Benign multicystic peritoneal mesothelioma in a sexagenerian man: an uncommon case presentation.

BACKGROUND: Multicystic mesothelial cyst is a rare, and usually benign, tumor which is rarely diagnosed preoperatively due to the poor specificity of its symptomatology. METHODS: We report the case of a 63-year-old man with multiple comorbidities (e.g. cryptogenic cirrhosis, chronic heart failure) and a history of surgical resection of a giant abdominal cyst, who complained of recurrent intermittent abdominal pain and vomiting that appeared several weeks before. Abdominal computed tomodensitometry (CT) revealed multiple diffusely localized cysts in the abdominal cavity, ranging from 30 mm to 210 mm. RESULTS: The patient underwent surgical resection of twelve intra-abdominal cysts, identified at final pathology as benign mesothelial cysts, which were probably a recurrence following the previous surgery for a single intra-abdominal cyst. Three months later, the patient recurred with development of two new intraperitoneal cysts, with an increasing volume on CT at last follow-up (18 months). Surveillance was recommended given the patient's comorbidities and the absence of symptoms. CONCLUSIONS: Surgical resection is the treatment of choice for multicystic peritoneal mesothelioma, a rare disease that should be considered more as a borderline tumor than a benign tumor, given the high risk of recurrence and possible malignant transformation.

SMAD4 Positive Pancreatic Ductal Adenocarcinomas Are Associated with Better Outcomes in Patients Receiving FOLFIRINOX-Based Neoadjuvant Therapy.

BACKGROUND: SMAD4 is inactivated in 50-55% of pancreatic ductal adenocarcinomas (PDACs). SMAD4 loss of expression has been described as a negative prognostic factor in PDAC associated with an increased rate of metastasis and resistance to therapy. However, the impact of SMAD4 inactivation in patients receiving neoadjuvant therapy (NAT) is not well characterized. The aim of our study was to investigate whether SMAD4 status is a prognostic and predictive factor in patients receiving NAT. METHODS: We retrospectively analyzed 59 patients from a single center who underwent surgical resection for primary PDAC after NAT. SMAD4 nuclear expression was assessed by immunohistochemistry, and its relationship to clinicopathologic variables and survival parameters was evaluated. Interaction testing was performed between SMAD4 status and the type of NAT. RESULTS: 49.15% of patients presented loss of SMAD4. SMAD4 loss was associated with a higher positive lymph node ratio (p = 0.03), shorter progression-free survival (PFS) (p = 0.02), and metastasis-free survival (MFS) (p = 0.02), but it was not an independent prognostic biomarker in multivariate analysis. Interaction tests demonstrated that patients with SMAD4-positive tumors receiving FOLFIRINOX-based NAT showed the best outcome. CONCLUSION: This study highlights the potential prognostic and predictive role of SMAD4 status in PDAC patients receiving FOLFIRINOX-based NAT.

Neoadjuvant chemotherapy associated with isotoxic high-dose stereotactic body radiotherapy does not increase postoperative complications after pancreaticoduodenectomy for nonmetastatic pancreatic cancer.

BACKGROUND AND OBJECTIVES: The role of radiotherapy in the therapeutic sequence of nonmetastatic pancreatic cancer (PC) is controversial, including isotoxic high-dose stereotactic body radiotherapy (iHD-SBRT). This study aimed to compare postoperative outcome of patients with nonmetastatic PC undergoing neoadjuvant treatment (NAT) including iHD-SBRT versus upfront pancreaticoduodenectomy (PD). METHODS: All patients undergoing PD for PC from 2017 to 2021 were retrospectively analyzed, identifying patients receiving NAT with iHD-SBRT. Toxicity of treatments and postoperative outcome were assessed and analyzed in a propensity score-matched population. RESULTS: Eighty-nine patients underwent upfront surgery (surgery group) and 22 after NAT and iHD-SBRT (SBRT group). No major side effects SBRT-related were identified preoperatively. Postoperative morbidity was similar between groups. There was no postoperative death in SBRT group, and six in surgery group (p = 0.597). No difference was observed in the rates of complications related to pancreatic surgery. The postoperative hospital stay was shorter in SBRT versus surgery groups (p = 0.016). After propensity score matching, no significant difference in the postoperative morbidity was observed between groups. CONCLUSIONS: Incorporation of iHD-SBRT in the NAT sequence before PD for PC did not increase postoperative morbidity compared with upfront surgery. These results confirm the feasibility and safety of iHD-SBRT for the upcoming STEREOPAC trial.

Opioid-free versus opioid-based anesthesia in pancreatic surgery.

BACKGROUND: Opioid-free anesthesia (OFA) is associated with significantly reduced cumulative postoperative morphine consumption in comparison with opioid-based anesthesia (OBA). Whether OFA is feasible and may improve outcomes in pancreatic surgery remains unclear. METHODS: Perioperative data from 77 consecutive patients who underwent pancreatic resection were included and retrospectively reviewed. Patients received either an OBA with intraoperative remifentanil (n = 42) or an OFA (n = 35). OFA included a combination of continuous infusions of dexmedetomidine, lidocaine, and esketamine. In OBA, patients also received a single bolus of intrathecal morphine. All patients received intraoperative propofol, sevoflurane, dexamethasone, diclofenac, neuromuscular blockade. Postoperative pain management was achieved by continuous wound infiltration and patient-controlled morphine. The primary outcome was postoperative pain (Numerical Rating Scale, NRS). Opioid consumption within 48 h after extubation, length of stay, adverse events within 90 days, and 30-day mortality were included as secondary outcomes. Episodes of bradycardia and hypotension requiring rescue medication were considered as safety outcomes. RESULTS: Compared to OBA, NRS (3 [2-4] vs 0 [0-2], P < 0.001) and opioid consumption (36 [24-52] vs 10 [2-24], P = 0.005) were both less in the OFA group. Length of stay was shorter by 4 days with OFA (14 [7-46] vs 10 [6-16], P < 0.001). OFA (P = 0.03), with postoperative pancreatic fistula (P = 0.0002) and delayed gastric emptying (P < 0.0001) were identified as only independent factors for length of stay. The comprehensive complication index (CCI) was the lowest with OFA (24.9 ± 25.5 vs 14.1 ± 23.4, P = 0.03). There were no differences in demographics, operative time, blood loss, bradycardia, vasopressors administration or time to extubation among groups. CONCLUSIONS: In this series, OFA during pancreatic resection is feasible and independently associated with a better outcome, in particular pain outcomes. The lower rate of postoperative complications may justify future randomized trials to test the hypothesis that OFA may improve outcomes and shorten length of stay.

Five-year Outcomes of Sleeve Gastrectomy: A Prospective Multicenter Study.

BACKGROUND: Sleeve gastrectomy (SG) is the most frequently performed bariatric procedure in the world. Our purpose was to evaluate the percentage of excess weight loss (%EWL), resolution of obesity-related comorbidities after SG, and identify predictive factors of weight loss failure. METHODS: A prospective cohort study of adults who underwent SG during 2014 in 7 Belgian-French centers. Their demographic, preoperative, and postoperative data were prospectively collected and analyzed statistically. RESULTS: Overall, 529 patients underwent SG, with a mean preoperative weight and body mass index (BMI) of 118.9 ± 19.9 kg and 42.9 ± 5.5 kg/m2, respectively. Body mass index significantly decreased to 32.2 kg/m2 at 5 years (P < .001). The mean %EWL was 63.6% at 5 years. A significant reduction in dyslipidemia (28.0%-18.2%), obstructive sleep apnea (OSAS) (34.6%-25.1%), and arterial hypertension (HTN) (30.4%-21.5%) was observed after 5 years, but not for diabetes and gastroesophageal reflux disease (GERD). At multivariate analysis, age >50 years old, BMI >50 kg/m2, and previous laparoscopic adjustable gastric banding (LAGB) remained independent predictors of weight loss failure. CONCLUSIONS: Five years after SG, weight loss was satisfactory; the reduction of comorbidities was significant for dyslipidemia, OSAS, and HTN, but not diabetes and GERD. Age >50 years old, BMI >50 kg/m2, and previous LAGB were independent predictors of weight loss failure.

Isotoxic high-dose stereotactic body radiotherapy integrated in a total multimodal neoadjuvant strategy for the treatment of localized pancreatic ductal adenocarcinoma.

BACKGROUND: Our aim was to evaluate the feasibility and safety of isotoxic high-dose (iHD) stereotactic body radiation therapy (SBRT) in a total neoadjuvant sequence for the treatment of localized pancreatic adenocarcinoma. MATERIALS AND METHODS: Biopsy-proven borderline resectable/locally advanced pancreatic cancer (BR/LAPC) patients were included in this observational prospective analysis from August 2017 to April 2020 without excluding tumours showing a radiological direct gastrointestinal (GI) invasion. An induction chemotherapy by modified fluorouracil, irinotecan and oxaliplatin was performed for a median of six cycles. In case of non-progression, an isotoxic high-dose stereotactic body radiotherapy (iHD-SBRT) was delivered in 5 fractions followed by a surgical exploration. The primary endpoint was acute/late gastrointestinal grade ⩾3 toxicity. Secondary endpoints were overall survival (OS), progression-free survival (PFS) and local control (LC). RESULTS: A total of 39 consecutive patients (21 BR and 18 LAPC) were included: 34 patients (87.2%, 18 BR and 16 LAPC) completed the planned neoadjuvant sequence. After iHD-SBRT, 19 patients [55.9% overall, 13/18 BR (72.2%) and 6/16 LAPC (37.5%)] underwent an oncological resection among the 25 patients surgically explored (73.5%). The median follow up was 18.2 months. The rates of acute and late GI grade 3 toxicity were, respectively, 2.9% and 4.2%. The median OS and PFS from diagnosis were, respectively, 24.5 and 15.6 months. The resected patients had improved median OS and PFS in comparison with the non-resected patients (OS: 32.3 versus 18.2 months, p = 0.02; PFS: 24.1 versus 7.1 months, p < 0.001). There was no survival difference between the BR and LAPC patients. The 1-year LC from SBRT was 74.1% and the median locoregional PFS was not reached for both BR and LAPC patients. CONCLUSIONS: iHD-SBRT displays an excellent toxicity profile, also for potentially high-risk patients with radiological direct GI invasion at diagnosis and can be easily integrated in a total neoadjuvant strategy. The oncological outcomes are promising and emphasise the need for further exploration of iHD-SBRT in phase II/III trials.

Laparoscopic sleeve gastrectomy for morbid obesity in a Belgian-French prospective multicenter study: outcomes and predictors weight loss failure.

INTRODUCTION: Laparoscopic sleeve gastrectomy (LSG) became the most frequently performed bariatric procedure worldwide, gaining rapidly popularity thanks to its technical simplicity and the relatively good results. The aim of this Belgian-French study was to evaluate postoperative complications, weight loss, and resolution of obesity-related comorbidities after LSG, and identify predictive factors of weight loss failure. PATIENTS AND METHODS: A prospective multicenter study was conducted on all LSG performed during 2014 in 7 centers. Their demographic, preoperative, and postoperative data were prospectively collected and analyzed statistically. RESULTS: Overall 529 patients underwent LSG, with a mean preoperative weight and body mass index (BMI) of 118.9 ± 19.9 kg and 42.9 ± 5.5 kg/m2, respectively. Postoperative mortality was null and early postoperative morbidity was 6%, including 2.5% of gastric leakage. BMI significantly decreased to 31.1 kg/m2 and 30.0 kg/m2 at 1 and 3 years, respectively (p < .001). The mean %EWL was 77.2 and 74.6% at 1 and 3 years. A significant reduction in dyslipidemia (28.0-16.8%), obstructive sleep apnea (OSAS) (34.6-23.3%) and arterial hypertension (HTN) (30.4-20.2%) was observed after 3 years, but it does not concern diabetes and gastroesophageal reflux disease (GERD). At multivariate analysis, age > 50 years old, BMI >50 kg/m2 and previous laparoscopic adjustable gastric banding (LAGB) remained independent predictors of weight loss failure. CONCLUSIONS: LSG for morbid obesity is safe and effective. Satisfactory outcome after 3 years can be achieved regarding %EWL and some comorbidities such as dyslipidemia, OSAS, and HTN, but not diabetes and GERD. Age > 50 years old, BMI > 50 kg/m2 and previous LAGB were independent predictors of weight loss failure.

Does Pancreaticogastrostomy Decrease the Occurrence of Delayed Gastric Emptying After Pancreatoduodenectomy?

OBJECTIVES: This study investigates the factors that could influence the development of delayed gastric emptying (DGE) after pancreatoduodenectomy (PD). Delayed gastric emptying is a common complication after PD. The postoperative course is affected by a lengthened hospital stay, a decrease of the patients' quality of life, and a delayed adjuvant treatment. METHODS: From January 2000 to December 2012, 257 patients underwent PD in the same center. Forty-six variables were retrospectively extracted from medical records. Delayed gastric emptying (grades A, B, and C) was defined by the International Study Group of Pancreatic Surgery classification. Univariate and multivariate analyses were performed to identify factors associated with DGE. RESULTS: Delayed gastric emptying occurred in 133 patients (51.8%), 89 grade A (66.9%), 27 grade B (20.3%), and 17 grade C (12.8%). Biliary fistula (odds ratio [OR], 8.87; 95% confidence interval [CI], 2.07-37.99, P = 0.003), sepsis (OR, 8.02; 95% CI, 3.22-19.99; P < 0.0001), and intra-abdominal collection (OR, 3.43; 95% CI, 1.06-11.06; P = 0.039) were identified as independent risk factors for DGE, whereas pancreaticogastrostomy (OR, 0.32; 95% CI, 0.16-0.64; P < 0.001) decreased the occurrence of DGE. CONCLUSIONS: Delayed gastric emptying was linked to the occurrence of postoperative intra-abdominal complications, and reconstruction by pancreaticogastrostomy was beneficial by decreasing its incidence.

Intraperitoneal mesh prosthesis metastasis from pancreatic cancer, after laparoscopic hernia repair.

Introduction There are very few case reports of metastasis on a mesh prosthesis following laparoscopic hernia repair in the literature and its incidence is completely unknown. Case report A 76-year-old male patient presented in December 2013 with a suspicious malignant lesion of the pancreatic tail on the MRI. He was also complaining of a painful mass in the right para-rectal area. An exploratory laparoscopy performed in December 2013 revealed microscopic whitish peritoneal implants in the left hypochondrium and a massive metastasis involving a mesh prosthesis placed é years before in the right para-rectal area. The pathology report of biopsies of the mesh confirmed a metastasis compatible with a pancreatic tumor. Discussion Possible modes of metastasis and limited published data to date on mesh prosthesis metastasis are presented. This situation can be assimilated to port-site metastasis after laparoscopy. Conclusion A mesh prosthesis metastasis after laparoscopic hernia repair is very rare.

Evaluation of total body weight and body mass index cut-offs for increased cefazolin dose for surgical prophylaxis.

French and American guidelines recommend increased dosage regimens of cefazolin (CFZ) for surgical prophylaxis in patients with a body mass index (BMI) ≥ 35 kg/m2 or with a total body weight (TBW) ≥ 120 kg. The objective of this study was to evaluate the accuracy of these cut-offs in identifying patients who require CFZ dose adjustment. A pharmacokinetic study was conducted in patients of varying TBW and BMI who received 2 g of CFZ intravenously for prophylaxis prior to digestive surgery. Adequacy of therapy, defined as a serum concentration of unbound CFZ (fCFZ) ≥ 4 mg/L, was evaluated 180 min (T180) and 240 min (T240) after the start of CFZ infusion. Possible factors associated with insufficient fCFZ levels were also assessed. A P-value of <0.05 was considered statistically significant. A total of 63 patients were included in the study, categorised according to BMI (<35 kg/m2, 20 patients; and ≥35 kg/m2, 43 patients) and TBW (<120 kg, 41 patients; and ≥120 kg, 22 patients). All patients had adequate drug levels at T180 but only 40/63 patients (63%) had adequate levels at T240. At T240, therapy was adequate in 15/20 patients (75%) and 25/43 patients (58%) with BMI <35 kg/m2 and ≥35 kg/m2, respectively (P = 0.20), and in 28/41 patients (68%) and 12/22 patients (55%) with TBW <120 kg and ≥120 kg, respectively (P = 0.28). No factor associated with insufficient fCFZ was identified. In conclusion, current BMI and TBW cut-offs are poor indicators of which patients could benefit from increased CFZ dosage regimens.

Transluminal or Percutaneous Endoscopic Drainage and Debridement of Abscesses After Bariatric Surgery: a Case Series.

BACKGROUND AND AIMS: Since redo surgery is associated with a high risk of morbidity and mortality after bariatric surgery in case of leakage, we sought to evaluate whether endoscopic drainage and debridement of collections following bariatric surgery is an efficient step-up approach to the management of these complications. METHODS: From 2007 to 2011, we retrospectively studied our cohort of nine cases treated by endoscopic drainage and debridement of abdominal abscesses secondary to postbariatric surgery leaks performed via the transluminal or percutaneous route. RESULTS: Three patients were treated by percutaneous endoscopic debridement of abscesses knowing that their leak was already closed by other endoscopic means and that their collection did not improve despite external drain in place. Six patients were treated by transluminal endoscopic drainage to perform necrosectomy as a first-line option or after failure of improvement after endoscopic treatment. The number of sessions required ranged from 1 to 3. Most severe patients had rapid improvement of their hemodynamic and respiratory conditions. In eight of the nine patients, we were able to close the fistula by stent, fistula plugs, or a macroclip. Resolution of collections was seen in seven out of nine patients, but two required further surgery. CONCLUSIONS: Endoscopic necrosectomy via the transluminal or percutaneous route is a feasible option in postbariatric surgery patients with necrotic abscesses not adequately managed by the classical combination of percutaneous drainage and stenting. Further wide-scale studies are needed to compare this non-surgical method with surgical necrosectomy in postbariatric surgery patients.

Endotherapy for paraduodenal pancreatitis: a large retrospective case series.

BACKGROUND AND STUDY AIMS: Paraduodenal pancreatitis is histologically well defined but its epidemiology, natural history, and connection with chronic pancreatitis are not completely understood. The aim of this study was to review the endoscopic and medical management of paraduodenal pancreatitis. PATIENTS AND METHODS: Medical records of all patients with paraduodenal pancreatitis diagnosed by magnetic resonance cholangiopancreatography (MRCP) or endoscopic ultrasonography (EUS) between 1995 and 2010 were retrospectively reviewed. Clinical features, imaging procedures, and treatments were investigated. The primary end point was the rate of clinical success, and the secondary end points were the radiological or endoscopic improvement, complication rate, and overall survival rate. RESULTS: A total of 51 patients were included in the study (88.2 % alcohol abuse; median age 49 years [range 37 - 70]; 50 men). The most frequent symptoms at presentation were pain (n = 50; 98.0 %) and weight loss (n = 36; 70.6 %). Chronic pancreatitis was present in 36 patients (70.6 %), and 45 patients (88.2 %) had cysts. Other findings included stricture of the pancreatic duct (n = 37; 72.5 %), common bile duct (n = 29; 56.9 %), and duodenum (n = 24; 47.1 %). A total of 39 patients underwent initial endoscopic treatment: cystenterostomy (n = 20), pancreatic and/or biliary duct drainage (n = 19), and/or duodenal dilation (n = 6). For the patients with available follow-up (n = 41), 24 patients required repeat endoscopy and 9 patients required surgery after the initial endoscopic management. After a median follow-up of 54 months (range 6 - 156 months), complete clinical success was achieved in 70.7 % of patients, and the overall survival rate was 94.1 %. CONCLUSIONS: This is the largest series concerning the management of paraduodenal pancreatitis using endotherapy as the first-line intervention. Although repeat endoscopic procedures were required in half of the patients, no severe complication was observed and surgical treatment was ultimately needed in less than 25 % of the patients.

Interferon regulatory factor 3 deficiency leads to interleukin-17-mediated liver ischemia-reperfusion injury.

UNLABELLED: Interferon regulatory factor 3 (IRF3) is an important transcription factor in Toll-like receptor 4 (TLR4) signaling, a pathway that is known to play a critical role in liver ischemia-reperfusion injury. In order to decipher the involvement of IRF3 in this setting, we first compared the intensity of hepatic lesions in IRF3-deficient versus wildtype mice. We found increased levels of blood transaminases, enhanced liver necrosis, and more pronounced neutrophil infiltrates in IRF3-deficient mice. Neutrophil depletion by administration of anti-Ly6G monoclonal antibody indicated that neutrophils play a dominant role in the development of severe liver necrosis in IRF3-deficient mice. Quantification of cytokine genes expression revealed increased liver expression of interleukin (IL)-12/IL-23p40, IL-23p19 messenger RNA (mRNA), and IL-17A mRNA in IRF3-deficient versus wildtype (WT) mice, whereas IL-27p28 mRNA expression was diminished in the absence of IRF3. The increased IL-17 production in IRF3-deficient mice was functionally relevant, as IL-17 neutralization prevented the enhanced hepatocellular damages and liver inflammation in these animals. Evidence for enhanced production of IL-23 and decreased accumulation of IL-27 cytokine in M1 type macrophage from IRF3-deficient mice was also observed after treatment with lipopolysaccharide, a setting in which liver gamma-delta T cells and invariant natural killer T cells were found to be involved in IL-17A hyperproduction. CONCLUSION: IRF3-dependent events downstream of TLR4 control the IL-23/IL-17 axis in the liver and this regulatory role of IRF3 is relevant to liver ischemia-reperfusion injury.

Laparoscopic gastric bypass as a revision procedure after transoral gastroplasty.

BACKGROUND: Transoral gastroplasty (TOGA) has been offered as an investigational alternative restrictive procedure in our hospital for the last 3 years. Since laparoscopic Roux-en-Y gastric bypass (LRYGBP) can be performed as a revisional surgery after failure of a restrictive surgery, this study reports on the feasibility of conversion of TOGA into a LRYGBP in case of failure of the endoscopic procedure. METHODS: Since 2006, 71 TOGA procedures were performed in morbidly obese patients. Four patients underwent an LRYGBP after TOGA procedure for unsatisfactory results after 1-year observation. All of them had undergone a second procedure in which additional TOGA restrictions were placed to attempt to tighten the pouch before being referred for LRYGBP. The surgical outcome of these patients was analysed. RESULTS: All four patients were easily converted to a LRYGBP with no major complication and no mortality. The operative results (operating time, morbidities, follow-up) of all LRYGBP post TOGA were similar to primary LRYGBP performed by the same operator. CONCLUSION: LRYGBP post-TOGA apparently can be done without any trouble. The performance of TOGA does not seem to interfere with the short-term results of the LRYGBP.

Neuroendocrine tumors of pancreas: how can we apply the 2006 TNM proposal?

BACKGROUND/AIMS: In 2006, a TNM system for foregut neuroendocrine tumors has been proposed. Our study aimed to present the management of neuroendocrine tumors of pancreas according to this classification and to highlight some of its limitations. METHODOLOGY: Clinical, biochemical, radiological, surgical and pathological data were retrospectively collected on 22 consecutives patients, who underwent surgery for neuroendocrine tumors of pancreas between November, 1991 and September, 2005. These data were used to set the TNM. RESULTS: After excluding 5 patients, the remaining 17 patients were analyzed. In 9 patients, with a mean age of 39 years, tumors were benign with a mean size of 1.8 cm, classed at stage I-IIa, whereas for 8 patients with a mean age of 57 years, tumors were malignant with a mean size of 6cm and were classed at stage IIb-IV. There were 3 deaths in stage IIb-IV, and none in stage I-IIa. CONCLUSION: TNM may be considered as a useful tool for prognostic stratification, but true benign tumors need to be excluded in order to improve the classification. Size and age appeared as variables affecting malignant behavior and the prognosis.

Experimental expansion of the regulatory T cell population increases resistance to African trypanosomiasis.

Inflammatory responses mounted to eliminate parasites can be lethal if not counterbalanced by regulatory responses protecting the host from collateral tissue damage. Here, we show that the maintained inflammation associated with tissue damage, anemia, and reduced survival of Trypanosoma brucei-infected mice correlates with the absence of the expansion of the regulatory T (T(reg)) cell population. Induction of T(reg) cell expansion via CD28 superagonist antibody treatment in these mice down-regulated interferon-gamma production by T cells and tumor necrosis factor-alpha and reactive oxygen species production by classically activated macrophages, triggered the development of alternatively activated macrophages, delayed the onset of liver injury, diminished the anemia burden, and prolonged the survival of infected animals. Thus, triggering the expansion of the T(reg) cell population coupled with the induction of alternatively activated macrophages can restore the balance between pro- and anti-inflammatory signals and thereby limit the pathogenicity of African trypanosomiasis.

African trypanosomiasis: naturally occurring regulatory T cells favor trypanotolerance by limiting pathology associated with sustained type 1 inflammation.

Tolerance to African trypanosomes requires the production of IFN-gamma in the early stage of infection that triggers the development of classically activated macrophages controlling parasite growth. However, once the first peak of parasitemia has been controlled, down-regulation of the type 1 immune response has been described. In this study, we have evaluated whether regulatory T cells (Tregs) contribute to the limitation of the immune response occurring during Trypanosoma congolense infection and hereby influence the outcome of the disease in trypanotolerant C57BL/6 host. Our data show that Foxp3+ Tregs originating from the naturally occurring Treg pool expanded in the spleen and the liver of infected mice. These cells produced IL-10 and limited the production of IFN-gamma by CD4+ and CD8+ effector T cells. Tregs also down-regulated classical activation of macrophages resulting in reduced TNF-alpha production. The Treg-mediated suppression of the type 1 inflammatory immune response did not hamper parasite clearance, but was beneficial for the host survival by limiting the tissue damages, including liver injury. Collectively, these data suggest a cardinal role for naturally occurring Tregs in the development of a trypanotolerant phenotype during African trypanosomiasis.

Nicotine protects kidney from renal ischemia/reperfusion injury through the cholinergic anti-inflammatory pathway.

Kidney ischemia/reperfusion injury (I/R) is characterized by renal dysfunction and tubular damages resulting from an early activation of innate immunity. Recently, nicotine administration has been shown to be a powerful inhibitor of a variety of innate immune responses, including LPS-induced toxaemia. This cholinergic anti-inflammatory pathway acts via the alpha7 nicotinic acetylcholine receptor (alpha7nAChR). Herein, we tested the potential protective effect of nicotine administration in a mouse model of renal I/R injury induced by bilateral clamping of kidney arteries. Renal function, tubular damages and inflammatory response were compared between control animals and mice receiving nicotine at the time of ischemia. Nicotine pretreatment protected mice from renal dysfunction in a dose-dependent manner and through the alpha7nAChR, as attested by the absence of protection in alpha7nAChR-deficient mice. Additionally, nicotine significantly reduced tubular damages, prevented neutrophil infiltration and decreased productions of the CXC-chemokine KC, TNF-alpha and the proinflammatory high-mobility group box 1 protein. Reduced tubular damage in nicotine pre-treated mice was associated with a decrease in tubular cell apoptosis and proliferative response as attested by the reduction of caspase-3 and Ki67 positive cells, respectively. All together, these data highlight that nicotine exerts a protective anti-inflammatory effect during kidney I/R through the cholinergic alpha7nAChR pathway. In addition, this could provide an opportunity to overcome the effect of surgical cholinergic denervation during kidney transplantation.