Separating chemotherapy-related developmental neurotoxicity from cytotoxicity in monolayer and neurosphere cultures of human fetal brain cells

Chemotherapy-induced neurotoxicity can reduce the quality of life of patients by affecting their intelligence, senses and mobility. Ten percent of safety-related late-stage clinical failures are due to neurological side effects. Animal models are poor in predicting human neurotoxicity due to interspecies differences and most in vitro assays cannot distinguish neurotoxicity from general cytotoxicity for chemotherapeutics. We developed in vitro assays capable of quantifying the paediatric neurotoxic potential for cytotoxic drugs. Mixed cultures of human fetal brain cells were differentiated in monolayers and as 3D-neurospheres in the presence of non-neurotoxic chemotherapeutics (etoposide, teniposide) or neurotoxicants (methylmercury). The cytotoxic potency towards dividing progenitors versus differentiated neurons and astrocytes was compared using: (1) immunohistochemistry staining and cell counts in monolayers; (2) through quantitative Western blots in neurospheres; and (3) neurosphere migration assays. Etoposide and teniposide, were 5–10 times less toxic to differentiated neurons compared to the mix of all cells in monolayer cultures. In contrast, the neurotoxicant methylmercury did not exhibit selectivity and killed all cells with the same potency. In 3D neurospheres, etoposide and teniposide were 24 to 10 times less active against neurons compared to all cells. These assays can be used prioritise drugs for local drug delivery to brain tumours

Acute success and short-term follow-up of catheter ablation of isthmus-dependent atrial flutter; a comparison of 8 mm tip radiofrequency and cryothermy catheters

Objectives: To compare the acute success and short-term follow-up of ablation of atrial flutter using 8 mm tip radiofrequency (RF) and cryocatheters. Methods: Sixty-two patients with atrial flutter were randomized to RF or cryocatheter (cryo) ablation. Right atrial angiography was performed to assess the isthmus. End point was bidirectional isthmus block on multiple criteria. A pain score was used and the analgesics were recorded. Patients were followed for at least 3 months. Results: The acute success rate for RF was 83% vs 69% for cryo (NS). Procedure times were similar (mean 144±48 min for RF, vs 158±49 min for cryo). More applications were given with RF than with cryo (26±17 vs. 18±10, p<0.05). Fluoroscopy time was longer with RF (29±15 vs. 19±12 min, p<0.02). Peak CK, CK-MB and CK-MB mass were higher, also after 24 h in the cryo group. Troponin T did not differ. Repeated transient block during application (usually with cryoablation) seemed to predict failure. Cryothermy required significantly less analgesia (p<0.01), and no use of long sheaths (p<0.005). The isthmus tended to be longer in the failed procedures (p=0.117). This was similar for both groups, as was the distribution of anatomic variations. Recurrences and complaints in the successful patients were similar for both groups, with a very low recurrence of atrial flutter after initial success. Concl

Biliary dyskinesia: a potentially unrecognized cause of abdominal pain in children

Biliary dyskinesia is defined as symptomatic biliary colic without cholelithiasis, and is diagnosed during cholescintigraphy by assessing gallbladder emptying with cholecystokinin (CCK) stimulation. Unfortunately, gallbladder emptying is not routinely assessed during cholescintigraphy in pediatric patients. The purpose of this review is to assess the effectiveness of cholecystectomy in patients with chronic abdominal pain and delayed gallbladder emptying and to assess whether these findings correlate with the histologic evidence of chronic cholecystitis. We retrospectively reviewed the medical records of all patients ( n =16) at our institution from October 1997 to August 2001 who underwent quantitative cholescintigraphy with CCK stimulation that demonstrated delayed gallbladder emptying (<35% at 60 min) and who subsequently underwent cholecystectomy. Laparoscopic cholecystectomy was performed in 16 patients with chronic abdominal pain. All 16 patients had delayed gallbladder emptying (mean ejection fraction : 15±8%, range: 3–32%). The mean age was 12±2 years (range: 8–17 years). Presenting symptoms included abdominal pain (86%), fatty food intolerance (27%), emesis (13%), and diarrhea (13%). Mean duration of abdominal pain before operation was 11±19 months (range: 2 weeks–6 years). One patient’s symptoms persisted postoperatively , but abdominal pain resolved in all other patient s. Histologic evidence of chronic cholecystitis was demonstrated in 86% of surgical specimens. Five patients underwent concurrent appendectomy , and all had normal appendiceal histology. Our experience suggests that children with chronic abdominal pain and delayed gallbladder emptying on CCK-stimulated cholescintigraphy are likely to benefit from cholecystectomy and to have histologic evidence of chronic cholecystitis.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47166/1/383_2004_Article_1234.pd

Matrix Metalloproteinases in Cytotoxic Lymphocytes Impact on Tumour Infiltration and Immunomodulation

To efficiently combat solid tumours, endogenously or adoptively transferred cytotoxic T cells and natural killer (NK) cells, need to leave the vasculature, traverse the interstitium and ultimately infiltrate the tumour mass. During this locomotion and migration in the three dimensional environment many obstacles need to be overcome, one of which is the possible impediment of the extracellular matrix. The first and obvious one is the sub-endothelial basement membrane but the infiltrating cells will also meet other, both loose and tight, matrix structures that need to be overridden. Matrix metalloproteinases (MMPs) are believed to be one of the most important endoprotease families, with more than 25 members, which together have function on all known matrix components. This review summarizes what is known on synthesis, expression patterns and regulation of MMPs in cytotoxic lymphocytes and their possible role in the process of tumour infiltration. We also discuss different functions of MMPs as well as the possible use of other lymphocyte proteases for matrix degradation