Fexofenadine inhibits TNF signaling through targeting to cytosolic phospholipase A2 and is therapeutic against inflammatory arthritis.

OBJECTIVE: Tumour necrosis factor alpha (TNF-α) signalling plays a central role in the pathogenesis of various autoimmune diseases, particularly inflammatory arthritis. This study aimed to repurpose clinically approved drugs as potential inhibitors of TNF-α signalling in treatment of inflammatory arthritis. METHODS: In vitro and in vivo screening of an Food and Drug Administration (FDA)-approved drug library; in vitro and in vivo assays for examining the blockade of TNF actions by fexofenadine: assays for defining the anti-inflammatory activity of fexofenadine using TNF-α transgenic (TNF-tg) mice and collagen-induced arthritis in DBA/1 mice. Identification and characterisation of the binding of fexofenadine to cytosolic phospholipase A2 (cPLA2) using drug affinity responsive target stability assay, proteomics, cellular thermal shift assay, information field dynamics and molecular dynamics; various assays for examining fexofenadine inhibition of cPLA2 as well as the dependence of fexofenadine's anti-TNF activity on cPLA2. RESULTS: Serial screenings of a library composed of FDA-approved drugs led to the identification of fexofenadine as an inhibitor of TNF-α signalling. Fexofenadine potently inhibited TNF/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-ĸB) signalling in vitro and in vivo, and ameliorated disease symptoms in inflammatory arthritis models. cPLA2 was isolated as a novel target of fexofenadine. Fexofenadine blocked TNF-stimulated cPLA2 activity and arachidonic acid production through binding to catalytic domain 2 of cPLA2 and inhibition of its phosphorylation on Ser-505. Further, deletion of cPLA2 abolished fexofenadine's anti-TNF activity. CONCLUSION: Collectively, these findings not only provide new insights into the understanding of fexofenadine action and underlying mechanisms but also provide new therapeutic interventions for various TNF-α and cPLA2-associated pathologies and conditions, particularly inflammatory rheumatic diseases.

Dietary pyruvate targets cytosolic phospholipase A2 to mitigate inflammation and obesity in mice.

Obesity has a multifactorial etiology and is known to be a state of chronic low-grade inflammation, known as meta-inflammation. This state is associated with the development of metabolic disorders such as glucose intolerance and nonalcoholic fatty liver disease. Pyruvate is a glycolytic metabolite and a crucial node in various metabolic pathways. However, its role and molecular mechanism in obesity and associated complications are obscure. In this study, we reported that pyruvate substantially inhibited adipogenic differentiation in vitro and its administration significantly prevented HFD-induced weight gain, white adipose tissue inflammation, and metabolic dysregulation. To identify the target proteins of pyruvate, drug affinity responsive target stability was employed with proteomics, cellular thermal shift assay, and isothermal drug response to detect the interactions between pyruvate and its molecular targets. Consequently, we identified cytosolic phospholipase A2 (cPLA2) as a novel molecular target of pyruvate and demonstrated that pyruvate restrained diet-induced obesity, white adipose tissue inflammation, and hepatic steatosis in a cPLA2-dependent manner. Studies with global ablation of cPLA2 in mice showed that the protective effects of pyruvate were largely abrogated, confirming the importance of pyruvate/cPLA2 interaction in pyruvate attenuation of inflammation and obesity. Overall, our study not only establishes pyruvate as an antagonist of cPLA2 signaling and a potential therapeutic option for obesity, but it also sheds light on the mechanism of its action. Pyruvate's prior clinical use indicates that it can be considered a safe and viable alternative for obesity, whether consumed as a dietary supplement or as part of a regular diet.

Emergency surgery in colonic diverticulitis in an Asian population.

INTRODUCTION: Diverticulitis in Asians differs significantly from their Western counterparts in various aspects. This study was performed to highlight our institution's surgical experiences in patients with diverticulitis. The secondary aim was to compare the patients who underwent surgery for right- and left-sided diverticulitis. METHODS: A retrospective review of all patients who underwent emergency surgery in patients with acute diverticulitis from July 2003 to April 2008 was performed. Right-sided pathology was regarded if it was located from the caecum till the transverse colon. Left-sided disease was regarded if it commenced from the splenic flexure. RESULTS: The study group comprised of 104 patients, 68 (65.4%) of whom had right-sided diverticulitis. Caecum was the commonest site of disease, and the majority had only mild disease. In the 36 (34.6%) patients with left-sided diverticulitis, majority (63.8%) had an ASA score of three or four, with the sigmoid colon being the most common site of involvement. Most (91.7%) had worse peritoneal contamination with Hartmann's procedure being performed in 22 (61.1%) patients. Worse peri-operative outcome was also seen in this group. After multivariate analysis, the independent factors for right-sided disease were younger age, lower ASA score and no necessity for stoma. CONCLUSIONS: In an Asian population, surgery in right-sided diverticulitis is more commonly performed and is associated with lower morbidity and mortality. Patients who underwent surgery for right-sided diverticulitis were younger, with lower ASA score and less likely to have stoma created.

Is emergency right hemicolectomy still associated with significant morbidity and mortality rates? An institution's experience of 207 cases over 6 years.

INTRODUCTION: Emergency right hemicolectomy has been associated with dismal outcome. But, data in Asians is lacking as pathologies that require emergency right hemicolectomy may differ from that in the Western population. The aims of our study were to review our institution's experience with emergency right hemicolectomies and to identify factors that could predict the per-operative outcome. METHODS: A retrospective review of all patients who underwent emergency right hemicolectomy from August 2003 to April 2008 was performed. Emergency right hemicolectomy was defined as a right colectomy, comprising of an ileo-colic resection, in the emergency setting without the benefit of preoperative bowel preparation. All the complications were graded according to the classification proposed by Clavien and group. RESULTS: A total of 207 patients, median age 62 years (range, 19-94 years), underwent emergency right hemicolectomy during the study period. Neoplasia and complicated diverticular disease were the most common pathologies in 46.4% and 21.7%, respectively. Intestinal obstruction (44.4%) and perforation (26.6%) were the two main indications for surgical intervention in our series. Twenty (9.7%) patients died, and another 39 patients (18.8%) had severe complications. Eight (3.9%) patients had anastomotic dehiscence, while burst abdomen was seen in ten (4.8%) patients. The two independent factors associated with worse outcome were high ASA score and stoma creation. Factors such as age and site of perforation were not related. CONCLUSION: Emergency right hemicolectomy is associated with a significant morbidity and mortality rate. Patients with higher ASA score and who had stoma created fared worse.

TNFR2/14-3-3ε signaling complex instructs macrophage plasticity in inflammation and autoimmunity.

TNFR1 and TNFR2 have received prominent attention because of their dominance in the pathogenesis of inflammation and autoimmunity. TNFR1 has been extensively studied and primarily mediates inflammation. TNFR2 remains far less studied, although emerging evidence demonstrates that TNFR2 plays an antiinflammatory and immunoregulatory role in various conditions and diseases. Herein, we report that TNFR2 regulates macrophage polarization, a highly dynamic process controlled by largely unidentified intracellular regulators. Using biochemical copurification and mass spectrometry approaches, we isolated the signaling molecule 14-3-3ε as a component of TNFR2 complexes in response to progranulin stimulation in macrophages. In addition, 14-3-3ε was essential for TNFR2 signaling-mediated regulation of macrophage polarization and switch. Both global and myeloid-specific deletion of 14-3-3ε resulted in exacerbated inflammatory arthritis and counteracted the protective effects of progranulin-mediated TNFR2 activation against inflammation and autoimmunity. TNFR2/14-3-3ε signaled through PI3K/Akt/mTOR to restrict NF-κB activation while simultaneously stimulating C/EBPß activation, thereby instructing macrophage plasticity. Collectively, this study identifies 14-3-3ε as a previously unrecognized vital component of the TNFR2 receptor complex and provides new insights into the TNFR2 signaling, particularly its role in macrophage polarization with therapeutic implications for various inflammatory and autoimmune diseases with activation of the TNFR2/14-3-3ε antiinflammatory pathway.

Surgery for perforated colorectal malignancy in an Asian population: an institution's experience over 5 years.

INTRODUCTION: Perforated colorectal malignancy is associated with numerous peri-operative complications and dismal long-term survival. The study aimed to review the outcome and factors predicting peri-operative complications and long-term survival of patients who underwent surgery for perforated colorectal malignancy. METHODS: A retrospective review of all patients who underwent operative intervention for perforated colorectal malignancy from February 2003 to April 2008 was performed. The severity of peritonitis was graded using the Mannheim peritonitis index (MPI). RESULTS: Forty-five patients, median age 67 years (36-97 years), formed the study group. Sigmoid colon (37.8%) and cecum (28.9%) were the most common sites of perforation. Sixteen (35.6%) patients had stage IV disease, while 14 (31.1%) had severe peritoneal contamination (MPI >26). Hartmann's procedure and right hemicolectomy were performed most frequently in 17 (37.8%) and 15 (33.4%) patients, respectively. The mortality rate in our series was 17.8%, with another 26.7% requiring surgical intensive care unit care. The independent variables predicting worse perioperative complications were American Society of Anesthesiologists (ASA) score >or= 3 and MPI >26. Left-sided perforation was the only independent factor predicting stoma creation. The only factor predicting long-term survival was the stage of malignancy (p<0.001). The overall mean survival time for stage II, III, and IV disease were 63.7, 38.1, and 13.8 months, respectively. CONCLUSIONS: Surgery for perforated colorectal malignancy is associated with high morbidity and mortality rates. Short-term outcome is determined by ASA score and severity of peritonitis, while long-term outcome is determined by staging of the cancer.

Colonic diverticulitis in young Asians: a predominantly mild and right-sided disease.

BACKGROUND: The management of diverticulitis in young Asian patients remains challenging. This study aimed to highlight the issues of managing diverticulitis in young Asians. METHODS: A retrospective review of all patients who were admitted for acute colonic diverticulitis from October 2003 to December 2008 was performed. Patients who were ≤50 year old were considered 'young' and formed the study group. RESULTS: The study group consisted of 142 patients. The majority (n = 126, 88.7%) had right-sided diverticulitis and most (n = 117, 82.4%) were mild in severity. Most of the patients who underwent emergency surgery were for suspected appendicitis (39/56, 69.6%). When we compared between those aged ≤50 and >50 years, the older group had worse diverticulitis (odds ratio (OR), 4.90, 95% confidence interval (CI), 2.00-11.99), been operated for indications other than suspected appendicitis (OR, 13.08, 95% CI, 5.42-31.56) and undergone a colectomy (OR, 9.96, 95% CI, 4.12-24.10). The younger group had a much higher incidence of right-sided disease (OR: 7.80, 95% CI: 4.32-14.07). Over a median follow-up of 40 (6-90) months, 7 (4.9%) patients were readmitted for a total of eight times for recurrent attacks of diverticulitis and all were successfully treated conservatively. Five other patients underwent elective surgery for persistent symptoms. CONCLUSION: Diverticulitis in young Asians is often right-sided and mild in severity. A significant proportion is only diagnosed when operated for presumed appendicitis. Recurrent attacks are uncommon and can often be treated non-surgically.

Long-term outcome following surgery for colorectal cancers in octogenarians: a single institution's experience of 204 patients.

BACKGROUND: The incidence of colorectal cancer in elderly patients is likely to increase with an aging population. The aims of this study are to review our experience in the surgical management of octogenarians with colorectal cancers and to identify factors that influence the short-term and long-term outcomes. METHODS: A retrospective review of all octogenarians who underwent surgery for colorectal cancer from December 2002 to October 2008 was performed. RESULTS: We identified 204 patients with a median age of 84 years (range, 80-97 years). The majority of patients had an American Society of Anesthesiologists score ≥3 (n = 142, 69.6%) and a Charlson Comorbidity Index of ≤3 (n = 128, 62.7%). Emergency surgery was performed in 83 (40.7%) patients. Left-sided malignancy was seen in 138 patients (67.6%). Most of the patients had either stage II (n = 75, 36.8%) or III (n = 69, 33.8%) diseases. The 30-day mortality rate was 16.2% (n = 33). After multivariate analysis, the independent variables predicting worse perioperative complications and death were age >85 years old, emergency surgery, and Charlson Comorbidity Index >3. The median follow-up for the 171 remaining patients was 27 months (range, 2-92 months). The 30-day readmission rate was 2.9% (n = 5). Thirty-one (21.2%) of 146 patients who survived curative surgery developed recurrent disease. Seventy (34.3%) patients died from various etiologies after their first 30 days postoperatively (60% cancer-specific with median survival of 15 months and 40% noncancer-related with median survival of 14 months). Overall and disease-free survivals were adversely affected in patients with advanced malignancy and in those with severe perioperative complications. CONCLUSIONS: Surgery for octogenarians with colorectal cancers is associated with significant morbidity and mortality rates which are associated with advanced age, emergency surgery, and Charlson Comorbidity Index >3. Long-term survival is dependent on the stage of the malignancy and the presence of severe perioperative complications.

Emergency surgery for jejunal diverticulosis: our experience and review of literature.

BACKGROUND: Jejunal diverticulosis is a rare entity and is often asymptomatic. However, some of its complications may require acute surgical intervention. This study was performed to evaluate the presentation and outcome of patients who underwent urgent surgery for complicated jejunal diverticulosis. METHODS: A retrospective review of all patients who underwent emergency surgery for complicated jejunal diverticulosis from November 2005 to December 2008 was performed. RESULTS: Six cases of complicated jejunal diverticulosis required urgent surgery during the study period. Three patients presented with acute abdomen from perforated jejunal diverticulum. Preoperative computed tomographic (CT) scans were useful in localizing the source of sepsis. One patient died from the subsequent complications. The other three patients presented with massive lower gastrointestinal haemorrhage for which CT angiography was able to localize the source of haemorrhage in two of them. Small bowel resection was then performed and all three were discharged well eventually. CONCLUSION: Though rare, jejunal diverticulosis can present with several life-threatening complications that mandates immediate surgery. While the surgical procedure may be technically simple, achieving the accurate preoperative diagnosis is often fraught with challenges. CT scan could prove invaluable in the management if the situation permits.

Predictors of outcome following surgery in colonic perforation: an institution's experience over 6 years.

BACKGROUND: Colonic perforation is associated with abysmal outcome. The aims of our study were to review the surgical outcome of patients with perforated colon and to identify factors predicting peri-operative complications. METHODS: A retrospective review of all patients who underwent surgery for colonic perforation from January 2003 to August 2008 was performed. Patients with iatrogenic or traumatic perforation were excluded. The severity of abdominal sepsis was graded using the Mannheim peritonitis index (MPI). RESULTS: A total of 129 patients, with median age of 65 years (22-97 years), formed the study group. While 29.5% had severe peritoneal contamination, 56.6% had an American Society of Anesthesiologists (ASA) score ≥3. Sigmoid colon (47.3%) and caecum (24.8%) were the most common sites of perforation. Diverticulitis and malignancy were the diagnoses in 51.9% and 34.9%, respectively. Hartmann's procedure and right hemicolectomy were performed in 43.4% and 34.1% of the patients, respectively. Stoma was created in 59.7%. The in-hospital mortality rate in our series was 15.5%. After multivariate analysis, the independent variables associated with worse peri-operative complications were ASA score ≥3, MPI >26 and creation of stoma. Malignant perforation was associated with higher ASA score and lower haematocrit level compared to diverticular perforation. Stoma was created more frequently in patients with MPI >26 and left-sided perforation, and was associated with worse complications. CONCLUSIONS: Surgery for colonic perforation is associated with high morbidity and mortality rates. Short-term outcome is determined by ASA score and severity of peritonitis. A lower haematocrit level must alert the possibility of malignancy.

Computed tomography has an important role in hollow viscus and mesenteric injuries after blunt abdominal trauma.

INTRODUCTION: Computed tomographic (CT) scans have become invaluable in the management of patients with blunt abdominal trauma. No clear consensus exists on its role in hollow viscus injuries (HVI) and mesenteric injuries (MI). The aim of this study was to correlate operative findings of HVI and MI to findings on pre-operative CT. METHODS: All patients treated for blunt abdominal trauma at Tan Tock Seng Hospital from January 2003 to January 2008 were reviewed. CT scans were only performed if the patients were haemodynamically stable and indicated. All scans were performed with intravenous contrast using a 4-slice CT scanner from 2003 to December 2004 and a 64-slice CT scanner from January 2005 onwards. All cases with documented HVI/MI that underwent both CT scans and exploratory laparotomy were analysed. RESULTS: Thirty-one patients formed the study group, with median age of 40 (range, 22-65) years and a significant male (83.9%) predominance. Vehicular-related incidents accounted for 67.7% of the injuries and the median Injury Severity Score (ISS) was 13 (4-50). The 2 commonest findings on CT scans were extra-luminal gas (35.5%) and free fluid without significant solid organ injuries (93.5%). During exploratory laparotomy, perforation of hollow viscus (51.6%) occurred more frequently than suspected from the initial CT findings of extra-luminal gas. Other notable findings included haemoperitoneum (64.5%), and mesenteric tears (67.7%). None of our patients with HVI and MI had a normal pre-operative CT scan. CONCLUSION: Our study suggests that patients with surgically confirmed HVI and MI found at laparotomy were very likely to have an abnormal pre-operative CT scan. Unexplained free fluid was a very common finding in blunt HVI/MI and is one major indication to consider exploratory laparotomy.

Right colonic perforation in an Asian population: predictors of morbidity and mortality.

INTRODUCTION: Perforation of the colon is associated with significant morbidity and mortality. Pathologies arising from the right colon differ greatly between Asians and the Western population. The aims of our study were to evaluate the implications of perforated right colon in an Asian population and to identify factors that could predict the perioperative outcome. METHODS: A retrospective review of all patients who underwent operative intervention for peritonitis from right colonic perforation from July 2003 to April 2008 was performed. Patients were identified from the hospital's diagnostic index and operating records. The severity of abdominal sepsis for all patients was graded using the Mannheim peritonitis index (MPI). All the complications were graded according to the classification proposed by Clavian and colleagues. RESULTS: Fifty-one patients with a median age of 60 years (range, 22-93 years) formed the study group. Diverticulitis (47.1%) and malignancy (37.3%) accounted for the majority of the pathologies. Right hemicolectomy without diverting stoma (n = 34, 66.7%) was performed most commonly. Of our patients, 74.5% had perioperative morbidity with 19 (37.3%) patients having grade III or worse complications. In our series, five (9.8%) patients died. On univariate analysis, American Society of Anesthesiologists (ASA) score >or=3, >or=2 premorbid conditions, raised MPI, raised creatinine, and stoma creation were related to more severe complications (grade III/IV). The following variables were correlated with in-hospital mortality: ASA score >or=3, raised MPI, hematocrit <33%, raised creatinine, malignant perforation, and stoma creation. On multivariate analysis, a higher ASA score >or=3 was predictive of significant morbidity, while both malignant perforation and stoma creation were associated with mortality. CONCLUSION: Diverticulitis is the commonest cause of right colonic perforation in Asians. Patients with higher ASA score and malignant perforation are at risk of higher morbidity and mortality. Resection with primary anastomosis is safe and patients who require stomas are more likely to do worse.