Effect of lithotripter focal width on stone comminution in shock wave lithotripsy.

Using a reflector insert, the original HM-3 lithotripter field at 20 kV was altered significantly with the peak positive pressure (p(+)) in the focal plane increased from 49 to 87 MPa while the -6 dB focal width decreased concomitantly from 11 to 4 mm. Using the original reflector, p(+) of 33 MPa with a -6 dB focal width of 18 mm were measured in a pre-focal plane 15-mm proximal to the lithotripter focus. However, the acoustic pulse energy delivered to a 28-mm diameter area around the lithotripter axis was comparable ( approximately 120 mJ). For all three exposure conditions, similar stone comminution ( approximately 70%) was produced in a mesh holder of 15 mm after 250 shocks. In contrast, stone comminution produced by the modified reflector either in a 15-mm finger cot (45%) or in a 30-mm membrane holder (14%) was significantly reduced from the corresponding values (56% and 26%) produced by the original reflector (no statistically significant differences were observed between the focal and pre-focal planes). These observations suggest that a low-pressure/broad focal width lithotripter field will produce better stone comminution than its counterpart with high-pressure/narrow focal width under clinically relevant in vitro comminution conditions.

Modulation of heat shock transcription factor 1 as a therapeutic target for small molecule intervention in neurodegenerative disease.

Neurodegenerative diseases such as Huntington disease are devastating disorders with no therapeutic approaches to ameliorate the underlying protein misfolding defect inherent to poly-glutamine (polyQ) proteins. Given the mounting evidence that elevated levels of protein chaperones suppress polyQ protein misfolding, the master regulator of protein chaperone gene transcription, HSF1, is an attractive target for small molecule intervention. We describe a humanized yeast-based high-throughput screen to identify small molecule activators of human HSF1. This screen is insensitive to previously characterized activators of the heat shock response that have undesirable proteotoxic activity or that inhibit Hsp90, the central chaperone for cellular signaling and proliferation. A molecule identified in this screen, HSF1A, is structurally distinct from other characterized small molecule human HSF1 activators, activates HSF1 in mammalian and fly cells, elevates protein chaperone expression, ameliorates protein misfolding and cell death in polyQ-expressing neuronal precursor cells and protects against cytotoxicity in a fly model of polyQ-mediated neurodegeneration. In addition, we show that HSF1A interacts with components of the TRiC/CCT complex, suggesting a potentially novel regulatory role for this complex in modulating HSF1 activity. These studies describe a novel approach for the identification of new classes of pharmacological interventions for protein misfolding that underlies devastating neurodegenerative disease.

Improving the lens design and performance of a contemporary electromagnetic shock wave lithotripter.

The efficiency of shock wave lithotripsy (SWL), a noninvasive first-line therapy for millions of nephrolithiasis patients, has not improved substantially in the past two decades, especially in regard to stone clearance. Here, we report a new acoustic lens design for a contemporary electromagnetic (EM) shock wave lithotripter, based on recently acquired knowledge of the key lithotripter field characteristics that correlate with efficient and safe SWL. The new lens design addresses concomitantly three fundamental drawbacks in EM lithotripters, namely, narrow focal width, nonidealized pulse profile, and significant misalignment in acoustic focus and cavitation activities with the target stone at high output settings. Key design features and performance of the new lens were evaluated using model calculations and experimental measurements against the original lens under comparable acoustic pulse energy (E+) of 40 mJ. The -6-dB focal width of the new lens was enhanced from 7.4 to 11 mm at this energy level, and peak pressure (41 MPa) and maximum cavitation activity were both realigned to be within 5 mm of the lithotripter focus. Stone comminution produced by the new lens was either statistically improved or similar to that of the original lens under various in vitro test conditions and was significantly improved in vivo in a swine model (89% vs. 54%, P = 0.01), and tissue injury was minimal using a clinical treatment protocol. The general principle and associated techniques described in this work can be applied to design improvement of all EM lithotripters.

Humoral response against heat shock proteins and other mycobacterial antigens after intravesical treatment with bacille Calmette-Guerin (BCG) in patients with superficial bladder cancer

Few studies have analysed the antibody response during intravesical BCG immunotherapy for superficial bladder cancer. We have examined the evolution in serum antibody response against several heat shock proteins (hsp), including the recombinant mycobacterial hsp65 and the native protein P64 from BCG, GroEL from Escherichia coli (hsp60 family), recombinant mycobacterial hsp70 and the E. coli DnaK (hsp70 family), against purified protein derivative of tuberculin (PPD) and the AG85 complex of Mycobacterium bovis BCG, as well as against tetanus toxoid in 42 patients with a superficial bladder tumour, 28 treated with six intravesical BCG instillations and 14 patients used as controls. We also analysed the lymphoproliferative response of peripheral blood mononuclear cells against PPD in this population. Data of antibody responses at 6 weeks post BCG were available in all 28 patients, and at 4 month follow up in 17 patients. All patients who demonstrated a significant increase in IgC antibodies against PPD at 4 months follow up had a significant increase already at 6 weeks of follow up. In contrast, IgG antibodies against hsp increased significantly from 6 weeks to 4 months post- treatment. A significant increase in IgG antibodies against PPD, hsp65, P64, GroEL, and hsp70 at 4 months follow up was observed in 10/17, 8/17, 10/17, 4/17 and 8/17 patients. Native P64 protein elicited a higher antibody response than recombinant mycobacterial hsp65. No increase in antibody response was observed against Dnak from E. coli, against AG85 or tetanus toxoid after BCG therapy. An increase in IgG antibodies against P64 at 4 months follow up compared with pretreatment values was found to be a significant predictor of tumour recurrence (P < 0.01). Further studies with a larger number of patients are needed to confirm the value of the antibody response against P64 as a clinical independent prognostic factor.

Guided waves in a fluid-loaded transversely isotropic place

Dispersion relations are obtained for the propagation of symmetric and antisymmetric modes in a free transversely isotropic plate. Dispersion curves are plotted for the first four symmetric modes for a magnesium plate immersed in water. The first mode is highly damped and switches over to the second mode when the normalized frequency exceeds 12.

Joint distributions of waves and rain

The transfer of gases between the atmosphere and ocean is affected by a number of processes, of which wave action and rainfall are two of potential significance. Efforts have been made to quantify separately their contributions; however such assessments neglect the interaction of these phenomena. Here we look at the correlation statistics of waves and rain to note which regions display a strong association between rainfall and the local sea state. The conditional probability of rain varies from ~0.5% to ~15%, with most of the equatorial belt (which contains the ITCZ) showing a greater likelihood of rain at the lowest sea states. In contrast the occurrence of rain is independent of wave height in the Southern Ocean. The 1997/98 El Niño enhances the frequency of rain in some Pacific regions, with this change showing some association with wave conditions.