Tracking CNS and systemic sources of oxidative stress during the course of chronic neuroinflammation

The functional dynamics and cellular sources of oxidative stress are central to understanding MS pathogenesis but remain elusive, due to the lack of appropriate detection methods. Here we employ NAD(P)H fluorescence lifetime imaging to detect functional NADPH oxidases (NOX enzymes) in vivo to identify inflammatory monocytes, activated microglia, and astrocytes expressing NOX1 as major cellular sources of oxidative stress in the central nervous system of mice affected by experimental autoimmune encephalomyelitis (EAE). This directly affects neuronal function in vivo, indicated by sustained elevated neuronal calcium. The systemic involvement of oxidative stress is mirrored by overactivation of NOX enzymes in peripheral CD11b(+) cells in later phases of both MS and EAE. This effect is antagonized by systemic intake of the NOX inhibitor and anti-oxidant epigallocatechin-3-gallate. Together, this persistent hyper-activation of oxidative enzymes suggests an "oxidative stress memory" both in the periphery and CNS compartments, in chronic neuroinflammation

Cancer Screening by Systemic Administration of a Gene Delivery Vector Encoding Tumor-Selective Secretable Biomarker Expression

Cancer biomarkers facilitate screening and early detection but are known for only a few cancer types. We demonstrated the principle of inducing tumors to secrete a serum biomarker using a systemically administered gene delivery vector that targets tumors for selective expression of an engineered cassette. We exploited tumor-selective replication of a conditionally replicative Herpes simplex virus (HSV) combined with a replication-dependent late viral promoter to achieve tumor-selective biomarker expression as an example gene delivery vector. Virus replication, cytotoxicity and biomarker production were low in quiescent normal human foreskin keratinocytes and high in cancer cells in vitro. Following intravenous injection of virus >90% of tumor-bearing mice exhibited higher levels of biomarker than non-tumor-bearing mice and upon necropsy, we detected virus exclusively in tumors. Our strategy of forcing tumors to secrete a serum biomarker could be useful for cancer screening in high-risk patients, and possibly for monitoring response to therapy. In addition, because oncolytic vectors for tumor specific gene delivery are cytotoxic, they may supplement our screening strategy as a “theragnostic” agent. The cancer screening approach presented in this work introduces a paradigm shift in the utility of gene delivery which we foresee being improved by alternative vectors targeting gene delivery and expression to tumors. Refining this approach will usher a new era for clinical cancer screening that may be implemented in the developed and undeveloped world

Decompressive Abdominal Laparotomy for Abdominal Compartment Syndrome in an Unengrafted Bone Marrow Recipient with Septic Shock

Objective. To describe a profoundly immunocompromised (panleukopenia) child with septic shock who developed abdominal compartment syndrome (ACS) and was successfully treated with surgical decompression. Design. Individual case report. Setting. Pediatric intensive care unit of a tertiary children's hospital. Patient. A 32-month-old male with Fanconi anemia who underwent bone marrow transplantation (BMT) 5 days prior to developing septic shock secondary to Streptococcus viridans and Escherichia coli ACS developed after massive fluid resuscitation, leading to cardiopulmonary instability. Interventions. Emergent surgical bedside laparotomy and silo placement. Measurements and Main Results. The patient's cardiopulmonary status stabilized after decompressive laparotomy. The abdomen was closed and the patient survived to hospital discharge without cardiac, respiratory, or renal dysfunction. Conclusions. The use of laparotomy and silo placement in an unengrafted BMT patient with ACS and septic shock did not result in additional complications. Surgical intervention for ACS is a reasonable option for high risk, profoundly immunocompromised patients

Concurrent esophageal atresia with tracheoesophageal fistula and Hirschsprung disease

We describe two cases of concomitant Hirschsprung disease and esophageal atresia and tracheoesophageal fistula in the newborn, both of which were successfully diagnosed and managed in the neonatal period. This is the first report in the English literature to identify the coexistence of these distinct congenital malformations

The transanal approach with laparoscopy or laparotomy for the treatment of rectal strictures in Crohn\u27s disease

Introduction: Rectal strictures in patients with Crohn\u27s colitis are common and options described for their treatment include direct steroid injection, injection of tumor necrosis factor (TNF) inhibitors, endoscopic balloon dilatation, use of Hegar dilators, stricturoplasty, and proctectomy. Adequate treatment is a challenge, especially with respect to the prevention of stricture recurrence. We present an option for the surgical treatment of these strictures using a transanal resection of the rectum with the addition of laparoscopy or laparotomy. Methods: Three patients who had medically refractory or chronic Crohn\u27s colitis with rectal strictures were referred to us after failed medical management, rectal dilation, and balloon dilation of the strictures. In each case, we performed a transanal sphincter preserving dissection in the prone position and used the lithotomy position for intraabdominal mobilization, completion of the rectosigmoid resection, pull-through of the left colon, and coloanal anastomosis. Results: We resected the rectal strictures transanally in all three cases. One case provided the opportunity to perform a laparoscopy-assisted procedure, whereas the other 2 patients had laparotomy-assisted rectosigmoid resections. We did a coloanal anastomosis in 2 patients with healthy left colon. In the third case, the anal canal was preserved, but the patient was left with a stoma. Conclusions: Transanal resection is feasible in the surgical treatment of rectal strictures in patients with Crohn\u27s colitis. It preserves the anal sphincteric mechanism and may help in avoiding a permanent stoma in a subgroup of patients. We found the prone position very helpful in performing the transanal rectal dissection. © Copyright 2010, Mary Ann Liebert, Inc

The association of the severity of anorectal malformations and intestinal malrotation

© 2016 Elsevier Inc. Introduction Intestinal malrotation is a known association of anorectal malformations (ARM). Exact incidence, prognosis and surgical implications related to ARM are unknown. The aim of this study was to identify relevant associations between ARM and the presence of malrotation. Methods Records of patients from two referral centers were retrospectively analyzed looking for malrotation associated to ARM and its management, as well as factors for functional prognosis. Results 40 patients out of 2572 with ARM (1.6%) were found to have malrotation. Females were more commonly affected, and severe malformations were more frequent (cloaca, covered cloacal exstrophy in females and rectoprostatic and rectobladder neck fistula in males). Factors significantly associated with malrotation included Müllerian or Wolffian duct anomalies (P \u3c 0.05), while fecal continence status, presence of constipation, and use of laxatives or enemas were not. Detecting and correcting malrotation early on or at the time of colostomy creation represented a protective factor against additional surgeries for bowel obstruction and volvulus (P \u3c 0.001). Removal of the appendix during malrotation treatment required constructing a neoappendicostomy using a cecal flap in 9 out of 14 patients needing antegrade enema administration. Conclusions Malrotation presence in patients with ARM has the same frequency as in the general population, but it is more common in severe malformations. Surgeons treating these patients should address the malrotation at the time of colostomy opening if detected. The appendix should be preserved for potential future use as an appendicostomy for antegrade administration of enemas

The role of a colon resection in combination with a Malone appendicostomy as part of a bowel management program for the treatment of fecal incontinence

Purpose Surgical options previously described by us as part of a bowel management program for the treatment of soiling and fecal incontinence include (1) resection of a megarectosigmoid to reduce a patient\u27s laxative requirement or (2) a Malone appendicostomy in patients who require enemas. We have found that some patients may benefit from both procedures. Methods We reviewed 18 fecally incontinent patients with structural or functional disorders of the anorectosigmoid (16 ARM, 1 spina bifida, and 1 SCT) who underwent both procedures. Results Of 18 patients, the enema regimen prior to resection had an average volume of 681 ml of saline (Range 400-1000 ml) and 60 ml (Range 48-117 ml) of additives (glycerine, castile soap and/or phosphate). Following the colon resection, the average volume of saline and additives was 335 ml (Range 130-650 ml) and 25 ml (Range 0-60 ml), respectively, a 50% reduction for both (P \u3c 0.01). The time for enema administration and evacuation was reduced by 25%, and the enemas were more effective, rendering the patients clean in 18 of 18 cases (follow-up was 3 months to 21 years). 2 patients later demonstrated that they could be managed with laxatives alone. Conclusion In patients with poor continence potential and a megarectosigmoid, combining a colon resection with a Malone appendicostomy can make the enema more effective. In some rare cases we found the resection may allow for a better response to laxatives. © 2013 Elsevier Inc. All rights reserved