Effects of amifostine on clonogenic mesenchymal progenitors and hematopoietic progenitors exposed to radiation

PURPOSE: To determine the radiation sensitivities of mesenchymal progenitors and hematopoietic progenitors, and to determine the in vitro effects of amifostine on hematopoietic and mesenchymal progenitors exposed to radiation. METHODS: Radiosensitivity of mesenchymal progenitor cells was determined by exposing marrow low-density cells to radiation at doses of 100 to 800 cGy. Mesenchymal cell colonies were established by plating 2.5 x 10(5) marrow low-density cells in long-term marrow culture medium (LTCM). The size, frequency, and cellular composition of the mesenchymal progenitor cells were scored after 14 days of incubation. Mesenchymal progenitor cells were subdivided into progenitors forming fibroblast and adipocyte mixed colonies (CFU-FA), and pure fibroblast colonies (CFU-F). Hematopoietic progenitors were assessed by methylcellulose-based assay. RESULTS: Radiation at 100 cGy caused a mild decrease in CFU-F and CFU-FA derived colonies by 12% and 13%, respectively; 200 cGy decreased CFU-F by 36% and CFU-FA by 52%; 400 cGy decreased CFU-F by 50% and CFU-FA by 86%; and 600 cGy decreased CFU-F by 24%, with total absence of CFU-FA. Pretreatment with amifostine protected 100% of CFU-F at 100 and 200 cGy, 84% at 400 cGy, 46% at 600 cGy, and 14% at 800 cGy. With CFU-FA colonies amifostine pretreatment provided only minimal radioprotection. For hematopoietic progenitors radiation at 100 cGy reduced CFU-GM by 74% but had no significant effect on CFU-GEMM and BFU-E. Radiation at 200 cGy decreased CFU-GEMM by 72%, BFU-E by 54%, and CFU-GM by 84%; 400 cGy further decreased CFU-GEMM by 83%, BFU-E by 81%, and CFU-GM by 93%. Pretreatment with amifostine resulted in twofold stimulation of CFU-GEMM and BFU-E colonies. All BFU-E colonies were protected up to 200 cGy. For CFU-GEMM amifostine pretreatment resulting in 68% at 200 cGy and 31% at 400 cGy. For CFU-GM colonies it was 54% at 100 cGy, 32% at 200 cGy, and 12% at 400 cGy. CONCLUSIONS: Mesenchymal progenitor cell subpopulations are differentially sensitive to radiation. Amifostine protects both mesenchymal and hematopoietic progenitors against radiation injury, though the level of protection appears to be dependent upon the sensitivities of these progenitor cells to radiation. Amifostine is a potent stimulant of BFU-E and CFU-GEMM progenitor colonies.     

Acute lymphocytic leukemia after fulminant varicella associated with severe neutropenia

Acute lymphocytic leukemia developed within 3 weeks after a fulminant case of varicella complicated by pneumococcal sepsis and severe bone marrow suppression in a child treated with filgrastim (human granulocyte colony-stimulating factor).     

Cyclooxygenase 2 mediates post-inflammatory colonic secretory and barrier dysfunction

BACKGROUND AND AIMS: The colonic epithelium plays a key role in host defence. During colitis, epithelial function is impaired, leading to elevated bacterial translocation and exacerbation of inflammation. We previously documented perturbation of epithelial function, in terms of secretion and as a barrier to bacterial translocation, that persisted long after resolution of a bout of colitis in the rat. The mechanisms underlying the epithelial dysfunction are not completely understood. METHODS: Given the ability of prostaglandin (PG) D2 to suppress colonic epithelial secretion, we investigated the potential roles of this eicosanoid and of cyclooxygenase 2 (COX-2) in mediating post-colitis epithelial secretory and barrier dysfunction. RESULTS: Six weeks after induction of colitis with trinitrobenzene sulphonic acid, there was marked elevated synthesis of PGD2 and elevated COX-2 expression. Selective COX-2 inhibition abolished the increase in PGD2 synthesis. Colonic chloride secretory responses (in vitro) were significantly diminished relative to those in controls, a defect that was reversed by pre-exposure to a selective COX-2 inhibitor (celecoxib) but not to a selective COX-1 inhibitor (SC-560). The hyporesponsiveness was mimicked by pre-exposure of normal colonic tissue to PGD2, but not to its metabolite, 15-deoxy-Delta(12-14)PGJ2. The post-colitis rats exhibited a 10-fold increase in bacterial colonisation of the colon, and >3-fold increase in bacterial translocation. Twice daily treatment for one week with a selective COX-2 inhibitor (rofecoxib) did not affect bacterial colonisation but abolished the increase in bacterial translocation. CONCLUSIONS: These studies demonstrate an important role for COX-2, possibly via generation of PGD2, in mediating the prolonged epithelial secretory and barrier dysfunction after a bout of colitis in the rat.     

The development of Partners for Health's integrated community pathway for postmyocardial infarction patients

Partners for Health convened an interdisciplinary team to evaluate the quality of care received by cardiac patients. The team detailed the suboptimal postacute care of patients with ischemic heart disease. To solve the quality problems, a cross-sectoral team, using an approach that is in accordance with the American Heart Association's Scientific Statement on Pathways, systematically developed and implemented an integrated community pathway for myocardial infarction patients. The paper contributes to the literature on pathways by presenting the lessons learned from the authors' first-hand experience. The paper concludes with recommendations based on those lessons.     

Congenital airway abnormalities in neonates

Airway malformations such as laryngeal atresia, tracheal agenesis and subglottic stenosis are rare and present at birth with significant respiratory distress with or without stridor. There may be an initial improvement on bag and mask ventilation. Repeated attempts at intubation are met with failure. The related embryology and clinical aspect of airway malformations have been discussed. The prognosis in tracheal agenesis is universally fatal but cases with laryngeal atresia and subglottic stenosis may be saved with prompt tracheostomy and later surgical reconstruction.     

Deficits in auditory brainstem pathway encoding of speech sounds in children with learning problems

Auditory brainstem responses were recorded in normal children (NL) and children clinically diagnosed with a learning problem (LP). These responses were recorded to both a click stimulus and the formant transition portion of a speech syllable /da/. While no latency differences between the NL and LP populations were seen in responses to the click stimuli, the syllable /da/ did elicit latency differences between these two groups. Deficits in cortical processing of signals in noise were seen for those LP subjects with delayed brainstem responses to the /da/, but not for LPs with normal brainstem measures. Preliminary findings indicate that training may be beneficial to LP subjects with brainstem processing delays.     

Ureteral tissue balloon expansion for laparoscopic bladder augmentation: survival study

BACKGROUND AND PURPOSE: The search for the perfect urinary bladder substitute continues. Despite their inherent limitations, intestinal segments remain the commonest material for bladder reconstruction. The ureter, with its transitional epithelium, may be the ideal tissue to augment the bladder. Ikeguchi et al reported the feasibility of chronic ureteral balloon expansion by open surgery (J Urol 1998;159:1665). Herein, we propose a completely minimally invasive approach to balloon overdilate a segment of juxtavesical ureter incrementally and to use this in-line tissue-expanded ureteral patch to augment the bladder laparoscopically. MATERIALS AND METHODS: In five female pigs, a novel ureteral expansion balloon device (Microvasive, MA) was inserted percutaneously and advanced antegrade into the juxtavesical ureter. The device has two channels: one for balloon inflation and the other for draining the kidney. After progressive ureteral expansion over a 3- to 4-week period, laparoscopic augmentation ureterocystoplasty was performed. Animals were euthanized at 15 days (N = 1), 1 month (N = 1), 2 months (N = 1), and 3 months (N = 2). RESULTS: Percutaneous balloon device placement was technically successful in all five cases (mean operating room time 52 minutes). The mean volume of the tissue-expanded ureter at 1, 2, and 3 weeks was 12.9 cc, 60.3 cc, and 171.8 cc, respectively. Laparoscopic augmentation ureterocystoplasty with (N = 3) or without (N = 2) concomitant subtotal cystectomy was technically successful in all five cases without any open conversion. The mean operative time was 126.5 minutes, and the mean blood loss was 29 mL. Postoperative complications consisted of one case each of pyelonephritis and ureteral stricture. At autopsy, the mean capacity of the bladder was 574 mL, and the P(ves) at maximum capacity was 14 cm H(2)O. Histologic examination of the tissue-expanded ureter revealed regenerated transitional epithelium and muscle hypertrophy. CONCLUSIONS: Chronic ureteral tissue expansion can be carried out safely and efficaciously. The expanded tissue is thick, healthy, and vascular, with histologic features of normal transitional epithelium and muscle hypertrophy and hyperplasia. This expanded ureteral tissue can be used to augment the bladder with laparoscopic techniques. Such augmented bladders do not show significant shrinkage and possess urodynamic characteristic of normal capacity and normal compliance over a follow-up of 3 months.     

Lack of effect of aprepitant on digoxin pharmacokinetics in healthy subjects

Aprepitant is a highly selective neurokinin-1 receptor antagonist that, in combination with a corticosteroid and a 5-hydroxytryptamine3 (5HT3) receptor antagonist, has been shown to be efficacious in the prevention of highly emetogenic chemotherapy-induced nausea and vomiting. In vitro data suggest that aprepitant is a substrate and a weak inhibitor of P-glycoprotein. Thus, the effect of aprepitant on the pharmacokinetics of digoxin, a P-glycoprotein substrate, was examined in a double-blind, placebo-controlled, randomized, two-period crossover study in 12 healthy subjects. Each subject received daily oral doses of digoxin 0.25 mg on Days 1 through 13 during both treatment periods. Aprepitant 125 mg (or matching placebo) was coadministered orally with digoxin on Day 7, and aprepitant 80 mg (or matching placebo) was coadministered orally with digoxin on Days 8 to 11. Aprepitant did not affect the pharmacokinetics of digoxin. The geometric mean ratios (90% confidence interval [CI]) for plasma AUC0-24 h of digoxin (with/without aprepitant) were 0.99 (0.91, 1.09) and 0.93 (0.83, 1.05) on Days 7 and 11, respectively, and the geometric mean ratios (90% CI) for the 24-hour urinary excretion of immunoreactive digoxin (with/without aprepitant) were 0.91 (0.80, 1.04) and 1.00 (0.91, 1.09) on Days 7 and 11, respectively. Thus, aprepitant, when dosed as a 5-day regimen, did not interact with a known substrate of the P-glycoprotein transporter.