Nitric oxide and chronic gut inflammation: controversies in inflammatory bowel disease.

One of the most consistent and dramatic findings in both experimental and human inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis) is the enhanced expression of the inducible isoform of nitric oxide synthase (iNOS) and the sustained overproduction of the free radical nitric oxide (NO). The role that iNOS-derived NO plays in the pathophysiology of inflammatory bowel disease remains the subject of intense investigation and active debate. Although several different studies using a variety of animal models of acute and chronic gut inflammation suggest that NO may promote intestinal inflammation, an equally impressive number of investigations suggest that iNOS may play no role or may act to attenuate or to limit the extent of inflammatory tissue injury. This review discusses some of the basic concepts related to the immunoregulation of chronic gut inflammation and summarizes the current state of knowledge of the role that NO may play in modulating inflammatory tissue injury.     

Cycle-related toxicity and transformation in 10T1/2 cells treated with N-methyl-N''-nitro-N-nitrosoguanidine.

Exposure of C3H 10T1/2 Cl 8 cells, synchronized by release from confluence-induced arest of proliferation, to different concentrations of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) for 30 min at various points during the cell cycle causes dose-dependent toxicity (decrease in relative colony-forming efficiency or "survival") that increases linearly during the first G1 phase, reaches a maximum in early to middle S phase, and decreases during late S. In the course of the second S phase, toxicity again becomes maximal. The transformation rate (type III foci) increases and decreases with a similar pattern, increasing during the first G1 phase to a maximum during early S phase, subsequently decreasing, and then increasing again during the second S phase. Although periods of maximal toxicity and transformation roughly coincide with some portion of the S phase, the mechanisms underlying these phenomena appear to differ for the following reasons: (a) toxicity is linearly related to dose of MNNG, whereas the latter is linearly related to the logarithm of transformation rate, and (b) the ratio between toxicity and transformation varies with the cycle phase and the dose of MNNG.     

Reactive Oxygen Species and Vascular Cell Adhesion Molecule-1 in Distant Organ Failure Following Bile Duct Obstruction in Mice

Pulmonary injury with leukocyte infiltration is a frequent occurrence in obstructive cholangitis patients. We wished to evaluate the roles of reactive oxygen species and vascular cell adhesion molecule-1 (VCAM-1) in this distant organ failure. Wild type (WT) and transgenic (SODtg) mice overexpressing superoxide dismutase underwent bile duct ligation and transection (BDL). VCAM-1 expression was quantified, and histopathology was assessed for the liver and lung. BDL resulted in increased leukocyte infiltration to the lung at five days in WT mice. VCAM-1 expression significantly increased in WT mouse liver at three days and WT mouse lung at five days. When these same experiments were performed in SODtg mice, these increases in leukocyte infiltration and VCAM-1 expression in lung were significantly attenuated. These data suggest that reactive oxygen species produced in response to BDL may up-regulate VCAM-1 expression in the lung and play an important role in the pathophysiology of this pulmonary injury.     

Cytokine and adhesion molecule expression in SCID mice reconstituted with CD4+ T cells

The objectives of this study were to quantify colonic cytokine and endothelial cell adhesion molecule (ECAM) expression in the colons of severe combined immunodeficient (SCID) mice reconstituted with different subsets of CD4+ T lymphocytes. We found that animals injected with CD45RBhigh but not CD45RBlow T cells or phosphate-buffered saline (PBS) developed clinical evidence of colitis at 6-8 weeks following reconstitution, as assessed by loss of body weight, development of loose stools and/or diarrhea, and histopathology. Concurrent with the onset of distal bowel inflammation was enhanced expression of a variety of Th1 and macrophage-derived cytokines including interferon gamma, tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-6, IL-12, and IL-18 lymphotoxin-beta. In addition, message levels and vascular surface expression of ICAM-1, VCAM-1, and MAdCAM-1 were all significantly enhanced in the colitic SCID mice reconstituted with CD45RBhigh T cells compared with SCID mice reconstituted with PBS or CD45RBlow T cells that did not develop disease. Significant increases in some of these ECAMs were also noted in the cecum and stomach and to a lesser degree in the small bowel. Our data confirm that reconstitution of SCID mice with CD45RBhigh but not CD45RBlow T cells induces chronic colitis, and that the colonic inflammation is associated with enhanced expression of proinflammatory cytokines and different ECAMs in the colon. Furthermore, our studies demonstrate that reconstitution of SCID mice with CD45RBhigh T cells enhances ECAM expression in tissues distant from the site of active inflammation.     

Survival outcomes of acute normovolemic hemodilution in patients undergoing primary debulking surgery for advanced ovarian cancer: A Memorial Sloan Kettering Cancer Center Team Ovary study

ObjectiveTo describe oncologic outcomes after using acute normovolemic hemodilution (ANH) to reduce requirement for allogenic red blood cell transfusions (ABT) in patients undergoing primary debulking surgery (PDS) for advanced ovarian cancer.MethodsWe performed a post-hoc analysis of a recent prospective trial investigating the safety and feasibility of ANH during PDS for advanced ovarian cancer. We report long-term survival outcomes. We compared demographics, clinicopathological characteristics, survival outcomes in this cohort of Stage IIIB-IVB high-grade serous ovarian cancer patients undergoing ANH (ANH group), with a retrospective cohort of all other patients (standard group) undergoing PDS during the same time period (01/2012–04/2017). Standard statistical tests were used.ResultsThere were no demographic or clinicopathological differences between ANH (n = 33) and standard groups (n = 360), except for higher median age at diagnosis (57 vs. 62 years, respectively; p = 0.044) and shorter operative time (357 vs. 446 min, respectively; p < 0.001) in the standard group. Cytoreductive outcomes (ANH vs. standard): 0 mm, 69.7 vs. 63.9%; gross residual disease (RD) ≤1 cm, 21.2 vs. 26.9%; >1 cm, 9.1 vs. 9.2% (p = 0.78). RD after PDS was the only independent factor associated with worse progression-free survival (PFS) on multivariable analysis (p < 0.001). Patients with BRCA mutations trended towards improved PFS (p = 0.057). Significant factors for overall survival (OS) on multivariable analysis: preoperative CA125 (p = 0.004), ascites (p = 0.018), RD after PDS (p = 0.04), BRCA mutation status (p < 0.001). After adjustment for potential confounders, ANH was not independently associated with PFS or OS [PFS: HR 0.928 (0.618–1.395); p = 0.721; OS: HR 0.588 (95%CI: 0.317–1.092); p = 0.093].ConclusionsANH is an innovative approach in intraoperative management. It was previously proven to decrease need for ABT while maintaining the ability to achieve complete gross resection and associated benefits.     

A phase I open-label study of selinexor with paclitaxel and carboplatin in patients with advanced ovarian or endometrial cancers

PurposeSelinexor, a selective inhibitor of nuclear export, monotherapy causes nuclear accumulation of tumor-suppressor proteins and has anti-tumor activity in ovarian and endometrial cancers. The safety and tolerability of oral selinexor plus intravenous carboplatin and paclitaxel chemotherapy (selinexor + CP) was evaluated in this population.Patients and methodsThis phase I, 3 + 3 dose-escalation study assessed 4 selinexor + CP regimens. Patients in cohorts of 3, regardless of disease type, were administered 1 of 4 alternating regimens (selinexor at 30 mg/m² or 60 mg plus CP at AUC 5 and 175 mg/m² or 80 mg/m², respectively) for 6–10 cycles (1 cycle = 21 days), followed by selinexor maintenance. Enrolled patients with ovarian cancer had received 1 prior platinum-based therapy. Patients with endometrial cancer were chemotherapy-naive or had received 1 prior platinum-based therapy. Response was evaluated every 9 weeks.ResultsTwenty-three patients were treated (5 serous ovarian cancer; 18 endometrial cancer, including 6 carcinosarcomas). The most common treatment-related adverse events (TRAEs) were thrombocytopenia (100%), leukopenia (91%), and hyperglycemia (87%). The most common grade 3/4 TRAEs were leukopenia (70%), neutropenia (70%), lymphopenia (61%), anemia (57%), and alanine transaminase increase (43%). One treatment-related dose-limiting toxicity (grade 3 syncope) occurred. Twelve patients achieved a partial response and 1 achieved a complete response. Responses to all four regimens were observed in ovarian and endometrial cancers.ConclusionsCombination selinexor + CP was safe and tolerated in advanced ovarian and endometrial cancers.     

A multidisciplinary approach to carotid paragangliomas

The surgical management of carotid paragangliomas can be problematic. A multidisciplinary approach was used to include vascular surgery, otolaryngology, and neuroradiology to treat these patients over 9 years. From January 1992 to July 2001, a multidisciplinary team evaluated patients with carotid paragangliomas. Analyzed patient data included age, gender, diagnostic evaluation, tumor size, preoperative tumor embolization, operative exposure, need for extracranial arterial sacrifice/reconstruction, postoperative morbidity including cranial nerve dysfunction, and long-term follow-up. Twenty-five carotid paragangliomas in 20 patients underwent multidisciplinary evaluation and management. Average age was 51 years (range, 28-83 years), and 52% were male. Diagnostic evaluation included computed tomography in 76%, magnetic resonance imaging/magnetic resonance angiography in 52%, catheter angiography in 60%, and duplex ultrasonography in 16%. An extended neck exposure was required in 11 cases (44%), mandibulotomy was used once (4%), and mandibular subluxation was never required. The external carotid artery (ECA) was sacrificed in 8 cases (32%). The carotid bifurcation was resected in 1 patient (4%) requiring interposition reconstruction of the internal carotid artery. Preoperative tumor embolization was performed for 13 tumors (52%). Operative blood loss for patients undergoing preoperative embolization (Group I) was comparable to the nonembolized group (group II): group I lost 365 +/-180 mL versus 360 +/- 101 mL for group II (P = .48). This occurred despite larger tumors (group I - 4.2 cm versus group II - 2.1 cm, P = .03) and a higher mean Shamblin class (group I - 2.5 versus group II - 1.45, P = .001) for group I. There were no perioperative mortalities. Transient cranial nerve dysfunction occurred in 13 CBTs (52%), 2 (8%) of which remained present after 4 months. Patients with carotid paragangliomas benefit from a multidisciplinary team approach. Neuroradiology has been used for selective preoperative embolization, which has decreased estimated blood loss during excision of larger complex tumors. A combined surgical team of otolaryngology and vascular surgery provides for exposure of the distal internal carotid artery as high as the skull base, limited permanent cranial nerve dysfunction, and selective early division and excision of the external carotid artery for complete tumor resection.     

The Predictors and Contents of Post-Event Processing in Social Anxiety

The present study investigated the factors that influence the likelihood that individuals engage in post-event processing (PEP)—the act of engaging in a detailed, negative, and self-focused review following social situations. This study also examined the cognitive contents of PEP in a nonclinical sample (N = 40). Participants undertook both a 5-min speech and conversation and then completed measures assessing cognitions, behaviours, and physiological processes that occurred during each task. Twenty-four hours later, PEP was measured in relation to both tasks. Results showed firstly that PEP was greater following the speech than the conversation. Secondly, negative assumptions were found to be a unique predictor of PEP over and above depression, trait anxiety, and other cognitive-behavioural variables. Finally, higher levels of social anxiety were associated with experiencing more negative self-perceptions and regret-based cognitions during PEP. Current findings underscore the importance of targeting negative assumptions, self-related cognitions, and regret-based thoughts in therapy.