticoid levels that play a critical role in the control of the innate immune response. The present study investigated the role of non-selective (ketorolac or indomethacin) or specific inhibitors of COX-1 (SC-560) and COX-2 (NS-398) in these effects. Mice challenged systemically with the endotoxin lipopolysaccharide (LPS) exhibited a robust hybridization signal for numerous inflammatory genes in vascular-associated cells of the brain and microglia across the cerebral tissue. Ketorolac, indomethacin and NS-398 significantly increased the ability of LPS to trigger such an innate immune response at time 3 h post challenge, whereas SC-560 failed to change gene expression in the brain of animals treated with the endotoxin. These data together with the crucial role of COX-2-derived prostaglandin E2 (PGE2) in the increase of glucocorticoids during systemic immune stimuli provide evidence that inhibition of this pathway results in an exacerbated early innate immune reaction. This may have a major impact on the use of these drugs in diseases where inflammation is believed to be a contributing and detrimental factor.

Unraveling the molecular details involved in the intimate link between the immune and neuroendocrine systems.

During systemic infections, the immune system can signal the brain and act on different neuronal circuits via soluble molecules, such as proinflammatory cytokines, that act on the cells forming the blood-brain barrier and the circumventricular organs. These activated cells release prostaglandin of the E(2) type (PGE(2)), which is the endogenous ligand that triggers the pathways involved in the control of autonomic functions necessary to restore homeostasis and provide inhibitory feedback to innate immunity. Among these neurophysiological functions, activation of the circuits that control the plasma release of glucocorticoids is probably the most critical to the survival of the host in the presence of pathogens. This review revisits this issue and describes in depth the molecular details (including the emerging role of Toll-like receptors during inflammation) underlying the influence of circulating inflammatory molecules on the cerebral tissue, focusing on their contribution in the synthesis and action PGE(2) in the brain. We also provide an innovative view supporting the concept of "fast and delayed response" involving the same ligands but different groups of cells, signal transduction pathways, and target genes.

Influence of chronic interleukin-2 infusion and stressors on sickness behaviors and neurochemical change in mice.

OBJECTIVES: Major depression is associated with increased circulating interleukin-2 (IL-2) levels, and IL-2 immunotherapy may provoke depressive symptoms, leading to the suggestion that this cytokine may contribute to the evolution of affective disorders. Although depression is a relatively chronic condition, and immunotherapy involves repeated cytokine administration, animal studies have typically assessed the consequences of acute cytokine treatment. The present investigation assessed several behavioral and neurochemical effects of chronic IL-2 infusion. METHODS: Behaviors reflecting anhedonia and/or anorexia, sickness behavior, plasma corticosterone and norepinephrine (NE) activity in the paraventricular nucleus (PVN) of the hypothalamus were assessed following continuous infusion of IL-2 over 7 days in CD-1 mice. RESULTS: The cytokine treatment reduced the consumption of a highly favored palatable substance (chocolate milk) and reduced locomotor activity monitored over the course of the 7-day period. Although sickness behaviors were also increased significantly by the treatment, the degree of sickness behavior was actually modest. While a chronic, variable stressor also affected consumption of the palatable food, this treatment did not enhance the effects of IL-2. Furthermore, in contrast to acute and chronic stressors that increased plasma corticosterone levels and the utilization of NE within the PVN of the hypothalamus, IL-2 did not promote such effects and did not modify the impact of the stressors. CONCLUSION: While IL-2 may induce anorexia or anhedonia, the effects of this treatment are distinguishable from those elicited by stressors and those typically elicited by proinflammatory cytokines. The data are related to findings suggesting a link between IL-2 and depressive illness.

Innate immune reaction in response to seizures: implications for the neuropathology associated with epilepsy.

In the present study, the expression of pro-inflammatory transcripts was assessed across the brain of mice having undertaken pilocarpine-induced seizures. Pilocarpine-induced marked neurodegeneration and demyelination in multiple regions of the forebrain. The pattern of genes encoding toll-like receptor type 2 (TLR2) and I kappa B alpha (index of NF-kappa B activation) was associated with the neurodegenerating areas, but this was not the case for the mRNA encoding other inflammatory proteins. Scattered tumor necrosis factor-alpha (TNF-alpha)-expressing cells were found across brain, whereas the signals for monocyte-chemoattractant protein-1 and microsomal prostaglandin mPGES E synthase were robust in thalamus and cerebral cortex and weak in the hippocampus and amygdala. TLR2 and TNF-alpha transcripts were expressed mainly in microglia/macrophages. Cyclooxygenase-2 was induced specifically in the hippocampus and piriform cortex. A low increase in interleukin-12 mRNA was detected in the brain, but the signal for interferon gamma (IFN-gamma) remained undetectable. Although pro-inflammatory markers were induced in a different manner across the CNS, their patterns were not characteristic of those caused by other inflammatory challenges, such as endotoxin. These data suggest a different mechanism involved in regulating the innate immune reaction in response to seizures and could have direct implications for the neuropathology associated with epilepsy.

Interleukin-1beta system in anorectic catabolic tumor-bearing rats.

PURPOSE OF REVIEW: The onset of cancer anorexia and the accompanying neurological symptoms and signs involve the general influence of cytokines on the brain. Using methylcholanthrene to induce tumors in Fischer 344 rats, we measured various specific components of the cytokine-induced anorectic reaction, including: (1) IL-1beta system components (ligand, signaling receptor, receptor accessory proteins, and receptor antagonist); (2) TNF-alpha; (3) TGF-beta1; and (4) IFN-gamma in the tumor tissue, the liver and the brain. RECENT FINDINGS: The data show that IL-1beta, TNF-alpha and IFN-gamma messenger RNA were detected in the tumor tissue of anorectic tumor-bearing rats. In brain regions, anorexia is associated with the upregulation of IL-1beta and its receptor mRNA. All other mRNA remained unchanged in the brain regions examined. SUMMARY: This suggests that IL-1beta and its receptor may play a significant role in this model of cancer-associated anorexia. In vivo, the characterization of cytokine components in the brain may provide data for potential pharmacological interventions to ameliorate the anorexia of disease.

Neurochemical sensitization associated with systemic administration of tumor necrosis factor-alpha: adjuvant action in combination with bovine serum albumin.

Tumor necrosis factor-alpha (TNF-alpha) provokes a time-dependent sensitization of brain monoamine activity, plasma corticosterone activity and sickness behavior, the latter being reminiscent of septic or anaphylactic shock. In this investigation, bovine serum albumin (BSA) elicited similar corticosterone and sickness profiles, whereas the monoamine changes were not observed. The sensitization elicited by mTNF-alpha plus BSA was markedly greater than that elicited by BSA alone. Carrier-free TNF-alpha promoted the sensitization of brain monoamine activity, but not sickness or corticosterone. It is suggested that mTNF-alpha acts as an adjuvant to the anaphylactic actions elicited by BSA, but may provoke a sensitization of monoamine activity which is time-dependent and varies across brain regions.