SUMMARY Neuromuscular junction (NMJ) formation requires precise interaction between motoneurons and muscle fibers. LRP4 is a receptor of agrin that is thought to act incis to stimulate MuSK in muscle fibers for postsynaptic differentiation. Here we dissected the roles of LRP4 in muscle fibers and motoneurons in NMJ formation by cell-specific mutation. Studies of muscle-specific mutants suggest that LRP4 is involved in deciding where to form AChR clusters in muscle fibers, postsynaptic differentiation, and axon terminal development. LRP4 in HEK293 cells increased synapsin or SV2 puncta in contacting axons of co-cultured neurons, suggesting a synaptogenic function. Analysis of LRP4 muscle and motoneuron double mutants and mechanistic studies suggest that NMJ formation may also be regulated by LRP4 in motoneurons, which could serve as agrin’s receptor in trans to induce AChR clusters. These observations uncovered distinct roles of LRP4 in motoneurons and muscles in NMJ development.

-Contemporary second-generation drug-eluting stents (DES) have superior efficacy and safety compared with early generation stents in patients undergoing percutaneous coronary intervention (PCI), in part related to their thinner struts. Whether newer generation ultra-thin DES further improve clinical outcomes compared with older second-generation thicker strut DES is unknown. -We searched PUBMED, EMBASE, and CENTRAL for randomized clinical trials that compared newer generation ultra-thin strut DES (defined as strut thickness<70 microns) versus thicker strut second-generation DES and reported clinical outcomes. The primary outcome was target lesion failure (TLF) (composite of cardiovascular death, target vessel myocardial infarction (MI) or ischemia-driven target lesion revascularization (TLR)) evaluated at 1-year follow-up. Tests for subgroup effects based on the ultra-thin strut DES type and based on the comparator DES type were performed using meta-regression analysis. -We identified 10 trials that randomized 11,658 patients and evaluated 3 newer generation ultra-thin strut DES: Orsiro stent (60 μm), MiStent (64 μm) and BioMime (65 μm). When compared with thicker strut second-generation DES, newer generation ultra-thin strut DES were associated with a 16% reduction in TLF (RR=0.84; 95% CI 0.72-0.99) driven by less MI (RR=0.80; 95% CI 0.65-0.99). Ultra-thin strut DES were also associated with qualitatively lower rates of any stent thrombosis (RR=0.72; 95% CI 0.51-1.01). Tests for subgroup effects based on the ultra-thin strut DES type (P=0.58) and the comparator DES type (P=0.98) were not significant, suggesting consistent outcomes across the three ultra-thin strut DES and with the different DES comparators. -In patients undergoing PCI, newer generation ultra-thin strut DES further improve 1-year clinical outcomes compared with contemporary thicker strut second-generation DES.

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As the efficacy of brachytherapy prostate treatment is becoming realized, new models of 125I seeds are being introduced. In this article we present thermoluminescent dosimetry (TLD) in a solid water phantom for a new design of 125I seed (UroMed/Bebig Symmetra, Model I25.S06). TLD cubes, LiF TLD-100, from Bicron (Solon, OH) with dimension 1 x 1 x 1 mm3 were irradiated at various distances from the seed at angles ranging from 0 degrees to 90 degrees in 10 degrees increments. The TLD detectors were calibrated by irradiation in a 60Co teletherapy beam. Monte Carlo simulation was used to account for TLD energy dependence and the deviation of solid water composition (as determined by chemical analysis of a sample) from liquid water. Dose rates per unit air kerma strength were determined based on calibrations traceable to the 1999 NIST standard (corrected for NIST measurement errors made in 1999) for the Symmetra seed. Dose data is presented in TG-43 format as a function of distance and angle. Values for lambda, F(r, theta), g(r), and the anisotropy constant are obtained for use in radiation treatment planning (RTP) software. The dose rate constant was determined to be 1.033+/-6.4% cGy h(-1) U(-1), which is comparable to model 6702 and higher than model 6711. We find the relative dose distributions of the Symmetra seed are similar to model 6702, and less anisotropic than model 6711. After accounting for deviation of measured solid water composition from the manufacturer's specification, good agreement between TLD results and Monte-Carlo-aided values was found.

Study Type – Therapy (case series) Level of Evidence 4 What’s known on the subject? and What does the study add? Laparoendoscopic single site surgery (LESS) is a novel technique for performing a variety of procedures including Urological upper tract reconstructive surgery. As of now few studies have compared perioperative factors and outcomes between LESS and standard laparoscopic or robotic approaches. In this comparison between LESS and standard laparoscopic pyeloplasty we identified no significant differences in terms of narcotic requirements, quality of life indicators, and outcomes although prospective evaluation is needed. OBJECTIVE • To compare laparoendoscopic single‐site (LESS) and standard laparoscopic pyeloplasty procedures with the aim of defining whether perioperative, recovery or health‐related quality of life (HRQL) benefits exist for the LESS procedure. PATIENTS AND METHODS • From November 2007 to August 2008, sixteen patients underwent LESS pyeloplasty at a tertiary care referral centre. These patients were compared with a matched cohort of patients undergoing standard laparoscopic pyeloplasty. • Matching criteria included gender and age (within 10 years), as well as preoperative degree of obstruction (T½ within 15 min) and differential renal function (within 10% ipsilaterally) based on diuretic radionuclide scanning. Mean follow‐up was 13 ± 4 months for the LESS group and 17 ± 3 months for the standard laparoscopic group. • LESS pyeloplasty procedures were all performed using a single‐port device in the umbilicus and suturing was assisted with a 2‐mm grasping instrument. Perioperative variables, successful relief of obstruction and HRQL measurements were compared between the two groups. RESULTS • Except for a lower body mass index in the LESS group (23 ± 6 kg/m2 vs 30 ± 7 kg/m2, P= 0.002), no difference was noted for perioperative variables between the two cohorts, including hospital stay and analgesic requirement. • No significant HRQL advantage was noted for either group based on a six‐item non‐validated questionnaire. • All patients in both groups experienced clinical resolution of their symptoms. A patient in the standard laparoscopy group and two patients in the LESS group had T½ > 20 min (0.063% vs 0.125%, P= 1.00) on diuretic radionuclide scanning. • Limitations include the retrospective nature of the present study, as well as the relatively small study population and short follow‐up. CONCLUSIONS • No benefit was noted for LESS pyeloplasty over the standard laparoscopic procedure beyond aesthetic advantages. • Further comparisons are needed to determine whether these results are generalizable to other LESS procedures.

Overexpression of Bcl-X L , an antiapoptotic Bcl-2 family member, occurs in a majority of head and neck squamous cell carcinomas (HNSCCs) and correlates with chemotherapy resistance in this disease. Overexpression of Bcl-2 is also observed in HNSCC, albeit less frequently. We have previously shown that peptides derived from the BH3 domains of proapoptotic proteins can be used to target Bcl-X L and Bcl-2 in HNSCC cells, promoting apoptosis. In this report, we examined the impact of ABT-737 (for structure, see Nature 435:677-681, 2005), a potent small-molecule inhibitor of Bcl-X L and Bcl-2, on HNSCC cells. As a single agent, ABT-737 was largely ineffective at promoting HNSCC cell death. By contrast, ABT-737 strongly synergized with the chemotherapy drugs cisplatin and etoposide to promote HNSCC cell death and loss of clonogenic survival. Synergism between ABT-737 and chemotherapy was associated with synergistic activation of caspase-3 and cleavage of poly(ADP-ribose) polymerase. Treatment with ABT-737 plus chemotherapy resulted in dramatic up-regulation of proapoptotic Noxa protein, and small interfering RNA (siRNA)-mediated inhibition of Noxa up-regulation partially attenuated cell death by the synergistic combination. Treatment with cisplatin or etoposide, alone or in combination with ABT-737, resulted in substantial down-regulation of Mcl-1L, a known inhibitor of ABT-737 action. Further down-regulation of Mcl-1L using siRNA failed to enhance killing by the cisplatin/ABT-737 synergistic combination, indicating that chemotherapy treatment of HNSCC cells is sufficient to remove this impediment to ABT-737. Together, our results demonstrate potent synergy between ABT-737 and chemotherapy drugs in the killing of HNSCC cells and reveal an important role for Noxa in mediating synergism by these agents.

This paper presents a systematic study of the dose response characteristics of two new models and one commonly used model of GAFCHROMIC film: HS, XR-T, and MD55-2, respectively. We irradiated these film models with three different radiation sources: I-125, Ir-192, and 6 MV photon beam (6 MVX). We scanned the films with three different densitometers: a He-Ne laser with a wavelength of 633 nm, a spot densitometer with a wavelength of 671 nm, and a CCD camera densitometer with interchangeable LED boxes with wavelengths of 665 nm (red), 520 nm (green), and 465 nm (blue). We compared the film sensitivities in terms of net optical density (NOD) per unit dose in Gy. The sensitivity of each film model depends on radiation energy and the densitometer light source. Using He-Ne laser based densitometer as a reference standard, we found the sensitivities (NOD/Gy) for the red lights of wavelengths, 671 nm and 665 nm, are higher by factors of about 2.5 and 2, respectively. The sensitivities for green (520 nm) and blue (465 nm) lights are lower than that for He-Ne laser (633 nm) by factors of about 2 and 4, respectively. The energy dependence of the sensitivity varies with the film model, but is similar for all densitometer light sources. Comparing I-125 to Ir-192 and 6MVX, we note that (a) model XR-T is about eight times more sensitive, and (b) models HS and MD55-2 are about 40% less sensitive. Relative to MD55-2, XR-T is 12 times more sensitive for I-125 but comparable for Ir-192 and 6MVX, whereas HS is 2 to 3 times more sensitive in all cases. This set of results can serve as useful information for making decisions in selecting the film model and compatible densitometer to achieve the best accuracy of dosimetry in the appropriate dose range.