Polymeric micelles containing reversibly phospholipid-modified anti-survivin siRNA: a promising strategy to overcome drug resistance in cancer.

The discovery that survivin, a small anti-apoptotic protein, is involved in chemoresistance, opens a new scenario to overcome the drug resistance in cancer. It was shown that siRNA can efficiently inhibit the expression of survivin in cancer cells. However, the clinical use of siRNA is still hampered by an unfavorable pharmacokinetic profile. To address this problem, earlier we developed a novel system to deliver siRNA into cancer cells. Namely, we reversibly modified the survivin siRNA with a phosphothioethanol (PE) portion via a reducible disulfide bond and incorporated the resulting siRNA-S-S-PE conjugate into nanosized polyethyelene glycol 2000-phosphatidyl ethanolamine (PEG2000-PE)-based polymeric micelles (PM), obtaining survivin siRNA PM. The activity of these nanopreparations was evaluated by survivin protein down-regulation, tumor cell growth inhibition, and chemosensitization of the treated tumor cells to paclitaxel (PXL). We found a significant decrease of cell viability and down-regulation of survivin protein levels after treatment with survivin siRNA PM in several cancer cell lines. In addition, the down-regulation of survivin by treating cells with survivin siRNA PM, elicited a significant sensitization of the cells to PXL, in both sensitive and resistant cancer cell lines. Finally, we demonstrated successful co-delivery of PXL and survivin siRNA in the same PM leading to superior therapeutic activity compared to their sequential administration. Our results support the use of this new platform for the treatment of the most aggressive tumors.

Indications of proton-dominated cosmic-ray composition above 1.6 EeV.

We report studies of ultrahigh-energy cosmic-ray composition via analysis of depth of air shower maximum (X(max)), for air shower events collected by the High-Resolution Fly's Eye (HiRes) observatory. The HiRes data are consistent with a constant elongation rate d/d[log(E)] of 47.9+/-6.0(stat)+/-3.2(syst) g/cm2/decade for energies between 1.6 and 63 EeV, and are consistent with a predominantly protonic composition of cosmic rays when interpreted via the QGSJET01 and QGSJET-II high-energy hadronic interaction models. These measurements constrain models in which the galactic-to-extragalactic transition is the cause of the energy spectrum ankle at 4x10(18) eV.

First observation of the Greisen-Zatsepin-Kuzmin suppression.

The High Resolution Fly's Eye (HiRes) experiment has observed the Greisen-Zatsepin-Kuzmin suppression (called the GZK cutoff) with a statistical significance of five standard deviations. HiRes' measurement of the flux of ultrahigh energy cosmic rays shows a sharp suppression at an energy of 6 x 10(19) eV, consistent with the expected cutoff energy. We observe the ankle of the cosmic-ray energy spectrum as well, at an energy of 4 x 10(18) eV. We describe the experiment, data collection, and analysis and estimate the systematic uncertainties. The results are presented and the calculation of the statistical significance of our observation is described.

Measurement of the flux of ultrahigh energy cosmic rays from monocular observations by the High Resolution Fly's Eye experiment.

We have measured the cosmic ray spectrum above 10(17.2) eV using the two air-fluorescence detectors of the High Resolution Fly's Eye observatory operating in monocular mode. We describe the detector, phototube, and atmospheric calibrations, as well as the analysis techniques for the two detectors. We fit the spectrum to a model consisting of galactic and extragalactic sources.

Soft drink consumption and urinary stone recurrence: a randomized prevention trial.

The object of this study was to determine if a strong association between soft drink (soda) consumption and recurrence of urinary stone disease, found in an earlier case-control study of adult males, had a causal component. The study sample consisted of 1009 male subjects, who completed an episode of urinary stone disease, who were aged 18-75 at that time, and who reported consuming at least 160 ml per day of soft drinks. Half of the subjects were randomized to refrain from consuming soft drinks, while the remaining subjects served as controls. The intervention group had an observed 6.4% advantage in actuarial 3 yr freedom from recurrence (p = 0.023 one-sided) over the control group. One important secondary finding was that for those who reported at the time of the index stone that their most consumed drink was acidified by phosphoric acid but not citric acid, the experimental group had a 15% higher 3 yr recurrence-free rate than the controls, p = 0.002, while for those who reported at the time of the index stone that their most consumed drink was acidified by citric acid with or without phosphoric acid, the experimental group had a similar 3 yr recurrence-free rate to the controls, p = 0.55. This interaction was significant, p = 0.019.

The fate of residual fragments after extracorporeal shock wave lithotripsy monotherapy of infection stones.

We reviewed 53 patients with infection stones treated by extracorporeal shock wave lithotripsy (ESWL*) monotherapy to determine the long-term rate free of stones and the stone recurrence rate as correlated with the pre-treatment stone burden and the radiological presence of sand or fragments after the procedure. Long-term followup (mean 26.6 months) was available on 33 patients representing 38 kidneys. Although only 3 kidneys were free of stones immediately after ESWL, 20 were without stones at 3 months and 18 (47%) were stone-free at followup. Of 9 kidneys with fragments of more than 5 mm. after the final treatment 7 (78%) had residual fragments at 3 months and experienced stone progression. Of 9 kidneys with sand remaining 6 (66%) and all 3 kidneys that appeared to be free of stones after ESWL were without stones at followup. The 3-month plain film of the kidneys, ureters and bladder was a reliable indicator of eventual outcome. Of 20 kidneys that were free of stones at 3 months 16 remained without stones. Of 18 kidneys with residual stone particles at 3 months 14 showed disease progression, 2 had stable disease and 2 passed residual sand. Only 1 of 17 patients who were free of stones or had stable stone disease had a positive urine culture at followup. Patients with infection stone fragments 3 months after ESWL monotherapy have a high rate of stone progression (78%) and should undergo further treatment. ESWL monotherapy of infection stones requires close patient followup to assure that all residual fragments have passed and urine remains sterile.

Hyperfiltration-induced renal injury in normal man: myth or reality.

Current knowledge fails to support the notion that adaptive hyperfiltration of the remnant kidney after donor nephrectomy is deleterious. Rather than being maladaptive, hyperfiltration appropriately compensates for the loss of functional renal mass. Accordingly, most kidney donors can be expected to maintain a stable level of renal function without proteinuria or hypertension. Essential to this is proper selection of donors for nephrectomy and exclusion of high risk potential donors, bearing in mind the fact that apparently healthy, asymptomatic relatives of end stage renal disease patients are prone to the same disease processes that inflict the general population and have a higher risk of underlying renal disease.

Selection criteria for the evaluation of living related renal donors.

The documented long-term health of the living related renal donor is a tribute to careful preoperative selection and surgical technique. At our medical center 187 prospective donors were evaluated during a 6-year period and 91 underwent donor nephrectomy. Hypertension, renal artery anomalies and donor indecision were the most common reasons for donor rejection. Recipient health and/or death, or a positive crossmatch after pre-transplant donor specific transfusion were other post-arteriogram reasons not to proceed with transplantation. Women were more likely to undergo nephrectomy than men, and older or heavier donors were more likely to be rejected. Using the transcostal, extrapleural surgical approach for nephrectomy there were no deaths or major complications, and the mean postoperative length of stay was 6.4 days. The average postoperative increase in serum creatinine was 0.33 mg./dl. with an average creatinine at discharge of the patient from the hospital of 1.2 mg./dl. The latter creatinine values varied concordantly with donor age. Only 56% of fully evaluated donors (91 of 159) actually underwent donor nephrectomy. The minimal morbidity sustained by these patients re-emphasizes the importance of careful donor selection.

Effects of the divalent cation ionophore ionomycin on the performance of isolated guinea-pig atria.

In isolated electrically driven left and in spontaneously beating right guinea-pig atria, the calcium ionophore ionomycin produced a concentration-dependent positive inotropic and chronotropic effect with a threshold near 10(-7) mol/l and a pD2 of 6.31 +/- 0.09 and 5.94 +/- 0.07, respectively. At low [Ca2+]o (0.5 mmol/l), the positive inotropic effect of ionomycin (3 X 10(-6) mol/l) was strongly attenuated by ryanodine and nifedipine, and slightly attenuated by pindolol and mepyramine; atropine had no effect. The positive chronotropic effect of ionomycin was slightly reduced by cimetidine or pindolol, whereas atropine, nifedipine, and ryanodine showed no inhibitory activity. The oxygen consumption of resting left atria was significantly enhanced by addition of ionomycin. It is concluded that the action of ionomycin involves at least the following mechanisms: I) release of Ca2+ from sarcoplasmic reticulum, II) influx of Ca2+ from the extracellular space, and, having little significance, III) release of catecholamines and histamine from sympathetic nerve endings and tissue mast cells. However, additional mechanisms of action of ionomycin cannot be excluded.

Evolution of pre-treatment stenting and local anesthesia for extracorporeal shock wave lithotripsy at a single university center.

Evolution of the extracorporeal shock wave lithotripsy technique involves not just second generation technology but operator innovations and experience. Retrospective analysis of the first 512 treatments at a university medical stone unit using the Dornier HM3 lithotriptor was compared to 3 intervals of 100 consecutive treatments during the next 2-year period (1985 to 1987). Patient referral and selection as well as treatment techniques and rates of endourological interventions were analyzed. Patient demographics, stone types and retreatment rates remained constant during 2,500 treatments. However, the use of local anesthesia and internal ureteral stents became increasingly common. Of the 1987 cohort 29% were treated with the patient under local anesthesia, and 23 of the 44 with a stent (52%) received internal ureteral stents. Other treatment trends identified during the study period included increasing number of large (greater than 2 cm.) and multiple stones treated; increasing use of internal and external ureteral catheters before treatment, fewer stents for small, mobile renal calculi and decreasing length of hospital stay (2.7 to 2.1 days) with increasing use of stents before lithotripsy. The increasing average number of shock waves per treatment (1,382 versus 1,580) during the study period can be attributed to the larger proportion of patients with high stone burdens and the impact of an increased number of operators with more varied criteria for endoscopy and treatment end point.

Morbidity associated with indwelling internal ureteral stents after shock wave lithotripsy.

Placement of internal ureteral stents before extracorporeal shock wave lithotripsy of large stone burdens has decreased the incidence of post-extracorporeal shock wave lithotripsy colic, secondary endoscopic procedures and prolonged hospital stays. However, indwelling stents have an associated patient morbidity and intolerance. A telephone survey of 50 patients (average stone burden 28 mm.) who were discharged from the hospital after treatment with an indwelling internal polymer stent was performed with a standard questionnaire. Symptoms reported with in situ internal ureteral stents included gross hematuria (42 per cent), fever or chills (20 per cent), and persistent discomfort or pain in the bladder and/or flank (26 to 38 per cent). Of the patients 44 per cent reported moderate to intolerable discomfort that was relieved by removal of the stent. The degree of symptoms was not associated with stent composition, style or length, or the presence of a transurethral string. Five patients had premature migration or dislodgment of the internal stent and 4 reported episodes of obstructive pyelonephritis requiring removal of an impacted stent or endourological intervention. Internal ureteral stents placed before extracorporeal shock wave lithotripsy have an identifiable patient morbidity while indwelling and, therefore, they should be used judiciously according to the stone burden, renal anatomy and body habitus.

Kidney transplantation in insulin dependent diabetic patients: improved survival and rehabilitation.

Between 1977 and 1986, 50 insulin-dependent diabetic patients received a kidney transplant, 19 from living related donors and 31 from cadaveric donors. Cumulative patient survival was 81% and graft survival was 64% and 33% for living related and cadaveric donor kidneys, respectively, at five years. These results are comparable to that of nondiabetic patients. While physical performance and visual acuity significantly improved after a successful kidney transplantation, neuropathies and angiopathies might not improve. Physical performance improved even in those patients whose nerve conduction time had deteriorated. These findings suggest that kidney transplantation is an effective means of improving survival and rehabilitation of diabetic patients with end-stage renal disease.

Selective use of ureteral stents before extracorporeal shock-wave lithotripsy.

Stents must be judiciously, not indiscriminately, used prior to lithotripsy to maximize successes. The documented advantages for specific stone burdens and patient types should not be taken as an endorsement for pretreatment stenting on a routine basis. Universal stenting is a costly adjunct to an already costly technology, not to mention the substantial number of patients with stents who report bladder or renal discomfort that is relieved when the stents are removed. Certainly, in some cases, the constant discomfort of bladder irritability and reflex voiding secondary to polymer stents may be more incapacitating than mild colic associated with fragment passage. Complications of internal ureteral stents do occur, so judicious selection of patients for pre-ESWL stenting is advised.

Extracorporeal shock-wave lithotripsy for children.

We report the cases of 17 children between the ages of 3 and 17 years who underwent 19 treatments using extracorporeal shock-wave lithotripsy. Stone size averaged 14.9 mm, with a range of 3 to 25 mm. The number of shock waves delivered averaged 1720, with a range of 600 to 2000. Treatment time averaged 36 minutes, with a range of 15 to 55 minutes. The average length of hospital stay was 2.2 days. In nine of the 19 treatments the kidneys were rendered free of stones. There were no complications.

Extracorporeal shock wave lithotripsy and its effect on renal function.

Extracorporeal shock wave lithotripsy has become a major treatment modality for symptomatic upper tract renal stone disease. Although proved to be effective in disintegrating stones the short-term and long-term effects on renal function are not yet known. We evaluated several basic physiological parameters, namely creatinine clearance, fractional sodium excretion, protein excretion and urine osmolality before and after extracorporeal shock wave lithotripsy in 26 consecutive patients in an attempt to quantitate changes in renal function. In addition, a 3 to 6-month followup study of patients showing excessive protein excretion with extracorporeal shock wave lithotripsy also is reported. Our data suggest that with extracorporeal shock wave lithotripsy transient nephrotic range proteinuria occurs immediately after treatment, returning to normal values within 3 to 6 months after treatment without a change in the glomerular filtration rate. The glomerular filtration rate increases after successful extracorporeal shock wave lithotripsy in patients with kidneys obstructed by the treated stone before the start of the procedure, and the kidney appears to maintain its ability to dilute urine and to conserve sodium after treatment.

Cost-effectiveness of extracorporeal shock-wave lithotripsy.

A study was done comparing the charges and outcomes for extracorporeal shock-wave lithotripsy (ESWL) with those for percutaneous nephrostolithotomy (PCN), which was the treatment of choice at our hospital for stones of the upper urinary tract when ESWL was introduced. Using a retrospective cohort design, patients were matched for age, sex, physical status index (American Society of Anesthesiologists), stone size, and urinary tract obstruction. Twenty-nine pairs of PCN and ESWL patients with complete data were matched. The groups were not significantly different in the matching parameters. Seventy-two per cent of patients in each group (21/29) were stone-free after the initial hospitalization. PCN patients required more auxiliary procedures per patient than did the ESWL patients; in addition, 5 (17%) of the PCN patients had perforation of the renal pelvis and 5 (17%) required transfusions. On discharge, 48 per cent (14/29) of the PCN patients had nephrostomies compared with none of the ESWL patients. The ESWL group had a shorter mean length of stay (2.9 vs 8.7 days, p less than 0.0005) and lower charges in all categories. Total charges were significantly less for ESWL ($9,290 vs $11,796 for PCN, p less than 0.005) as were physicians' fees ($3,391 vs $5,607, p less than 0.0005), room and board charges ($825 vs $2,164, p less than 0.0005), and operating room fees ($313 vs $1,452, p less than 0.0005). We conclude that ESWL is a cost-effective means for treating stones of the kidney and upper urinary tract.

Variables influencing radiation exposure during extracorporeal shock wave lithotripsy. Review of 298 treatments.

Retrospective review of 298 extracorporeal shock wave lithotripsy (ESWL) treatments was undertaken to determine the factors which influence radiation exposure during ESWL. Fluoroscopy time averaged 160 seconds (3-509), and the average number of spot films taken per patient was 26 (5-68). The average stone burden was 19.3 mm (3-64). Average calculated skin surface radiation exposure was 17.8 R per treatment. Radiation exposure increased with increasing stone burden and patient weight. Stones treated in the ureter resulted in a higher average patient radiation exposure than for renal stones (19 R vs 16 R), even though the average size of these ureteral stones (11.3 mm) was significantly less than the mean. However, type of anesthetic (general or regional) used was not a significant factor. Operator training, experience, and familiarity with radiation physics should significantly decrease the amount of imaging time and consequent patient radiation exposure during ESWL.

Initial experience with extracorporeal shock wave lithotripsy in children.

The clinical experience is presented of 4 United States centers at which extracorporeal shock wave lithotripsy was used for the treatment of renal calculi in 38 children 12 months to 16 years old. Patient characteristics, treatment specifics and followup data are detailed. Complete fragmentation of calculi was obtained in 97 per cent of those treated, with a 5 per cent complication rate. This experience demonstrates that with proper safeguards, extracorporeal shock wave lithotripsy can be performed safely and effectively in the pediatric population.