Clearance Of Fragments Research Articles

A Prospective Randomized Controlled Trial of the Efficacy of Tamsulosin After Extracorporeal Shock Wave Lithotripsy for a Single Proximal Ureteral Stone

PurposeThe objective of this study was to evaluate the efficacy of tamsulosin on stone clearance after extracorporeal shock wave lithotripsy (ESWL) in patients with a single proximal ureteral stone.Materials and MethodsThis prospective randomized controlled trial was performed on 88 patients with a single proximal ureteral stone. After consenting with a doctor, the patients were allocated to the treatment (tamsulosin 0.2 mg once a day) or control (no medication) group, and the efficacy of tamsulosin was evaluated. The primary outcome of this study was the stone-free rate, and the secondary outcomes were the period until clearance, pain intensity, analgesic requirement, and incidence of complications.ResultsA stone-free state was reported in 37 patients (84.1%) in the treatment group and 29 (65.9%) in the control group (p=0.049). The mean expulsion period of the stone fragments was 10.0 days in the treatment group and 13.2 days in the control group (p=0.012). There were no statistically significant differences in aceclofenac requirement or pain score between the two groups. Only one patient in the treatment group experienced transient dizziness associated with medical expulsive therapy, and this adverse event disappeared spontaneously.ConclusionsThe results of this prospective randomized controlled trial of the efficacy of tamsulosin after ESWL for a single proximal ureteral stone suggest that tamsulosin helps in the earlier clearance of stone fragments and reduces the expulsion period of stone fragments after ESWL.

Partial in Vivo FVIII Stabilization by VWF Fragments

Abstract 15Plasma factor VIII (fVIII) circulates in complex with von Willebrand factor (VWF) and is rapidly cleared in the absence of VWF. Previous in vitro studies have 1) localized the fVIII-binding region of VWF to the N-terminus, comprised of the contiguous D’ and D3 domains and 2) observed reduced affinity for fVIII upon alterations to the tertiary structure of VWF. To gain insight into the structure-function of VWF for fVIII stabilization, we tested VWF fragments for in vivo fVIII stabilization and investigated the architecture of a VWF fragment in complex with fVIII. For the in vivo study, fragments of murine Vwf cDNA were cloned into the hepatic-specific expression vector, pLIVE, and modified to fuse tandem E and FLAG tags to the C-terminus. The following VWF fragments were expressed in vivo by hydrodynamic tail vein injection into Vwf−/− mice: 1) a monomer of the VWF D’D3 domains (monoD’D3; M1-C22, S764-P1274); 2) a truncation of monomeric D’D3 (truncD’D3; M1-C22, S764-R1035); 3) dimers of D’D3 (diD’D3; M1-P1274); 4) multimers of D’D3 (multiD’D3; M1-P1274, G2713-K2813); 5) dimers of mature VWF subunits (DPro, M1-C22, S764-K2813); or 6) full length, multimeric VWF (wtVWF, M1-K2813). Expression of all VWF fragments persisted throughout the period of observation (4 weeks) with peak antigenic levels at 1 or 3 days post-injection. Prolonged elevation of plasma fVIII activity (fVIIIa) from ∼10% to ∼50–200% were observed (100% defined as the fVIIIa level of pooled platelet poor plasma from 10 wild type C57BL/6 mice) for all but the truncated monomer of D’D3 (Figure 1). Significantly increased fVIIIa levels (p<0.05, relative to pre-injection) were first observed at 1 day, peaked at 3 days, and persisted for the duration of observation. A minimal VWF fragment (S764-R1035, truncD’D3) reported to bind fVIII in vitro significantly increased plasma fVIIIa to 34% only at 3 days post-injection. Clearance of VWF fragments from circulation were determined from injections of pooled platelet poor plasma containing recombinant VWF fragments derived from hydrodynamically injected mice into naïve Vwf−/− mice. Nonlinear regression estimated the half-life for monoD’D3 (3.4hr), diD’D3 (2.1hr), multiD’D3 (2.3hr), DPro (2.8hr), and wtVWF (3.5hr). To examine how dimers of D’D3 bind fVIII, diD’D3 from HepG2 conditioned media was purified either alone or with recombinant fVIII, and negative stained samples were visualized by electron microscopy (EM). Single-particle EM analysis revealed that each subunit of the dimer binds 1 fVIII molecule. 3D EM reconstructions indicate that the light chain of fVIII directly interacts with, and potentially induces torsion in the flexible D’D3 domains of VWF. Together, these results emphasize the importance of VWF’s tertiary structure in fVIII stabilization and that the N-terminal D’D3 alone is sufficient to support fVIII survival in vivo. These findings could lead to improved methods of recombinant fVIII production and the development of novel approaches to treatment for hemophilia and von Willebrand disease. [Display omitted] Disclosures:Ginsburg:Shire Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees; Portola Pharmaceuticals: Consultancy; Catalyst Biosciences: Consultancy; Baxter Pharmaceuticals: benefit from payments to Children’s Hosptial, Boston, and the University of Michigan Patents & Royalties; Merck Pharmaceuticals: Consultancy.

Paradoxical clearance of hyaluronan fragments during haemodialysis and haemodiafiltration

The physiological clearance of hyaluronic acid (HA), a mortality marker in end-stage kidney disease (ESKD) patients, occurs in the liver and in the kidneys and depends on its molecular mass. The aim of this study was to examine the effect of different modes of renal replacement therapy on levels of low- and high-molecular-mass HA (LMWHA and HMWHA, respectively). Levels of total plasma HA as well as LMWHA and HMWHA fractions were measured before and after haemodialysis (HD) and haemodiafliltration (HDF) treatments and compared with those in normal controls. Plasma β2-microglobulin was determined to be an independent inflammation marker. The isolated effect of the extracorporeal system on HMWHA fractions was investigated in a separate in vitro study. In 150 ESKD patients, LMWHA (135 ng/mL) and HMWHA fractions (386 ng/mL) were elevated (P < 0.01), compared with those in 80 healthy persons. The LMWHA fraction remained unchanged both during HD and HDF, whereas the fraction of HMWHA, which is incapable of passing through dialysis membranes, decreased by about 40% (P < 0.05). The concentration of plasma β2-microglobulin correlated with the pro-inflammatory LMWHA (P < 0.0001; r = 0.67) but not with total HA. In vitro dialysis runs suggested that this decrease was not caused by degradation or adsorption of HMWHA fragments. Our data suggest that the decrease in the high-mass HA level during HD and HDF mirrors a physiological clearance initiated by HD and HDF rather than by physical elimination in the extracorporeal circulation.

Adjuvant alpha adrenergic blockers: Are they equally efficient for renal and upper ureteral calculi disintegrated by shock wave lithotripsy?

Abstract Objectives To evaluate the effects of tamsulosin on stone clearance and analgesic requirements after shock wave lithotripsy (SWL) for solitary renal and upper ureteral calculi. Patients and methods A prospective randomized placebo controlled study was carried out on 126 patients who underwent SWL for solitary radio-opaque renal or upper ureteral calculi ≤20 mm. Patients were randomized into two groups receiving either 0.4 mg of tamsulosin (GT) or placebo (GP). SWL was performed 3-weekly until patients became stone-free or for a maximum of 3 months. Analgesics were used on demand and pain was evaluated by a visual pain scale. Results Renal stones represented 55.6% and 66.7% for GT and GP, respectively ( p = 0.27). Mean renal and ureteral stone size were (12.3 ± 1.8 mm vs. 11.5 ± 2.3 mm, p = 0.14) and (9.7 ± 2.6 mm vs. 8.6 ± 1.7 mm, p = 0.1) for the GT and GP, respectively. GT required fewer SWL sessions for ureteral (1.2 vs. 1.6, p = 0.02) and renal stones (1.8 vs. 2.3, p = 0.08). Stone-free rate (SFR) was higher in GT for upper ureteral stones (96.4% vs. 66.7%, p = 0.01) and renal pelvis stones at a cutoff size >10 mm ( p = 0.01). The mean time of stone clearance was significantly lower in GT (4.2 ± 1.9 weeks vs. 7.5 ± 2.3 weeks, p = 0.001) for ureteral stones. Attacks of renal colic were more frequent in GP (82.5% vs. 44.4%, p = 0.04) with increased demand for analgesia ( p = 0.04). Steinstrasse was recorded in 3 and 7 patients of the GT and GP, respectively ( p = 0.32). Conclusion Tamsulosin facilitates clearance of upper ureteral stone fragments after SWL and decreases the analgesic requirements. These effects were not similarly evident for renal stones.

The Ubiquitin-Proteasome System in Huntington's Disease: Are Proteasomes Impaired, Initiators of Disease, or Coming to the Rescue?

Huntington's disease is a progressive neurodegenerative disease, caused by a polyglutamine expansion in the huntingtin protein. A prominent hallmark of the disease is the presence of intracellular aggregates initiated by N-terminal huntingtin fragments containing the polyglutamine repeat, which recruit components of the ubiquitin-proteasome system. While it is commonly thought that proteasomes are irreversibly sequestered into these aggregates leading to impairment of the ubiquitin-proteasome system, the data on proteasomal impairment in Huntington's disease is contradictory. In addition, it has been suggested that proteasomes are unable to actually cleave polyglutamine sequences in vitro, thereby releasing aggregation-prone polyglutamine peptides in cells. Here, we discuss how the proteasome is involved in the various stages of polyglutamine aggregation in Huntington's disease, and how alterations in activity may improve clearance of mutant huntingtin fragments.

Acoustic radiation force applied to the treatment of lower pole kidney stones

Lower pole kidney stones have lower rates of clearance after shock wave lithotripsy or ureteroscopy compared to other stone locations. Residual stone fragments, post treatment, often lead to additional morbidity and secondary surgery. We describe the use of acoustic radiation force created by transcutaneous focused ultrasound to manipulate the location of stone fragments within the collecting system in order to facilitate their passage. Artificial and human stones were placed in the lower pole of kidneys of a porcine animal model. An open architecture, software based diagnostic ultrasound system and scanhead were modified to produce roughly 100 μs pulses of up to 16 MPa peak positive pressure in water. Stone motion was observed in real-time with simultaneous imaging through the same scanhead and with fluoroscopy. All stones were seen to move. Stone velocities were on the order of 1 cm/s. Stone displacement distance was up to 3 cm, and operators could generally control the direction of stone movement. No evidence of thermal necrosis or mechanical damage of renal tissue was observed. Thus acoustic radiation force can be used to facilitate lower pole stone fragment clearance. [Work supported by NIH DK43881, DK086371, DK092197, and NSBRI through NASA NCC 9-58.]

Elevated Proteasome Capacity Extends Replicative Lifespan in Saccharomyces cerevisiae

Aging is characterized by the accumulation of damaged cellular macromolecules caused by declining repair and elimination pathways. An integral component employed by cells to counter toxic protein aggregates is the conserved ubiquitin/proteasome system (UPS). Previous studies have described an age-dependent decline of proteasomal function and increased longevity correlates with sustained proteasome capacity in centenarians and in naked mole rats, a long-lived rodent. Proof for a direct impact of enhanced proteasome function on longevity, however, is still lacking. To determine the importance of proteasome function in yeast aging, we established a method to modulate UPS capacity by manipulating levels of the UPS–related transcription factor Rpn4. While cells lacking RPN4 exhibit a decreased non-adaptable proteasome pool, loss of UBR2, an ubiquitin ligase that regulates Rpn4 turnover, results in elevated Rpn4 levels, which upregulates UPS components. Increased UPS capacity significantly enhances replicative lifespan (RLS) and resistance to proteotoxic stress, while reduced UPS capacity has opposing consequences. Despite tight transcriptional co-regulation of the UPS and oxidative detoxification systems, the impact of proteasome capacity on lifespan is independent of the latter, since elimination of Yap1, a key regulator of the oxidative stress response, does not affect lifespan extension of cells with higher proteasome capacity. Moreover, since elevated proteasome capacity results in improved clearance of toxic huntingtin fragments in a yeast model for neurodegenerative diseases, we speculate that the observed lifespan extension originates from prolonged elimination of damaged proteins in old mother cells. Epistasis analyses indicate that proteasome-mediated modulation of lifespan is at least partially distinct from dietary restriction, Tor1, and Sir2. These findings demonstrate that UPS capacity determines yeast RLS by a mechanism that is distinct from known longevity pathways and raise the possibility that interventions to promote enhanced proteasome function will have beneficial effects on longevity and age-related disease in humans.

E77 Role of alpha-adrenergic blockers in enhancing clearance of stone fragments after ESWL of renal calculi

E77 Role of alpha-adrenergic blockers in enhancing clearance of stone fragments after ESWL of renal calculi

Is the gravity effect of radiographic anatomic features enough to justify stone clearance or fragments retention following extracorporeal shock wave lithotripsy (SWL)

We determined whether the gravity effect of radiographic anatomic features on the preoperative urography (IVP) are enough to predict fragments clearance after shock wave lithotripsy (SWL). A Total of 282 patients with mean age 45.8 ± 13.2 years (189 male, 93 female), who underwent SWL due to renal calculi between October 2005 and August 2009 were enrolled. The mean calculi load was 155.72 ± 127.66 mm². The patients were stratified into three groups: patients with pelvis calculi (group 1); patients with upper or middle pole calculi (group 2) and patients with lower pole calculi (group 3). Three angles on the pretreatment IVP were measured: the inner angle between the axis of the lower pole infundibular and ureteropelvic axis (angle I); the inner angle between the lower pole infundibular axis and main axis of pelvis-ureteropelvic (UP) junction point (angle II) and the inner angle between the lower pole infundibular axis and perpendicular line (angle III). Multivariate analysis was used to define the significant predictors of stone clearance. The overall success rate was 85.81%. All angles, sessions number, shock waves number and stone burden were significant predictors of success in patients in group 1. However, in group 2 only angle II and in group 3 angles I and II had significant effect on stone clearance. Radiographic anatomic features have significant role in determining the stone-free rate following satisfactory fragmentation of renal stones with SWL. The measurement of infundibulopelvic angle in different manner helps to predict the stone-free status in patients with renal calculi located not only in lower pole, but also in renal pelvis and upper or middle pole. Gravity effect is not enough to justify the significant influence of the radiographic anatomic features on the stone clearance and fragments retention after SWL.

2238 ADJUVANT USE OF TAMSULOSIN AND NIFEDIPINE AFTER EXTRACORPOREAL SHOCK WAVES LITHOTRIPSY IN PATIENTS WITH KIDNEY STONES - A PROSPECTIVE, DOUBLE-BLIND AND RANDOMIZED STUDY

INTRODUCTION AND OBJECTIVES: Extracorporeal shock wave lithotripsy (SWL) is the most employed treatment for renal stones up to 20 mm. Adjuvant use of some drugs may increase the rates of success of the procedure and reduce its morbidity. This is the first trial that evaluate the effects of Tamsulosin and Nifedipine, compared to placebo, in the success rates, episodes of pain and velocity of clearance of fragments after treatment of radiopaque renal stones between 5–20 mm with only one session of SWL. METHODS: We conducted a prospective, randomized and double-blind trial involving 136 patients with radiopaque renal stones between 2006 and 2009. Patients were divided in three groups to receive daily Tamsulosin 0.4 mg, Nifedipine Retard 20mg or placebo for up to 30 days after one session of SWL. The parameters assessed were success rate, analgesic requirements, pain intensity, velocity of elimination of fragments, adverse effects and occurrence of Steinstrasse. RESULTS: The rate of success was 60.5% (23 of 38) in Tamsulosin Group, 48.6% (17 of 35) in Nifedipine Group and 36.8% (14 of 38) in the Placebo Group. (p 0.118) Between the stones of 10 and 20 mm, the success rates were significantly higher in Tamsulosin (61.9%) and Nifedipine Groups (60.0%) than in the Placebo Group (26.1%) (p 0.024) but not so between the stones of 5–9 mm (p 0.128). The Number Needed to Treat (NNT) was 2.9 for Tamsulosin and 3 for Nifedipine. Occurrence of adverse effects was higher in Nifedipine Group than the Placebo Group (28.5% vs. 2.6% respectively, p 0.009). There was no difference among groups with respect to stone and demographic data, pain intensity (p 0.28), velocity of elimination of fragments (p 0.6) and occurrence of Steinstrasse (p 0.48). CONCLUSIONS: Adjuvant use of Tamsulosin or Nifedipine after SWL for renal stone 10 to 20 mm increases the success rates, but without reducing the intensity of pain or the need for analgesia neither the velocity of eliminations of fragments.

Oral Lead Bullet Fragment Exposure in Northern Bobwhite (Colinus virginianus)

Lead (Pb) is a worldwide environmental contaminant known to adversely affect multiple organ systems in both mammalian and avian species. In birds, a common route of exposure is via oral ingestion of lead particles. Data are currently lacking for the retention and clearance of Pb bullet fragments in gastrointestinal (GI) tract of birds while linking toxicity with blood Pb levels. In the present study, northern bobwhite quail fed a seed-based diet were orally gavaged with Pb bullet fragments (zero, one or five fragments/bird) and evaluated for rate of fragment clearance, and changes in peripheral blood, renal, immune, and gastrointestinal parameters. Based on radiographs, the majority of the birds cleared or absorbed the fragments by seven days, with the exception of one five-fragment bird which took between 7 and 14 days. Blood Pb levels were higher in males than females, which may be related to egg production in females. In males but not females, feed consumption, body weight gain, packed cell volume (PCV), plasma protein concentration, and δ-aminolevulinic acid dehydratase (δ-ALAD) activity were all adversely affected by five Pb fragments. Birds of both sexes that received a single Pb fragment displayed depressed δ-ALAD, suggesting altered hematologic function, while all birds dosed with five bullet fragments exhibited greater morbidity.

Is There a Role for Tamsulosin After Shock Wave Lithotripsy in the Treatment of Renal and Ureteral Calculi?

Our study aimed at defining the role of tamsulosin as adjunctive therapy after extracorporeal shock wave lithotripsy (ESWL) in patients with stones in the kidney and ureter. A placebo-controlled, randomized, double-blind clinical trial prospectively performed between February 2008 and September 2009 on 150 patients with 4-20 mm in diameter renal and ureteral stones referred to our ESWL center. After ESWL, all patients randomly assigned to two groups (placebo and tamsulosin). The drugs administration was started immediately after ESWL and was continued for a maximum of 30 days. From 150 patients, 71 in control group and 70 in case group completed the study. Of 71 patients (60.56%) in control group, 43 patients became stone free; and other patients (39.44%) did not succeed in stone expulsion during 12 weeks after ESWL. In case group of 70 patients (71.4%), 50 patients became stone free. Time of stone passage in most of the patients happened between 20th and 30th day in control group (32.6%) and between 10th and 20th day (50%) in case group after ESWL. There is no statistically significant difference between stone passage in two groups (p = 0.116) and location of stone (p = 0.114), but there is statistically significant difference in time of stone passage from onset of treatment in case and control groups (p = 0.002). At last, this study suggested that tamsulosin facilitate earlier clearance of fragments after ESWL.

In vitro evaluation of the Lithoclast Ultra Vario combination lithotrite

Rigid intracorporeal lithotrites can be invaluable in the removal of large stone burdens during percutaneous nephrolithotomy. One such device, the Lithoclast Ultra Vario (LUV) has an outer ultrasound probe and inner pneumatic-ballistic probe. The ballistic probe can be advanced or retracted and run at 1-12 Hz. Since it can be difficult to predict optimal settings with any new device, we asked if in vitro testing could give insight into how best to operate this lithotrite. We tested the LUV under hands-free conditions that simulate treatment of fixed stones and freely movable stones. A fixed-stone test system measured the time to penetrate a gypsum model stone placed atop the probe and a movable-stone system determined time for comminution of a stone within a confined space. In addition, the time to evacuate 2-mm stone particles was measured. For hands-on testing, model stones were placed in a plastic dish submerged in water and the time to comminution was measured. Penetration time of fixed stones was faster with the ballistic probe extended 2.5 mm than when retracted (5.30 ± 0.85 vs. 8.75 ± 1.07 s, p < 0.0001). Comminution of free stones was faster with the ballistic probe retracted than when it was extended 1 mm or 2.5 mm (9.7 ± 0.9, 13.8 ± 1.3, 23.7 ± 3.2 s, p < 0.0001). In hands-on testing, extending the ballistic probe substantially reduced the efficiency of comminution (36.7 ± 6.4 vs. 131.3 ± 15.3 s, p < 0.0001). Clearance of fragments was considerably faster when the pneumatic-ballistic rate was 12 Hz compared to 1 Hz (12.3 ± 1.1 vs. 28.3 ± 2.2 s, p < 0.0001). These in vitro findings suggest ways to take advantage of the positive features while minimizing potential limitations of this lithotrite. Extending the ballistic probe is an advantage when the stone is immobile, as would be the case in treating a large stone that can be isolated against the wall of the pelvicalyceal system, but is a distinct disadvantage--due to retropulsion--when the stone is free to move. Operation of the LUV at fast ballistic rate significantly improved its ability to aspirate stone fragments.

Novel ultrasound method to reposition kidney stones

The success of surgical management of lower pole stones is principally dependent on stone fragmentation and residual stone clearance. Choice of surgical method depends on stone size, yet all methods are subjected to post-surgical complications resulting from residual stone fragments. Here we present a novel method and device to reposition kidney stones using ultrasound radiation force delivered by focused ultrasound and guided by ultrasound imaging. The device couples a commercial imaging array with a focused annular array transducer. Feasibility of repositioning stones was investigated by implanting artificial and human stones into a kidney-mimicking phantom that simulated a lower pole and collecting system. During experiment, stones were located by ultrasound imaging and repositioned by delivering short bursts of focused ultrasound. Stone motion was concurrently monitored by fluoroscopy, ultrasound imaging, and video photography, from which displacement and velocity were estimated. Stones were seen to move immediately after delivering focused ultrasound and successfully repositioned from the lower pole to the collecting system. Estimated velocities were on the order of 1 cm/s. This in vitro study demonstrates a promising modality to facilitate spontaneous clearance of kidney stones and increased clearance of residual stone fragments after surgical management.

1899 LONG-TERM RETREATMENT AFTER URETEROSCOPIC LASER LITHOTRIPSY DEPENDS ON EFFECTIVENESS OF INITIAL FRAGMENT CLEARANCE

You have accessJournal of UrologyStone Disease: SWL, Ureteroscopic or Percutaneous Stone Removal IV1 Apr 20101899 LONG-TERM RETREATMENT AFTER URETEROSCOPIC LASER LITHOTRIPSY DEPENDS ON EFFECTIVENESS OF INITIAL FRAGMENT CLEARANCE Penny Tatman, Andrew Heinisch, Mark Laliberte, Caroline Dietz-Carlson, and Andrew Portis Penny TatmanPenny Tatman More articles by this author , Andrew HeinischAndrew Heinisch More articles by this author , Mark LaliberteMark Laliberte More articles by this author , Caroline Dietz-CarlsonCaroline Dietz-Carlson More articles by this author , and Andrew PortisAndrew Portis More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.1853AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Ureteroscopic laser lithotripsy (URS) is an effective method for clearing moderate volume stone burden. In long-term follow-up, we examine retreatment rates and explore prognostic factors. METHODS All patients treated by flexible URS with laser lithotripsy for upper tract calculi by a single surgeon with a standardized technique attempting complete fragment clearance between 04/2003 and 05/2005 were identified. Combining chart review and computer record review, details of procedures and outcomes were collected. RESULTS A total of 239 renal units in 227 subjects were evaluated. Multiple calculi were treated in 43% of renal units. Excluding renal units with nephrocalcinosis, the average number of stones was 1.7±1.2. Stones were located in the proximal ureter (42%), lower pole (38%), and renal non-lower pole (54%). Predominant stone composition was calcium oxalate (68%), calcium phosphate (21%), uric acid (9%), or cystine (1%). Computed tomography (CT) was performed approximately 1 month after surgery in 181 (76%) renal units and categorized as stone free (49%), <2mm (22%), 2-4mm (19%), >4mm (10%). Mean follow-up was 3.8±1.3 years. Future ipsilateral procedures were performed in 28 (12%) patients at an average of 1.2±1.2 years. Retreatment was greater in renal units with multiple calculi (17% vs 7%, p=0.02) and nephrocalcinosis (25% vs 10%, p=0.02). There was no difference in retreatment by stone volume, location or composition. Cumulative retreatment rate (CRR) at 5 years was associated with size of residual fragments with stone free (5.7%), <2mm (5.3%), 2-4mm (20.5%), and >4mm (44.4%) (p<0.001, figure 1). Cox regression demonstrated that patients with > 2mm residual fragments were 4.6 times more likely to be retreated than stone-free patients after adjustment for stone number and nephrocalcinosis. There was no increased risk of retreatment for patients with ≤2mm residual fragments compared to stone-free. After adjustment for residual fragments, neither multiple stones nor nephrocalcinosis increased risk of retreatment. CONCLUSIONS Patients with residual fragments < 2mm on postoperative CT following URS can expect long-term freedom from retreatment. Residual fragments > 2mm were associated with higher retreatment rates. St. Paul, MN© 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e738 Peer Review Report Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Penny Tatman More articles by this author Andrew Heinisch More articles by this author Mark Laliberte More articles by this author Caroline Dietz-Carlson More articles by this author Andrew Portis More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Chemical Inducers of Autophagy That Enhance the Clearance of Mutant Proteins in Neurodegenerative Diseases

Many of the neurodegenerative diseases that afflict people are caused by intracytoplasmic aggregate-prone proteins. These include Parkinson disease, tauopathies, and polyglutamine expansion diseases such as Huntington disease. In Mendelian forms of these diseases, the mutations generally confer toxic novel functions on the relevant proteins. Thus, one potential strategy for dealing with these mutant proteins is to enhance their degradation. This can be achieved by up-regulating macroautophagy, which we will henceforth call autophagy. In this minireview, we will consider the reasons why autophagy up-regulation may be a powerful strategy for these diseases. In addition, we will consider some of the drugs and associated signaling pathways that can be used to induce autophagy with these therapeutic aims in mind.

2107 FOCUSED ULTRASOUND APPLICATION TO REPOSITION KIDNEY STONES AND FACILITATE PASSAGE OF RESIDUAL FRAGMENTS

You have accessJournal of UrologyStone Disease: New Technology1 Apr 20102107 FOCUSED ULTRASOUND APPLICATION TO REPOSITION KIDNEY STONES AND FACILITATE PASSAGE OF RESIDUAL FRAGMENTS Anup Shah, Mathew Sorensen, Jonathan Harper, Bryan Cunitz, Wei Lu, and Michael Bailey Anup ShahAnup Shah More articles by this author , Mathew SorensenMathew Sorensen More articles by this author , Jonathan HarperJonathan Harper More articles by this author , Bryan CunitzBryan Cunitz More articles by this author , Wei LuWei Lu More articles by this author , and Michael BaileyMichael Bailey More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.2194AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Lower pole kidney stones have lower rates of stone clearance after shock wave lithotripsy (SWL) and ureteroscopic treatment compared to other stone locations because of dependant positioning and difficult access. Residual stone fragments often lead to additional morbidity and need for secondary surgery. We describe the use of acoustic force and streaming created by transcutaneous focused ultrasound to manipulate the location of stone fragments within the collecting system in order to facilitate stone clearance. METHODS A newly developed focused ultrasound therapy probe consists of an 8-element annular array with a nominal frequency of 2.0 MHz, acoustic power output of 5-20W, and programmable focal depth of 4.5-8.5 cm. There is an opening in the center of the therapy probe for an HDI P4-2 imaging probe to provide ultrasound image guidance in a 2D plane. Artificial and human stones were placed into the lower pole of transparent kidney phantoms and live porcine kidneys using retrograde ureteroscopy. Focused ultrasound was applied. Stone motion was observed visually in the kidney phantom and using both diagnostic ultrasound and fluoroscopy in the porcine kidneys. Any tissue effects caused by focused ultrasound were assessed. RESULTS All stones placed in the kidney phantoms and live porcine kidneys were seen to move. Stone size ranged from 2 mm to 6 mm in maximal dimension. Stone velocities were on the order of 1 cm/s. Stone displacement distance was up to 3 cm and operators could generally control the direction of stone movement. No evidence of thermal necrosis or mechanical damage of renal tissue was observed on gross and microscopic examination. CONCLUSIONS Focused ultrasound can be used to move stones within the collecting system and may be able to improve rates of lower pole stone fragment clearance. Other applications for this new technology may include adjunctive use with medical expulsive therapy, repositioning of obstructing ureteropelvic junction stones, and ensuring complete clearance of infectious stones. Seattle, WA© 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e819 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Anup Shah More articles by this author Mathew Sorensen More articles by this author Jonathan Harper More articles by this author Bryan Cunitz More articles by this author Wei Lu More articles by this author Michael Bailey More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Posttranslational Modification of Ataxin-7 at Lysine 257 Prevents Autophagy-Mediated Turnover of an N-Terminal Caspase-7 Cleavage Fragment

Polyglutamine (polyQ) expansion within the ataxin-7 protein, a member of the STAGA [SPT3-TAF(II)31-GCN5L acetylase] and TFTC (GCN5 and TRRAP) chromatin remodeling complexes, causes the neurodegenerative disease spinocerebellar ataxia type 7 (SCA7). Proteolytic processing of ataxin-7 by caspase-7 generates N-terminal toxic polyQ-containing fragments that accumulate with disease progression and play an important role in SCA7 pathogenesis. To elucidate the basis for the toxicity of these fragments, we evaluated which posttranslational modifications of the N-terminal fragment of ataxin-7 modulate turnover and toxicity. Here, we show that mutating lysine 257 (K257), an amino acid adjacent to the caspase-7 cleavage site of ataxin-7 regulates turnover of the truncation product in a repeat-dependent manner. Modification of ataxin-7 K257 by acetylation promotes accumulation of the fragment, while unmodified ataxin-7 is degraded. The degradation of the caspase-7 cleavage product is mediated by macroautophagy in cell culture and primary neuron models of SCA7. Consistent with this, the fragment colocalizes with autophagic vesicle markers, and enhanced fragment accumulation increases in these lysosomal structures. We suggest that the levels of fragment accumulation within the cell is a key event in SCA7 neurodegeneration, and enhancing clearance of polyQ-containing fragments may be an effective target to reduce neurotoxicity in SCA7.

Extracorporeal Shock Wave Lithotripsy Monotherapy for Renal Stones >25 mm in Children

To determine the safety and efficacy of extracorporeal shock wave lithotripsy (ESWL) as monotherapy for renal stones >25 mm in children. Our prospective study included 24 children <14 years old with radiopaque renal stones >25 mm treated by ESWL as first-line treatment using the electromagnetic Dornier DoLi S device. Pretreatment kidney, ureter, and bladder plain films and intravenous urography and post-treatment ultrasonography and kidney, ureter, and bladder plain films were used to monitor the clearance of fragments. Stone clearance was assessed at 1 and 3 months. A stone-free state was defined as no radiologic evidence of stone. Asymptomatic noninfectious and nonobstructive fragments <3 mm were considered insignificant. The 24 children, aged 2-14 years (mean 7) underwent 53 ESWL sessions. Of the 24 children, 10 had stones located in the left kidney and 14 had stones located in the right kidney. The stone size was 25-35 mm (average 31). The average number of shock waves was 3489 per session. All children underwent lithotripsy with a gradual incremental energy increase from 14 to 20 kV. The overall stone-free rate was 83.3%. Four patients had clinically insignificant fragments and were followed up for the possibility of stone regrowth, microscopic hematuria, and urinary tract infection. Complications affected 25% of patients. ESWL is highly effective for treatment of large renal stones in children as a first-line treatment with minimal morbidity. The placement of a stent is not a prerequisite for success of treatment.

Nephritogenic Potential of Anti-DNA Antibodies against Necrotic Nucleosomes

Systemic lupus erythematosus is an inflammatory autoimmune syndrome of unknown cause. Kidney disease is a central and serious complication in this syndrome. Deposition of chromatin-containing immune complexes within glomerular membranes is considered a key event in the pathogenesis of lupus nephritis. One set of autoantibodies that participate in these complexes is directed against components of chromatin, particularly against double-stranded DNA (dsDNA). Matzinger's danger model implicates chromatin fragments as both inducers and glomerular targets for nephritogenic anti-dsDNA and anti-nucleosome antibodies. In context of this model, apoptosis, secondary necrosis, and exposure of chromatin fragments may causally trigger autoimmunity and subsequent lupus nephritis. The exposure of glomerular basement membrane-associated extracellular chromatin depends on an observed acquired downregulation of renal DNase1 transcription and loss of nuclease activity preceding development of severe nephritis; this downregulation would result in reduced fragmentation and clearance of chromatin fragments. These fragments bind glomerular basement membrane structures with high affinity. In addition, exposed chromatin fragments contain structures that stimulate the innate immune system through Toll-like receptors and the adaptive immune system to produce affinity-maturated pathogenic anti-chromatin and anti-dsDNA antibodies that are central to the development of lupus nephritis.