Affective Behavior Shows Sex Differences in Mid-adulthood Rats Following Postnatal Immune Stimulation.

Mid-adulthood represents the critical window period usually associated with the development of age-related diseases. Despite several attempts to delineate the pathological mechanisms underlying postnatal immune challenge and altered brain functions, the role of sex-dependent changes in affective behaviors of middle-aged animals requires more attention. In this study, we sought to investigate behavioral and molecular response patterns at mid-adulthood linked to early-life immune activation. Using affective behavioral test batteries, we showed that lipopolysaccharide (LPS)-induced postnatal immune challenge caused anxiety-like behaviors in both male and female Wistar rats at mid-adulthood, whereas only female rats exhibited depression-like behaviors. Our data further demonstrated a significant increase in microglial complexity and increased levels of tumor necrosis factor (TNFα), nitric oxide (NOx), and lipid peroxidation in the prefrontal cortex of female rats compared to their male counterparts and phosphate-buffered saline (PBS) littermate controls. With these results, we established significant interaction between sex differences and LPS-induced alterations in behavior and associated oxidative and immunohistochemical changes. These findings may provide an insight to better understand the neuroimmunological mechanisms of sex-dependent brain pathological manifestations occurring at mid-adulthood.

Long-Term Effects of Pregnancy on Renal Graft Function in Women After Kidney Transplantation Compared With Matched Controls.

BACKGROUND: An important benefit associated with kidney transplantation in women of child-bearing age is increased fertility. We retrospectively evaluated the maternal and fetal complications and evolution of graft function associated with 22 pregnancies post-kidney and kidney-pancreas transplantation, compared with controls without pregnancy post-transplantation, who were matched for gender, year of transplantation, type of donor, age at transplantation, number of transplants, type of transplant (kidney vs kidney-pancreas), and cause of native kidney failure, as well as for renal parameters including serum creatinine and urine protein excretion 1 year before delivery. RESULTS: The mean age at time of transplantation was 22.32 (range, 19.45-33.1) years. The mean interval between transplantation and delivery was 75.7 (range, 34-147.8) months. Main maternal complications were pre-eclampsia in 27.3%. The main fetal complications included delayed intrauterine growth (18.2%), preterm deliveries (89.4%), and one death at 3 days postdelivery. The mean serum creatinine level pre-pregnancy was 1.17 (range, 0.7-3.1) mg/dL. Graft failure was higher in the pregnancy group (6 vs 3) but did not differ statistically from the control group, and was associated with creatinine pre-pregnancy (odds ratio [OR], 1.71; 95% confidence interval [CI], 1.15-3.45; P = .04), age at transplantation (1.13 [1.03-1.21]; P = .032), and time of follow-up (2.14 [1.27-2.98]; P = .026). Delta serum creatinine was not different in both groups: 1.05 ± 0.51 versus 0.99 ± 0.92 mg/dL, study versus control group, respectively (P = .17). CONCLUSION: Pregnancy after kidney transplantation is associated with serious maternal and fetal complications. We did not observe a significantly increased risk of graft loss or reduced graft function in comparison with recipients with similar clinical characteristics.

Thymelaea lythroides extract attenuates microglial activation and depressive-like behavior in LPS-induced inflammation in adult male rats.

Thymelaea lythroides extract is widely used as a traditional folk medicine in Morocco, especially for the treatment of diabetes, rheumatism and Inflammatory disease. The aim of the study is to evaluate the possible effect of methanolic extract of Thymelaea lythroides in repressing the inflammatory responses and long-lasting depression-like behavior associated with neuroinflammation in adult rats after neonatal LPS exposure. Male rat pups were treated systemically with either LPS (250??g/kg) or vehicle (phosphate buffer saline) on postnatal day 14. Six hours later, the LPS groups were assigned to intraperitoneal (ip) injection of Minocycline (50?mg/kg) or Thymelaea lythroides (200?mg/kg). Thereafter, in adulthood (postnatal days 90-97), the spontaneous locomotor activity and depression-like behavior were assessed successively in open field and forced swim tests. The levels of proinflammatory cytokines, oxidative damage, and activation of microglia were determined in the hippocampus (HP) of male rats on (PND90-97). Our results showed that open field hypoactivity and increased immobility period in LPS-induced adult rats were normalized on treatment with Thymelaea lythroides and minocycline. Both treatments attenuate the overactivated microglial cells in the CA1 and CA3 of hippocampus (HP) and significantly reduced the oxidative-nitrosative stress markers and cytokine (TNF ?) production in the HP. Thymelaea lythroides seems to have similar neuroprotective effects to Minocycline, and such protection may be due to: reduction of oxidative stress, upregulation of inflammatory mediators production, antidepressant behavior which all are associated with neuroinflammation.

Postnatal melatonin treatment protects against affective disorders induced by early-life immune stimulation by reducing the microglia cell activation and oxidative stress.

BACKGROUND: Systemic inflammation induced by neonatal infection may result as long-term hyper-activation of microglial cells followed by an overproduction of pro-inflammatory cytokines, such as tumor necrosis factor-alpha, nitric oxide and lipid peroxidation. Those inflammation mediators can trigger behavioral disruption and/or cognitive disorders. OBJECTIVE: The present work aims to evaluate the effect of melatonin (a cytokine release modulator and antioxidant agent) in the reduction of the prefrontal microglia activation and depressive-like behaviors induced by lipopolysaccharide (LPS) injection in adult rats. RESULTS: The effect of melatonin (5 mg/kg) was compared to minocycline (50 mg/kg), a well-known anti-inflammatory drug with potent inhibitory effect on microglial activation. Our results showed that LPS injection induced a significant increase in prefrontal cortex tumor necrosis factor-alpha and nitric oxide levels. Furthermore, lipid peroxidation and microglial activation were highly increased in the prefrontal cortex compared to control. The melatonin treatment induced a significant decrease on nitric oxide and lipid peroxidation levels in the prefrontal cortex and significant decrease on tumor necrosis factor-alpha and microglia activation. Melatonin can also induce a significant reduction in the anxiety and depression-like effect induced by PND9 LPS administration. CONCLUSION: Our results demonstrated that melatonin possesses potent protective effect against the depression and anxiety induced by LPS. The underlying effect of melatonin is probably due to the reduction of nitric oxide toxic effect and lipid peroxidation in addition to its anti-inflammatory effect.

Solid pseudopapillary neoplasm of the pancreas: Management and long-term outcome.

BACKGROUND: Solid pseudopapillary neoplasm (SPN) of pancreas is a rare pancreatic neoplasm with a low metastatic potential. Our aim was to study the clinical-pathological characteristics, and long-term outcome of this tumor. MATERIALS: Rretrospective single center study of patients operated for SPN of pancreas. Clinical and pathological data were collected. RESULTS: From 1995 to 2016, 1320 patients underwent pancreatic resection. SPN was confirmed in 32 cases (2.46%), including 29 (90.6%) female and three (9.4%) male, with a mean age of 28.4 ± 12.2 years. SPN was the most common pathology among female patients under age of 40 (72.4%). Abdominal pain was the most frequent presenting symptom (48%), whereas none of the patients presented with jaundice. Mean tumor diameter was 5.9 cm (range, 0.9-14 cm). All patients underwent margin-negative surgical resection. Two patients demonstrated gross malignant features, including liver metastases at presentation (n = 1), and adjacent organ and vascular invasion (n = 1). Microscopic malignant features were present in thirteen patients (40.6%). Recurrence occurred in the retroperitoneal lymph nodes (n = 1, 7 years post resection) and in the liver (n = 2, 1 and 5 years post resection). Mean follow-up was 49.2 months (range, 1-228 months). Five and 10-year disease-free survival was 96.5% and 89.6% respectively. CONCLUSIONS: SPNs are low-grade tumors with a good prognosis. Margin-negative surgical resection is curative in most patients. However, almost 15% of patients demonstrate malignant features including invasion of adjacent organs or metastatic disease. Patients with malignant disease are still expected to have long survival, and aggressive surgical approach is advocated.

Number of evaluated lymph nodes and positive lymph nodes, lymph node ratio, and log odds evaluation in early-stage pancreatic ductal adenocarcinoma: numerology or valid indicators of patient outcome?

BACKGROUND: We evaluated the prognostic significance and universal validity of the total number of evaluated lymph nodes (ELN), number of positive lymph nodes (PLN), lymph node ratio (LNR), and log odds of positive lymph nodes (LODDS) in a relatively large and homogenous cohort of surgically treated pancreatic ductal adenocarcinoma (PDAC) patients. METHODS: Prospectively accrued data were retrospectively analyzed for 282 PDAC patients who had pancreaticoduodenectomy (PD) at our institution. Long-term survival was analyzed according to the ELN, PLN, LNR, and LODDS. RESULTS: Of these patients, 168 patients (59.5 %) had LN metastasis (N1). Mean ELN and PLN were 13.5 and 1.6, respectively. LN positivity correlated with a greater number of evaluated lymph nodes; positive lymph nodes were identified in 61.4 % of the patients with ELN ≥ 13 compared with 44.9 % of the patients with ELN < 13 (p = 0.014). Median overall survival (OS) and 5-year OS rate were higher in N0 than in N1 patients, 22.4 vs. 18.7 months and 35 vs. 11 %, respectively (p = 0.008). Mean LNR was 0.12; 91 patients (54.1 %) had LNR < 0.3. Among the N1 patients, median OS was comparable in those with LNR ≥ 0.3 vs. LNR < 0.3 (16.7 vs. 14.1 months, p = 0.950). Neither LODDS nor various ELN and PLN cutoff values provided more discriminative information within the group of N1 patients. CONCLUSIONS: Our data confirms that lymph node positivity strongly reflects PDAC biology and thus patient outcome. While a higher number of evaluated lymph nodes may provide a more accurate nodal staging, it does not have any prognostic value among N1 patients. Similarly, PLN, LNR, and LODDS had limited prognostic relevance.

Laparoscopic versus open liver resection for metastatic colorectal cancer.

BACKGROUND: Application of minimally invasive surgery for oncologic liver resection is still limited to expert centers. We describe our experience in laparoscopic liver resection (LLR) for colorectal liver metastases (CLM). PATIENTS AND METHODS: Between February 2010 and February 2015, 174 patients underwent resection of CLM. LLR was chosen according to surgeon's preferences. Data was retrieved from the institutes' electronic charts and retrospectively analyzed. RESULTS: LLR was performed in 42 patients (24.5%) and OLR in 132. Increased number of metastases were found in OLR (2.82 ± 2.81 versus 1.78 ± 1.16, P = 0.02), with no difference in maximal lesion size (33.1 ± 22 versus 34.9 ± 27.5 cm, P = 0.7). Altogether 55 patients underwent major hepatectomy, and 50 of the OLR group (37.8%, 37 right hepatectomy and 7 left hepatectomy) (P = 0.02). In 5 patients (11.6%) a conversion to open surgery was indicated. Operative time was longer in LLR. Estimated blood loss was decreased in laparoscopic minor resections. One OLR patient died during the postoperative period (0.7%). Eight patients in the OLR group had major complications, versus 1 in the LLR group (P = 0.0016). Reoperation within 30 days was performed in 4 OLR patients and none in the LLR group. Patients in the LLR group had shorter length of stay (LOS) (6.78 ± 2.75 versus 8.39 ± 5.64 days, P = 0.038). R0 resection was 88% in both groups. CONCLUSIONS: In selected patients with CLM, LLR is feasible, safe and may achieve shorter LOS without inferior oncologic outcome.

Immunosuppression in pancreas transplantation: the Euro SPK trials and beyond.

The Immunosuppression in Pancreas Transplantation was historically based on the fact that the pancreas is an extremely immunogenic organ. Quadruple drug therapy with polyclonal or monoclonal antibodies induction was the mainstay therapy since the introduction of Cyclosporine A. In the modern era of Immunosuppression, Mycophenolate Mofetil replaced Azathioprine while Tacrolimus-another potent calcineurin inhibitor-had-and still has-a difficult challenge to replaced Cyclosporine A, due to its potential diabetogenic effect. Thanks to the first two EuroSPK studies which prospectively tried to answer several questions in that field. But, the future challenge will be in understanding the impact of innate immunity and ischemic reperfusion injuries on the long-term graft function. Hopefully, new drugs will be available and tested to block unspecific deleterious reactions to attenuate the proinflammatory response. It will be the aim of the third Euro SPK Study.

The low-dose (1 microg) adrenocorticotropin stimulation test in kidney and kidney-pancreas transplant patients: a potential guideline for steroid withdrawal.

Chronic steroid treatment is known to impair the hypothalamic-pituitary adrenal axis (HPA) but the need to assess HPA function prior to withdrawal of steroid therapy in post-transplant patients has not been uniformly accepted. We evaluated the status of the HPA axis in 48 kidney or kidney-pancreas transplant patients who were considered for possible discontinuation of glucocorticoid therapy using a recently validated dynamic test of HPA integrity, the low-dose (1 microg) adrenocorticotropin (ACTH) test. HPA suppression was detected in 29 (60%) of the patients, four of which had severe hypoadrenalism prohibitive of steroid withdrawal. Neither the duration of steroid treatment nor 8:00 am serum cortisol was a useful marker of hypoadrenalism. 8:00 am cortisol in subjects with normal HPA reserve and subjects with partial hypoadrenalism overlapped considerably but levels <5 microg/dL were indicative of severe hypoadrenalism. Pre-withdrawal diagnosis of partial hypoadrenalism allowed the identification of subjects requiring no further steroid replacement under regular daily circumstances. However glucocorticoid supplementation was prescribed in the event of stress such as infection, exceptional effort, trauma or surgery. Individuals with partial HPA impairment, but not patients with severe HPA suppression, improved upon retesting 3 months later. Patients exhibiting normal response to 1 mcg ACTH enjoyed an uneventful course following steroid withdrawal. Since hypoadrenalism is extremely common in post-transplant patients, we recommend the use of the low-dose ACTH test as a convenient method to identify patients with various degrees of hypoadrenalism prior to steroid withdrawal.

Corticosteroid withdrawal in simultaneous pancreas-kidney transplantation: a 3-year report.

UNLABELLED: Corticosteroids are an important element of immunosuppressive protocols, but their long-term use has detrimental effects on patient health, requiring eventual discontinuation. Herein, we present an evaluation of the safety and feasibility of corticosteroid withdrawal based on the findings of the Euro-SPK001 study. PATIENTS AND METHODS: In this prospective, multicenter study, 205 simultaneous pancreas-kidney (SPK) transplant recipients were randomized to immunosuppressive treatment with either tacrolimus and mycophenolate mofetil (MMF) (n = 103) or cyclosporine microemulsion (CsA-ME) and MMF (n = 102). All patients received concomitant rATG induction therapy, MMF, and short-term corticosteroids. RESULTS: Corticosteroid withdrawal was successful in the majority of in-study patients: 66% tacrolimus and 73% cyclosporin-ME. In-study patients selected for corticosteroid withdrawal experienced fewer pancreatic or kidney graft losses and fewer episodes of acute rejection compared with out-of-study patients or those continuing corticosteroid therapy. Acute rejection episodes occurred after corticosteroid withdrawal in two patients who had a previous rejection and in five patients who were rejection free before corticosteroid withdrawal. No rejection episodes were associated with graft loss or immediate serious consequences. Overall, corticosteroid withdrawal was achieved with an increase in both MMF and tacrolimus dosage. CONCLUSION: Corticosteroid withdrawal was successful in the majority of in-study patients. A long-term survey of corticosteroid withdrawal in SPK transplantation with multifactorial analyses is necessary to confirm these early results and to evaluate possible positive effects on glucose metabolism and hypertension.

Analysis of late operations in transplant patients.

OBJECTIVE: The charts of 174 consecutive patients were analyzed for incidence, etiology, and outcome of late operations (1 month or more posttransplant) following liver (OLT), kidney (KT), or pancreas-kidney (SPK) transplantation. MATERIALS AND METHODS: Clinical and demographic data were analyzed by chi-square analysis and Fisher exact tests to compare subpopulations. All P values <.05 were considered statistically significant. RESULTS: Censured data revealed 155 patients who did not suffer death or organ loss within 30 days of transplant. Late operations were performed on 89 occasions in 57 patients (65% occurred within 1 year posttransplant) with 20 patients having two or more late operations. Of these 89 procedures, 40% were emergent, 37% were related to the transplant operation, 38% were related to the initial disease, and 73% were major interventions. Fifty-six procedures were performed by the transplant surgery team and all occurred in the same facility as the transplant. CONCLUSIONS: Transplant recipients have a high incidence (36%) of late operations, most within the first year and most related to either the transplant or the original disease. This heavy operative load is important in planning resource allocation. Oversight by and involvement of the transplantation service in these procedures may contribute to the favorable outcome of these operations.