P2X(7) receptors are expressed during mouse nephrogenesis and in collecting duct cysts of the cpk/cpk mouse.

BACKGROUND: Purinergic receptors are cell-surface molecules that bind extracellular nucleotides, notably ATP. The P2X family includes seven nonselective ion channels with one member, P2X(7), implicated in cytolytic pore formation and cell death. MATERIALS AND METHODS: We sought P2X(7) expression in mouse nephrogenesis and cpk/cpk renal cyst growth, conditions in which both proliferation and apoptosis are prominent. RESULTS: P2X(7) immunolocalized to condensed metanephric mesenchyme: both proliferation and apoptosis were detected in this compartment, assessed by proliferating cell nuclear antigen expression and propidium iodide-stained pyknotic nuclei respectively. Later in nephrogenesis, P2X(7) was detected in collecting ducts, a pattern persisting to maturity. A mesenchymal to epithelial shift of P2X(7) expression was also documented in ureter development. In cpk/cpk kidneys, P2X(7)-expressing collecting duct cysts dominated histology from two weeks until four weeks after birth, when animals die from uremia. In polycystic kidneys pyknotic nuclei were rarely identified in P2X(7)-expressing epithelia, but were detected between cysts, consistent with a non-apoptotic role for P2X(7) in cyst enlargement. CONCLUSION: P2X(7) is expressed during normal nephrogenesis and in a model of congenital polycystic kidney disease. Further experiments are necessary to define possible functions of P2X(7) in these settings.     

Differential Effects of Anesthetics on Mitochondrial KATP Channel Activity and Cardiomyocyte Protection

Background: Mitochondrial adenosine triphosphate-sensitive potassium (mitoKATP) channels play a pivotal role in mediating cardiac preconditioning. The effects of intravenous anesthetics on this protective channel have not been investigated so far, but would be of importance with respect to experimental as well as clinical medicine.

Methods: Live cell microscopy was used to visualize and measure autofluorescence of flavoproteins, a direct reporter of mitoKATP channel activity, in response to the direct and highly selective mitoKATP channel opener diazoxide, or to diazoxide following exposure to various anesthetics commonly used in experimental and clinical medicine. A cellular model of ischemia with subsequent hypoosmolar trypan blue staining served to substantiate the effects of the anesthetics on mitoKATP channels with respect to myocyte viability.

Results: Diazoxide-induced mitoKATP channel opening was significantly inhibited by the anesthetics R-ketamine, and the barbiturates thiopental and pentobarbital. Conversely, urethane, 2,2,2-trichloroethanol (main metabolite of [alpha]-chloralose and chloral hydrate), and the opioid fentanyl potentiated the channel-opening effect of diazoxide, which was abrogated by coadministration of chelerythrine, a specific protein kinase C inhibitor. S-ketamine, propofol, xylazine, midazolam, and etomidate did not affect mitoKATP channel activity. The significance of these modulatory effects of the anesthetics on mitoKATP channel activity was substantiated in a cellular model of simulated ischemia, where diazoxide-induced cell protection was mitigated by R-ketamine and the barbiturates, while urethane, 2,2,2-trichloroethanol, and fentanyl potentiated myocyte protection.     

Physiologic mechanism and preoperative prediction of new-onset dysphagia after laparoscopic Nissen fundoplication

The aim of this study was to determine whether preoperative physiologic factors can account for and be used to predict the development of postoperative dysphagia after laparoscopic Nissen fundoplication. One hundred sixty-three patients with gastroesophageal reflux disease underwent laparoscopic Nissen fundoplication with a median follow-up of 14 months (range 6 to 81 months). Preoperative dysphagia was present in 37% (60 of 163) and was relieved in all but five patients (92%). Female sex (P = 0.01) and the presence of a stricture (P = 0.02) were the only preoperative variables associated with the presence of preoperative dysphagia. Eight percent (8 of 103) of patients without preoperative dysphagia developed new-onset dysphagia, and of these 63% (5 of 8) had a normal lower esophageal sphincter (LES) (pressure >6 mm Hg; length >2 cm; abdominal length >1 cm). New-onset dysphagia was significantly more common in patients with a normal LES (22% [5 of 23] vs. 4% [3 of 80], P = 001). Patients with a normal LES had almost a sixfold increase in the risk of developing dysphagia as those with an abnormal LES (relative risk = 5.8). Only a preoperative normal LES (P = 0.02) or mean LES pressures (P = 0.04) were positively associated with the development of postoperative dysphagia. The severity of this dysphagia also showed a strong positive trend of increasing with mean preoperative LES pressures (P = 0.07). Finally, preoperative LES pressure significantly correlated with postoperative LES pressure (r = 0.48, P = 0.01) and with mean residual LES (nadir) pressure (r = 0.33, P = 0.05) offering insight into the mechanism of this dysphagia. In conclusion, preoperative LES parameters play a role in the development of dysphagia after laparoscopic Nissen fundoplication. Patients with a normal LES or high mean LES pressures are at increased risk for developing this complication and should be informed of this before laparoscopic Nissen fundoplication. Presented at the Forty-Second Annual Meeting of The Society for Surgery of the Alimentary Tract, Atlanta, Ga., May 20–23, 2001.     

P6 Acupoint Injections Are as Effective as Droperidol in Controlling Early Postoperative Nausea and Vomiting in Children

Background: P6 acupuncture in adults is reported to be an effective preventive treatment for postoperative nausea and vomiting (PONV). It is not clear, however, whether this technique is effective as a preventive treatment for PONV in children.

Methods: Children undergoing anesthesia and surgery were randomized to four groups: (a) intravenous saline + bilateral P6 acupoint injections (n = 50); (b) intravenous droperidol + bilateral P6 sham acupuncture (n = 49); (c) intravenous saline + bilateral sham point injections (n = 43); (d) intravenous saline +bilateral P6 sham acupuncture (n = 45). The perioperative anesthetic technique was standardized in all subjects. The incidence of postoperative nausea and vomiting (PONV) was evaluated in postanesthesia care unit (PACU) and 24 h after surgery.

Results: Incidence of nausea in the PACU was significantly lower in the acupoint group as compared with the sham point group (32%vs. 56%, P = 0.029) and P6 sham group (32%vs. 64%, P = 0.002) but not as compared with the droperidol group (32%vs. 46%, P = ns). Similarly, subjects in the acupoint group had a significantly lower incidence of vomiting in the PACU as compared with the sham point group (12%vs. 33%, P = 0.026) and P6 sham group (12%vs. 31%, P = 0.029) but not as compared with the droperidol group (12%vs. 18%, P = ns). The combined incidence of early PONV was also lower in the acupoint group as compared with the sham point group (P = 0.045) and P6 sham group (P = 0.004) but not as compared with the droperidol group (42%vs. 51%, P = ns). Finally, significantly fewer subjects in the acupoint group required intravenous ondansetron as an initial rescue therapy (P = 0.024). At 24 h after surgery, however, the incidence of late PONV was similar among the four study groups (P = ns).     

Persistent reversal of diabetes by transplantation of fetal pig proislets into nude mice

Facing the limited availability of human adult and fetal pancreases, fetal pig proislets (pancreatic islet precursors) were investigated in view of several inherent advantages. Six litters of fetuses of mean +/- SE gestational age 75 +/- 3 days were obtained from commercially available farm pigs. Pancreatic tissue was gently digested with collagenase, then a 10-day culture was performed. During culture, fetal proislets showed no insulin response to glucose alone but a significant response to glucose plus theophylline. The insulin content per microgram of DNA in the cultured proislets continuously increased. Histological examination by immunoperoxidase staining showed that, apart from single insulin- and glucagon-positive cells, there were no discrete islets in the pancreatic tissue and the cultured proislets. Diabetes was induced with streptozocin (STZ) in eight nude mice 3-4 wk after proislet transplantation and in another eight nude mice without transplantation. During the initial week, blood glucose levels of mice in both groups increased rapidly. The mean +/- SE peak value of blood glucose levels in the transplanted group was 20.4 +/- 2.0 mM and was 20.1 +/- 1.3 mM in the group without transplantation. Simultaneously, body weight decreased from 29.5 +/- 0.7 to 21.5 +/- 0.9 g and from 27.9 +/- 0.7 to 19 +/- 1 g in the groups, respectively. Afterward, blood glucose levels of mice in the transplanted group gradually decreased, and normoglycemia was achieved in all mice within 50 +/- 13 days after injection of STZ, i.e., 74 +/- 13 days after transplantation. The group without transplantation persistently maintained blood glucose levels greater than 16.7 mM.(ABSTRACT TRUNCATED AT 250 WORDS)     

Stereoselectivity of idarubicin reduction in various animal species and humans

1. The (13S)-dihydro derivative of idarubicin, (13S)-idarubicinol, is the major urinary metabolite of idarubicin in humans. Idarubicinol epimers were quantified by h.p.l.c. in urine from rats, mice, rabbits, dogs and man after i.v. administration of idarubicin, and in man after oral dosing. The (13R)- and (13S)-epimers of idarubicinol were determined in rat bile. 2. After i.v. injection of idarubicin. (13R)-idarubicinol was not detectable in mice and rabbit urine and no more than 0.5% of the dose was present in the urine of other species. In man, the proportion of (13R)-idarubicinol in total idarubicinol was similar after i.v. (4.1%) and oral (3.8-5.0%) administration of idarubicin; the same applies to rat bile and urine. 3. Reduction of idarubicin in vivo is dependent upon ketone reductases, and proceeds more stereoselectively than that of most ketones giving rise to the (13S)-epimer almost exclusively. The high stereospecificity in idarubicin reduction might result from chiral induction due to the presence of asymmetric centres near to the carbonyl group in idarubicin.     

Kaposi's sarcoma. CT-radiographic correlation

The role of CT in the diagnosis of intrathoracic Kaposi's sarcoma (KS) was evaluated retrospectively in 24 patients, in the absence of coexistent opportunistic infections. In all cases the diagnosis of KS was initially established by histologic evaluation of extrathoracic disease: 15 patients had verified parenchymal KS and nine patients endobronchial KS. (Chest roentgenograms were analyzed separately for each group: in 14 patients serial films were available for review. The predominant radiographic findings was the presence of nonspecific, bilateral, perihilar infiltrates in 22 of 24 cases (92 percent). Corresponding CT scans documented the presence of abnormal hilar densities characteristically extending into the adjacent pulmonary parenchyma along distinctly perivascular and peribronchial pathways. Discrete, poorly marginated nodules were identified radiographically in ten cases (42 percent); these proved to be randomly distributed throughout the parenchyma on CT. Radiographic evidence of mediastinal adenopathy was distinctly unusual, seen in only two cases (8 percent). While CT typically demonstrated shotty adenopathy, significantly enlarged nodes (greater than 1 cm) were rarely identified. We concluded that CT is more specific than routine roentgenograms for identifying pulmonary KS. While not pathognomonic, peribronchial and perivascular disease is sufficiently characteristic to obviate more invasive diagnostic procedures, especially in patients with established KS.