Quetiapine attenuates cadmium neurotoxicity by suppressing oxidative stress, inflammation, and pyroptosis.

BACKGROUND: Cadmium (Cd) is a heavy metal with extremely harmful toxic effects on the brain. Quetiapine (QTP) has unique neuroprotective effects with anti-inflammatory and antioxidant actions. However, its neuroprotective effect against Cd-induced neurotoxicity has not been previously studied. METHODS: QTP was administered in 10 and 20 mg/kg doses, while Cd was given in a dose of 6.5 mg/kg. RESULTS: In our study, QTP dose-dependently attenuated neuronal injury by downregulating p-tau and ß-amyloid. QTP potently attenuates histological abrasions induced by Cd. QTP counteracted oxidative injury by decreasing neuronal MDA and increased GSH levels mediated by downregulating Keap1 and upregulating Nrf2 and HO-1. QTP mitigated inflammation by decreasing MPO and NO2 and neuronal cytokines TNF-α and IL-1ß and upregulating IL-10 levels mediated by NF-κB downregulation. Additionally, QTP counteracted Cd-induced pyroptosis by downregulating caspase-1, ASC, and NLRP3 protein levels. CONCLUSION: In conclusion, QTP mitigates neurotoxicity induced by Cd through suppression of inflammation, pyroptosis, and oxidative stress by controlling the NF-κB, Keap1/Nrf2, and pyroptosis signals.

Vinpocetine mitigates methotrexate-induced duodenal intoxication by modulating NF-κB, JAK1/STAT-3, and RIPK1/RIPK3/MLKL signals.

OBJECTIVES: Methotrexate (MTX) is an antimetabolite agent widely used to manage a variety of tumors and autoimmune diseases. Nonetheless, MTX-induced intestinal intoxication is a serious adverse effect limiting its clinical utility. Inflammation and oxidative stress are possible mechanisms for MTX-induced intestinal toxicity. Vinpocetine (VNP) is a derivative of the alkaloid vincamine with potent anti-inflammatory and antioxidant effects. The current study investigated the protective intestinal impact of VNP in attenuating MTX-induced intestinal intoxication in rats. MATERIALS AND METHODS: VNP was administered orally in a dose of 20 mg/kg, while MTX was injected intraperitoneal in a dose of 20 mg/kg. RESULTS: VNP administration attenuated drastic histological changes induced by MTX and preserved both normal villus and crypt histology. VNP significantly attenuated oxidative injury by upregulating intestinal Nrf2 and HO-1 expression. VNP attenuated inflammation by reducing MPO, NO2-, TNF-α, and IL-1ß levels mediated by downregulating NF-κB, NDAPH-oxidase, IRF3, p-JAK-1, and p-STAT-3 expressions. Moreover, VNP potently counteracted intestinal necroptosis by effectively downregulating RIPK1, RIPK3, MLKL, and caspase-8 proteins. CONCLUSION: Therefore, VNP may represent a promising approach that can attenuate intestinal toxicity in patients receiving MTX.

miR-33a Inhibits the Differentiation of Bovine Preadipocytes through the IRS2-Akt Pathway.

Several microRNAs (miRNAs) are known to participate in adipogenesis. However, their role in this process, especially in the differentiation of bovine preadipocytes, remains to be elucidated. This study was intended to clarify the effect of microRNA-33a (miR-33a) on the differentiation of bovine preadipocytes by cell culture, real-time fluorescent quantitative PCR (qPCR), Oil Red staining, BODIPY staining, and Western blotting. The results indicate that overexpression of miR-33a significantly inhibited lipid droplet accumulation and decreased the mRNA and protein expression of adipocyte differentiation marker genes such as peroxisome proliferator-activated receptor gamma (PPARγ), sterol regulatory element-binding protein 1 (SREBP1), and fatty acid-binding protein 4 (FABP4). In contrast, the interference expression of miR-33a promoted lipid droplet accumulation and increased the expression of marker genes. Additionally, miR-33a directly targeted insulin receptor substrate 2 (IRS2) and regulated the phosphorylation level of serine/threonine kinase (Akt). Furthermore, miR-33a inhibition could rescue defects in the differentiation of bovine preadipocytes and the Akt phosphorylation level caused by small interfering IRS2 (si-IRS2). Collectively, these results indicate that miR-33a could inhibit the differentiation of bovine preadipocytes, possibly through the IRS2-Akt pathway. These findings might help develop practical means to improve the quality of beef.

Isolated pulmonary cryptococcosis in a patient with Crohn's disease treated with infliximab: A case report and literature review.

Tumor necrosis factor-alpha (TNF-α) inhibitors are widely used to treat various inflammatory conditions, where they have demonstrated excellent efficacy and tolerability. However, increased risk of infections is one of the most important concerns associated with these agents. Reactivation of tuberculosis and fungal infections have emerged as significant infective complications of anti-TNF-α therapy. Cryptococcus infection is an opportunistic fungal infection that can occur in patients receiving anti-TNF-α treatment. We report a rare case of isolated pulmonary cryptococcosis in a patient undergoing anti-TNF-α therapy for Crohn's disease. Our case should alert clinicians to the increased incidence and atypical presentation of pulmonary cryptococcosis in patients receiving anti-TNF-α treatment.

Extrapulmonary Tuberculosis masquerading as chest wall malignancy: Just never ceases to surprise!

With the emergence of the acquired immunodeficiency syndrome, we witnessed a higher incidence of disseminated and extrapulmonary tuberculosis. The infection sites commonly include lymph nodes, pleura, and osteoarticular areas, although any organ can be involved. Given the atypical presentation of the extrapulmonary disease, it poses a significant diagnostic challenge for the physicians; therefore, a high index of suspicion should be maintained, particularly where tuberculosis is endemic. Here we present a case of isolated chest wall tuberculosis in an immunocompetent patient.

Combination of coumarin and doxorubicin induces drug-resistant acute myeloid leukemia cell death.

BACKGROUND: Chemotherapy remains to be the method of choice used by clinicians to treat acute myeloid leukemia (AML) patients. However, the most common problem usually faced in the course of treatment is multidrug resistance (MDR). Nowadays, combination therapy involving natural products as adjuvant therapy to chemotherapy and radiotherapy has been used for many of health problems. Coumarin is a natural compound with known chemotherapeutic activity, as well as other pharmacological properties. We focused on the combination of coumarin and doxorubicin in overcoming of drug-resistance in acute myeloid leukemia. METHODS: Cell viability, Apoptotic and necrotic cell death with FACS, oxidative stress detection, and protein expression analysis were used in this study. RESULTS: Coumarin as a single drug exerts a significant cell death on Human acute myeloid leukemia (HL60); however, it does not show the same effect on drug-resistant acute myeloid leukemia (HL60/ADR). Comparing the effects of doxorubicin and coumarin as single drugs versus a combination of coumarin and doxorubicin showed a significant apoptotic cell death. CONCLUSION: In AML patients, the development of multiple drug resistance (MDR) is the biggest challenge in treating AML patients. Combination therapy with coumarin may be a good choice to overcome the drug resistance in AML patients.

Impact of postoperative pancreatic fistula on long-term oncologic outcomes after pancreatic resection.

BACKGROUND: The short-term morbidity associated with post-operative pancreatic fistula (POPF) is well established, however data regarding the long-term impact are lacking. We aim to characterize long-term oncologic outcomes of POPF after pancreatic resection through a single institution, retrospective study of pancreatic resections performed for adenocarcinoma from 2009 to 2016. METHODS: Kaplan-Meier survival analysis, logistic regression, and multivariate analysis (MVA) were used to evaluate impact of POPF on overall survival (OS), disease free survival (DFS), and receipt of adjuvant chemotherapy (AC). RESULTS: 767 patients were included. 82 (10.6%) developed grade B (n = 67) or C (n = 15) POPF. Grade C POPF resulted in decreased OS when compared to no POPF (20.22 vs 26.33 months, p = 0.027) and to grade B POPF (20.22 vs. 26.87 months, p = 0.049). POPF patients were less likely to receive AC than those without POPF (59.5% vs 74.9%, p = 0.003) and grade C POPF were less likely to receive AC than all others (26.7% vs 74.2%, p = 0.0001). CONCLUSION: POPF patients are less likely to receive AC and more likely to have delay in time to AC. These factors are exacerbated in grade C POPF and likely contribute to decreased OS. These findings validate the clinical significance of the ISGPF definition of POPF.

Ptosis and Miosis Associated with Fibrosing Mediastinitis.

BACKGROUND Fibrosing mediastinitis is a rarely seen, progressive disease. It results from an excessive fibrotic reaction in the mediastinum. We describe a presentation of fibrosing mediastinitis that, to our knowledge, has never been seen before. CASE REPORT A 30-year-old female Colombian flight attendant presented with a right eyelid droop. Examination revealed partial right-sided ptosis and miosis but no anhidrosis. An ill-defined firm swelling was palpable at the root of the neck. Chest radiography revealed a widened mediastinum, and computerized tomography (CT) showed a right paratracheal mass without calcification extending to the thoracic inlet, encasing multiple blood vessels. All basic blood tests, magnetic resonance imaging of the head, and ultrasound Doppler of the neck vessels were normal. History and work up for infections including fungal diseases, granulomatous diseases, vasculitis, and autoimmune diseases were negative. Positron emission tomography (PET) showed significant FDG uptake in the mediastinum. Mediastinal biopsy was histologically consistent with fibrosing mediastinitis. All relevant immunohistochemistry and microbiological studies were negative. Subsequently, the patient developed signs of superior vena cava compression; this was managed by balloon angioplasty, which resulted in improvement of symptoms. However, over time, her symptoms worsened progressively, resulting in a left-sided ptosis and radiological progression of the mass on CT. She received treatment with rituximab and concomitant steroids, which yielded excellent results: the treatment led to both resolution of her symptoms and regression of the mass and its metabolic activity on PET scan. CONCLUSIONS Fibrosing mediastinitis can present with an incomplete Horner's syndrome. Treatment with rituximab and steroids shows promising results in select cases of metabolically active idiopathic fibrosing mediastinitis.

Gene Expression Profiling to Delineate the Anticancer Potential of a New Alkaloid Isopicrinine From Rhazya stricta.

Background:Rhazya stricta has been used as a folkloric medicinal herb for treating various diseases such as diabetes, inflammatory disorders, and sore throat. Several studies have revealed the potential of this plant as an important source of phytochemicals with anticancer properties. Objective: The present study was designed to isolate a novel anticancer compound from Rhazya stricta and elucidate its mechanism of action using genomics approach. Methods:Rhazya stricta leaves extract was prepared, and several alkaloids were purified and characterized. These alkaloids were screened for their anticancer potential. One of the alkaloids, termed as isopicrinine, showed efficient cytotoxicity against MCF7 breast cancer cell line and was selected for further analysis. RNA-Seq transcription profiling was conducted to identify the affected genes and cellular pathways in MCF7 cells after treatment with isopicrinine alkaloid. Results: In vitro studies revealed that newly identified isopicrinine alkaloid possess efficient anticancer activity. Exposure of MCF7 cells with isopicrinine affected the expression of various genes involved in p53 signaling pathway. One of the crucial proapoptotic genes, significantly upregulated in MCF7 after exposure to alkaloid, was PUMA (p53 upregulated modulator of apoptosis), which is involved in p53-dependent and -independent apoptosis. Moreover, exposure of sublethal dose of isopicrinine alkaloid in breast cancer cell line led to the downregulation of survivin, which is involved in negative regulation of apoptosis. Besides, several genes involved in mitosis and cell proliferation were significantly downregulated. Conclusion: In this article, we report the determination of a new alkaloid isopicrinine from the aerial parts of Rhazya stricta with anticancer property. This compound has the potential to be developed as a drug for curing cancer.

CA19-9 Change During Neoadjuvant Therapy May Guide the Need for Additional Adjuvant Therapy Following Resected Pancreatic Cancer.

BACKGROUND: Neoadjuvant therapy (NAT) is increasingly utilized for pancreatic cancer, however the added benefit of adjuvant therapy (AT) in this setting is unknown. We hypothesized that the magnitude of CA19-9 response to NAT can guide the need for further AT in resected pancreatic cancer. METHODS: CA19-9 secretors who received NAT for pancreatic cancer during 2008-2016 at a single institution were analyzed and CA19-9 response (difference between pre- and post-NAT values) was measured. Kaplan-Meier estimators and Cox proportional hazard ratio models were used to determine the optimal CA19-9 response at which AT ceases to confer any additional survival benefit after NAT. RESULTS: A total of 241 patients (mean age 65.4 years, 50% female) with complete CA19-9 data who underwent NAT followed by resection were analyzed. In a cohort of patients (n = 78) in whom CA19-9 normalized with a decrease > 50% after NAT (optimal responders), AT was not associated with additional survival benefit (40.6 vs. 39.0 months, p = 0.815). Conversely, in the cohort of patients (n = 163) in whom NAT was not associated with normalization and a decrease of ≤ 50% in CA19-9 (suboptimal responders), receipt of AT was associated with a survival benefit (34.5 vs. 19.1 months, p < 0.001) following NAT. A Cox proportional hazards model confirmed CA19-9 normalization and decrease > 50% during NAT to predict no additional survival benefit from AT. CONCLUSIONS: The magnitude of CA19-9 response to NAT may predict the need for further AT in resected pancreatic cancer. Prospective studies are needed to elucidate the optimal interplay of NAT and AT in pancreatic cancer.

Prevalence of gastroesophageal reflux and risk factors for erosive esophagitis in obese patients considered for bariatric surgery.

BACKGROUND: Gastroesophageal reflux disease (GERD) is common in obese individuals. Prospective studies investigating validated GERD questionnaires and clinical parameters at identifying erosive esophagitis (EE) in this population are limited. OBJECTIVE: To prospectively evaluate the prevalence of GERD in obese patients considered for bariatric surgery and identify risk and predictive factors for EE. METHODS: Eligible patients completed two validated questionnaires: GERDQ and Nocturnal Symptom Severity Impact (N-GSSIQ) before routine esophagogastroduodenoscopy. RESULTS: 242 consecutive patients were enrolled (130 females; mean age 37.8 ± 11.8 years; mean BMI 40.4 ± 5.3 kg/m2). The overall prevalence of gastroesophageal reflux (GERDQ ≥ 8, EE and/or PPI use) was 62.4%. EE was identified in 82 patients (33.9%) including 13/62 (21.0%) receiving PPIs at baseline. Multivariate logistic regression identified GERDQ ≥ 8 (OR = 6.3, 95%CI 3.0-13.1), hiatal hernia (OR = 4.2, 95%CI 1.6-10.7), abnormal Hill grade (OR = 2.7, 95%CI 1.4-5.4), and tobacco use (OR = 2.5, 95%CI 1.2-4.9) as independent risk factors for EE. A pre-endoscopic composite assessment including GERDQ ≥ 8 and presence of severe nocturnal reflux symptoms had 90% specificity and 20.7% sensitivity in identifying EE (NPV 68.9% and PPV 51.5%). CONCLUSION: GERD is highly prevalent in obese patients. Anthropometric data and GERD questionnaires have limited accuracy at predicting erosive disease. Pre-operative endoscopic assessment in this population appears warranted.

Risk of Venous Thromboembolism for Patients with Pancreatic Ductal Adenocarcinoma Undergoing Preoperative Chemotherapy Followed by Surgical Resection.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDA) is associated with a hypercoagulable state, resulting in a high risk of venous thromboembolism (VTE). Risk of VTE is well established for patients receiving chemotherapy for advanced disease and during the perioperative period for patients undergoing surgical resection. However, data are lacking for patients undergoing neoadjuvant treatment followed by resection, who may have a unique risk of VTE because of exposure to both chemotherapy and surgery. METHODS: The study included patients with PDA who underwent neoadjuvant therapy followed by surgery from 2007 to June 2017. Development of VTE was evaluated from the start of treatment through the 90-day postoperative period. Risk factors including demographic, treatment, and laboratory variables were evaluated. RESULTS: The study investigated 426 patients receiving neoadjuvant therapy before surgical resection. Of these patients, 20% had a VTE within 90 days postoperatively (n = 87), and 70% of the VTE occurred during the postoperative period. The VTE included pulmonary embolism (30%), deep vein thrombosis (33%), and thrombosis of the portal vein (PV)/superior mesenteric vein (SMV) (40%). A pretreatment hemoglobin level lower than 10 g/dL and a platelet count higher than 443 were independently associated with VTE during neoadjuvant treatment. The independent predictors of postoperative VTE were a body mass index higher than 35 kg/m2, a preoperative platelet-to-lymphocyte ratio higher than 260, resection with distal pancreatectomy with celiac axis resection/total pancreatectomy, PV/SMV resection, and longer operative times. Development of VTE was associated with worse overall and disease-free survival and an independent predictor of survival and decreased likelihood of receiving adjuvant chemotherapy. CONCLUSIONS: Venous thromboembolism during neoadjuvant therapy and the subsequent perioperative period is common and has a significant impact on outcome. Further study into novel thromboprophylaxis measures or protocols during neoadjuvant treatment and the perioperative period is warranted.

Robotic Inguinal Hernia Repair: A Large Health System's Experience With the First 300 Cases and Review of the Literature.

BACKGROUND: Over the past 5 y, robotic surgery has expanded within general surgery, especially in regard to hernia repairs. We aimed to evaluate the outcomes of the early experience of over 300 consecutive robotic inguinal hernia repairs performed in an academic multihospital system. METHODS: Consecutive robotic inguinal hernia repairs performed between December 2015 and June 2017 were analyzed. Retrospective chart review was performed, and hospital records were queried. Descriptive statistics were performed. A surgical learning curve case study is presented, breakdown of operative time is delineated, and review of the literature performed. RESULTS: Over a period of 19 mo, 335 robotic inguinal hernia repairs were performed across seven hospitals by 18 surgeons. The mean patient age was 59 y (standard deviation [SD] 14), 93% were male, and the mean body mass index was 27 (SD 4.6). Bilateral hernia repairs were performed on 131 patients (39%). The mean operative time was 102 min (SD 38) and a resident or fellow trainee was present in the operating room for 119 cases (36%). Minor postoperative complications occurred in 54 patients (16%), including 14 with urinary retention (4.2%) and 13 with scrotal swelling (3.9%). The learning curve of the first adopted surgeon was 11-12 cases. CONCLUSIONS: In the largest case series of robotic inguinal hernia repairs to date reporting short-term outcomes, early experience in an academic multihospital system produced safe outcomes including no open conversions, reoperations, and one readmission. In addition, the learning curve is manageable showing improvement in operating time with experience.

Correction to: Evolution of a Novel Robotic Training Curriculum in a Complex General Surgical Oncology Fellowship.

In the XML of the original article, L. Mark Knab's first name was tagged incorrectly.

Evolution of a Novel Robotic Training Curriculum in a Complex General Surgical Oncology Fellowship.

BACKGROUND: Robotic surgery is increasingly being used for complex oncologic operations, although currently there is no standardized curriculum in place for surgical oncologists. We describe the evolution of a proficiency-based robotic training program implemented for surgical oncology fellows, and demonstrate the outcomes of the program. METHODS: A 5-step robotic curriculum began integration in July 2013. Fellows from July 2013 to August 2017 were included. An education portfolio was created for each fellow, including pre-fellowship experience, fellowship experience with data from robotic curriculum and operative experience, and post-fellowship practice information. RESULTS: Of 30 fellows, 20% completed a prior fellowship, 97% trained at an academic residency, 57% had prior robotic training (median 5 h), and 43% had performed robotic surgery (median 0 cases). In fellowship, on average, fellows spent 5 h on the virtual reality curriculum and performed 19 biotissue anastomoses. For total surgeries, fellows operating from the console increased over time (p = 0.005). For pancreas, the average percentage of robotic pancreaticoduodenectomy (PD) steps completed increased (p < 0.011), as did the number of PDs in which the fellow completed the entire resection (p = 0.013). Fellows were 10 times more likely to complete the entire distal than PD from the console (p < 0.01). Post-fellowship, 83% of fellows obtained an academic position, 88% utilized robotics, and 91% performed pancreatic surgery. CONCLUSIONS: With dedicated training, fellows can safely primarily perform complex gastrointestinal robotic surgeries and, after graduation, take jobs incorporating this skill set. In this era of scrutiny on cost and outcomes, specialized training programs offer a safe integration option for complex technical skills.

Outcome of combination antiviral therapy in chronic hepatitis C virus infection during therapy of acute lymphoblastic leukemia.

Chronic hepatitis C virus (HCV) infection is not uncommon in patients with acute leukemia due to frequent blood transfusions. The treatment of HCV in patients with acute leukemia can produce profound immune dysfunction with the risk of severe cytopenia. We report the case of a young man who was treated with combined therapy of peginterferon α 2a and ribavirin for HCV while he was on maintenance anti-leukemic treatment. The patient required reduction in the dose of peginterferon α 2a and the addition of filgrastim due to neutropenia. Therapy for HCV was continued for 72 weeks and at the end of therapy, the patient had undetectable HCV RNA. The patient maintained a sustained viral response two years after the end of therapy and developed complete remission of leukemia, whereupon his anti-leukemic therapy was also discontinued. We recommend conducting further large prospective studies in HCV patients treated for leukemia to determine the safety and efficacy of antiviral therapy in this group of patients.

Laparoscopic procurement of single versus multiple artery kidney allografts: is long-term graft survival affected?

BACKGROUND: Living donor kidneys with multiple arteries (MA) are increasingly procured laparoscopically for transplant. METHODS: We compare long-term graft function and survival of kidneys with single arteries (SA) and MA over a 10-year period. RESULTS: There were a total of 218 grafts with SA and 60 grafts with MA. The MA group had longer operative and ischemic times than SA group. There was a small increase in ureteral complication (8.3% vs. 2.3% P=0.06) and a significantly higher incidence of rejection (23.3% vs. 10.1%, P=0.01) in MA group than in SA group. Graft function was lower in MA group than SA group. The 5-year graft survival by Kaplan Meier analysis was better in SA group than in MA group (P=0.023). The estimated graft survivals at 1, 3, and 5 year were 94.4%, 90.6%, and 86% for SA group and 89.6%, 83.2%, and 71.8% for MA group. There was a higher percentage of graft loss from chronic allograft nephropathy in MA group than in SA group (16.7% vs. 5.5%, P=0.01). The presence of MA (vs. SA) was an independent risk for acute rejection (OR 3.60, 95% CI 1.59-8.14, P=0.002) and for graft loss (HR 2.31, 95% CI 1.05-5.09, P=0.038). CONCLUSION: Laparoscopic procurement of living donor kidneys with SA may be associated with a lower risk of rejection, better function, and superior long-term survival when compared with kidneys with MA.