Patrizia Loi

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 α7 nicotinic acetylcholine receptor (α7nAChR). 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 α7nAChR, as attested by the absence of protection in α7nAChR-deficient mice. Additionally, nicotine significantly reduced tubular damages, prevented neutrophil infiltration and decreased productions of the CXC-chemokine KC, TNF-α 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 α7nAChR pathway. In addition, this could provide an opportunity to overcome the effect of surgical cholinergic denervation during kidney transplantation.

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-γ 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-γ by CD4+ and CD8+ effector T cells. Tregs also down-regulated classical activation of macrophages resulting in reduced TNF-α 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.

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.

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

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. (HEPATOLOGY 2013)

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.

Gastric Bypass for Morbid Obesity in a Patient with Situs Inversus Totalis.

Abstract The aim of this case report is to outline the challenge and the feasibility of laparoscopic gastric bypass in a patient with situs inversus totalis. Situs inversus totalis does not seem to be a contraindication for laparoscopic surgery.

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 AimsSince 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.MethodsFrom 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.ResultsThree 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.ConclusionsEndoscopic 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.

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

Abstract 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.

A primary peritoneal pseudomyxoma peritonei arising from the mullerian tissue: A case report

Abstract A primary Pseudomyxoma Peritonei is uncommon. For a long time, ovaries, colon and appendix were proposed like a site origin of these enigmatic lesions. Recent publications show that the majority of cases are due to a rupture of appendicle adenoma. We report a case of a pseudomyxoma peritonei arising in an elderly patient with a previous medical history of appendectomy undergone in infancy. The pseudomyxoma was misdiagnosed as an abdominal abscess related to colitis. In our opinion, metaplasia of the Müllerian system is a possible source of a primary peritoneal pseudomyxoma.