Prophylactic exposure to oral riluzole reduces the clinical severity and immune-related biomarkers of experimental autoimmune encephalomyelitis.

Glutamate-mediated excitotoxicity and immune cell infiltration are hallmarks of multiple sclerosis. The glutamate release inhibitor, riluzole (RIL), has been shown to attenuate the clinical symptoms of experimental autoimmune encephalomyelitis (EAE) in mice, but an association between glutamate excitotoxicity and the progression of MOG35-55-induced EAE has not been well defined. This study investigated the effects of prophylactic and chronic oral RIL on the clinical severity of EAE. Prophylactic+chronic RIL reduced the presence of inflammatory infiltrates, altered GFAP and Foxp3, and attenuated disease severity. These findings indicate a need to delineate the distinct role of glutamate in EAE symptomatology.

Variability in effective radiating area at 1 MHz affects ultrasound treatment intensity.

BACKGROUND AND PURPOSE: Previous research has indicated that not all ultrasound transducers heat at equal rates; however, the cause of this disparity is unclear. Variability in spatial average intensity (SAI) has been implicated in this disparity at 3 MHz. This variability has not been explored at 1 MHz. METHODS: Sixty-six 5-cm(2) ultrasound transducers were purchased from 6 different manufacturers. Transducers were calibrated and assessed for effective radiating area (ERA), total output power, and SAI using standardized measurement techniques. RESULTS: Total output power values fell within US Food and Drug Administration guidelines, but there were large variations in ERA. The resulting SAI values showed large deviations (-43% to +61%) from the digitally displayed value. Intra-manufacturer SAI values varied up to 53%. DISCUSSION AND CONCLUSION: Spatial average intensity can vary largely from the values displayed on these ultrasound generators; in a calibrated cohort, this difference is primarily attributable to differences in measured ERA. Patterns of SAI variability within the manufacturer at 1 MHz do not follow previous reports of variability at 3 MHz.

Blisters on the anterior shin in 3 research subjects after a 1-MHz, 1.5-W/cm , continuous ultrasound treatment: a case series.

CONTEXT: Clinicians should consider multiple factors when estimating tissue-heating rates. OBJECTIVE: To report 3 separate occurrences of blisters during an ultrasound treatment experiment. BACKGROUND: While we were conducting a research experiment comparing the measurement capabilities of 2 different intramuscular temperature devices, 3 female participants (age = 26.33 +/- 3.79 years, height = 169.34 +/- 3.89 cm, mass = 63.39 +/- 3.81 kg) out of 16 healthy volunteers (7 men: age = 22.83 +/- 1.17 years, height = 170.61 +/- 7.77 cm, mass = 74.62 +/- 19.24 kg; 9 women: age = 24.22 +/- 2.73 years, height = 171.88 +/- 6.35 cm, mass = 73.99 +/- 18.55 kg) developed blisters on the anterior shin after a 1-MHz, 1.5-W/cm (2) continuous ultrasound treatment delivered to the triceps surae muscle. DIFFERENTIAL DIAGNOSIS: Allergies; chemical reaction with cleaning agents; sunburn; negative interaction between the temperature measurement instruments and the ultrasound field; the ultrasound transducer not being calibrated properly, producing a nonuniform field and creating a hot spot or heating differently when compared with other ultrasound devices; the smaller anatomy of our female subjects; or a confounding interaction among these factors. TREATMENT: Participants were given standard minor burn care by a physician. UNIQUENESS: (1) The development of blisters on the anterior aspect of the shin as a result of an ultrasound treatment to the posterior aspect of the triceps surae muscle and (2) muscle tissue heating rates ranging from 0.19 degrees C to 1.1 degrees C/min, when ultrasound researchers have suggested tissue heating in the range of 0.3 degrees C/min with these settings. CONCLUSIONS: These adverse events raise important questions regarding treatment application and potential differences in heating and quality control among different ultrasound devices from different manufacturers.

Ultrasound heating is curvilinear in nature and varies between transducers from the same manufacturer.

CONTEXT: Ultrasound heating rates are known to differ between various manufacturers; it is unknown whether this difference exists within a manufacturer. OBJECTIVE: Determine if intramuscular heating differences exist between transducers from the same manufacturer. STUDY DESIGN: 3 x 10 repeated measures. Independent variables were Transducer (A, B, and C) and Time (10-min time points during the treatment). SETTING: Controlled laboratory. PARTICIPANTS: Twelve volunteers (M = 4, F = 8; age: 23 +/- 4 years; calf-girth: 37.94 +/- 4.16 cm; calf-skinfold: 27 +/- 17 mm). INTERVENTION: Three 10-min 1MHz continuous ultrasound treatments performed at an intensity of 1.2 W/cm2, over an area 2x transducer. MAIN OUTCOME MEASURES: Calf temperature increase. RESULTS: Heating curve generated for each transducer were significantly different (P = .034) but the overall temperature increases following 10 minutes of treatment were within 0.1 degree C (F = 1.023 P = .573). CONCLUSION: Heating curves differ between transducers from the same manufacturer but peak heating at 10 minutes was similar.

The role of quantitative Schlieren assessment of physiotherapy ultrasound fields in describing variations between tissue heating rates of different transducers.

Differences in tissue heating rates between ultrasound transducers have been well documented; however, comparative analysis between ultrasound fields to determine why tissue heating rates may differ is lacking. We selected three transducers from the same manufacturer with similar effective radiating area, output power, effective intensity and beam nonuniformity ratio [as defined by the FDA, 21 CFR Chap. 1, part 1,050 (10)], but markedly different Schlieren images. Each transducer was utilized to heat tissue with a standardized ultrasound application to determine whether Schlieren analysis may be useful in understanding variability in tissue heating rates. Thermocouples were inserted into the left triceps surae of 12 volunteers at a depth of 1.5 cm below one half the measured skin fold thickness (estimated average depth of the thermocouple was 1.99 +/- 0.27 cm). Each subject received one treatment from each transducer in a single session (n = 3); 3 MHz at 1.2 W/cm(2) for 8 min with a 100% duty cycle. Each transducer increased the IM temperature over time (p < 0.0001). IM temperatures were not significantly different between transducers from time zero to the fourth minute of treatment. After the fourth min, transducers B and C generated significantly higher tissue temperatures (p < 0.01). Transducer A, B and C increased IM temperature from 34.9 +/- 0.5 to 41.2 +/- 1.3 degrees C, 34.9 +/- 0.6 to 42.5 +/- 1.4 degrees C and 34.9 +/- 0.5 to 42.7 +/- 1.7 degrees C, respectively. Interestingly, transducer C emitted 22% lower output power but heated 24% higher than transducer A and our Schlieren images demonstrate that transducers B and C produced a more concentrated field compared with transducer A. The data we present here supports the general contention that a more concentrated field will heat to a higher temperature than a more disperse field, however, technical challenges in estimating output power, ERA and Schlieren analysis remain an issue.

Variability in effective radiating area and output power of new ultrasound transducers at 3 MHz.

CONTEXT: Spatial average intensity (SAI) is often used by clinicians to gauge therapeutic ultrasound dosage, yet SAI measures are not directly regulated by US Food and Drug Administration (FDA) standards. Current FDA guidelines permit a possible 50% to 150% minimum to maximum range of SAI values, potentially contributing to variability in clinical outcomes. OBJECTIVE: To measure clinical values that describe ultrasound transducers and to determine the degree of intramanufacturer and intermanufacturer variability in effective radiating area, power, and SAI when the transducer is functioning at 3 MHz. DESIGN: A descriptive and interferential approach was taken to this quasi-experimental design. SETTING: Measurement laboratory. PATIENTS OR OTHER PARTICIPANTS: Sixty-six 5-cm(2) ultrasound transducers were purchased from 6 different manufacturers. INTERVENTION(S): All transducers were calibrated and then assessed using standardized measurement techniques; SAI was normalized to account for variability in effective radiating area, resulting in an nSAI. MAIN OUTCOME MEASURE(S): Effective radiating area, power, and nSAI. RESULTS: All manufacturers with the exception of Omnisound (P = .534) showed a difference between the reported and measured effective radiating area values (P < .001). All transducers were within FDA guidelines for power (+/-20%). Chattanooga (0.85 +/- 0.05 W/cm(2)) had a lower nSAI (P < .05) than all other manufacturers functioning at 3 MHz. Intramanufacturer variability in SAI ranged from 16% to 35%, and intermanufacturer variability ranged from 22% to 61%. CONCLUSIONS: Clinicians should consider treatment values of each individual transducer, regardless of the manufacturer. In addition, clinicians should scrutinize the power calibration and recalibration record of the transducer and adjust clinical settings as needed for the desired level of heating. Our data may aid in explaining the reported heating differences among transducers from different manufacturers. Stricter FDA standards regarding effective radiating area and total power are needed, and standards regulating SAI should be established.

Analysis of effective radiating area, power, intensity, and field characteristics of ultrasound transducers.

OBJECTIVE: To characterize the ultrasound fields produced by a cohort of transducers from a single manufacturer via hydrophone and Schlieren technology. DESIGN: Descriptive study. SETTING: Measurement laboratory. PARTICIPANTS: Seven same-model ultrasound transducers from a single manufacturer. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Effective radiating area (ERA), total power, spatial average intensity (SAI), beam nonuniformity ratio (BNR), and Schlieren beam widths at 1.0 and 3.3 MHz. RESULTS: Values for ERA (1.0 MHz range, 3.62-4.38 cm(2); 3.3 MHz range, 3.74-4.76 cm(2)), total power (1.0 MHz range, 5.0-5.6 W; 3.3 MHz range, 4.7-5.7 W), SAI (1.0 MHz range, 1.2-1.4 W/cm(2); 3.3 MHz range, 1.0-1.5 W/cm(2)), and BNR (1.0 MHz range, 2.79-5.85; 3.3 MHz range, 2.51-4.56) fell within manufacturer's specifications and U.S. Food and Drug Administration (FDA) regulations. Schlieren analysis showed significantly larger beam widths at 3.3 MHz compared with 1.0 MHz and a large degree of variability in the ultrasound fields generated by the different transducers. There were no significant correlations between beam widths and ERA values. CONCLUSIONS: ERA and total power values in a test cohort exist within a range that met FDA regulations. Individual variability in ERA and total power resulted in 50% variability in SAI. This variability may help explain previous reports of heating differences between transducers.

Pre-exposure effects of 1 and 3 MHz therapeutic ultrasound on ConA activated spleenocytes.

This study was performed to evaluate the pre-exposure effects of ultrasound (1 MHz or 3 MHz) on ConA activated spleenocyte proliferation and cytokine production. Cells were treated for 10 min at various intensities, rested for 1h and stimulated with the T cell activator ConA. The cells were then analyzed for the effects of non-thermal ultrasound on cell growth and the presence of IL-2, IL-4 and IFN-g. The data show that pre-exposure of spleenocytes had no significant effects on the proliferation of ConA activated spleenocytes at either 1 or 3 MHz (10 min at 0.1 or 0.5 W/cm(2)). Significant increases in IL-2 were observed in both 1 and 3 MHz pre-treated and ConA activated spleenocytes. Cells pre-treated with 1 MHz and stimulated with ConA showed a significant increase in IL-4 and IFN-g. Conversely, cells pre-treated with 3 MHz and stimulated with ConA show a significant decrease in IL-4 and IFN-g. Interleuken-4 is known to increase the growth of mast cells, inhibit macrophage activation and increases the activity of the T cell subpopulation, T(H2). Interferon-gamma is known to stimulate production of collagen in fibroblasts, enhance debridement activity of macrophage and inhibit activity of the T cell subpopulation, T(H2).

Nonthermal effects of therapeutic ultrasound: the frequency resonance hypothesis.

OBJECTIVE: To present the frequency resonance hypothesis, a possible mechanical mechanism by which treatment with non-thermal levels of ultrasound stimulates therapeutic effects. The review encompasses a 4-decade history but focuses on recent reports describing the effects of nonthermal therapeutic levels of ultrasound at the cellular and molecular levels. DATA SOURCES: A search of MEDLINE from 1965 through 2000 using the terms ultrasound and therapeutic ultrasound. DATA SYNTHESIS: The literature provides a number of examples in which exposure of cells to therapeutic ultrasound under nonthermal conditions modified cellular functions. Nonthermal levels of ultrasound are reported to modulate membrane properties, alter cellular proliferation, and produce increases in proteins associated with inflammation and injury repair. Combined, these data suggest that nonthermal effects of therapeutic ultrasound can modify the inflammatory response. CONCLUSIONS: The concept of the absorption of ultrasonic energy by enzymatic proteins leading to changes in the enzymes activity is not novel. However, recent reports demonstrating that ultrasound affects enzyme activity and possibly gene regulation provide sufficient data to present a probable molecular mechanism of ultrasound's nonthermal therapeutic action. The frequency resonance hypothesis describes 2 possible biological mechanisms that may alter protein function as a result of the absorption of ultrasonic energy. First, absorption of mechanical energy by a protein may produce a transient conformational shift (modifying the 3-dimensional structure) and alter the protein's functional activity. Second, the resonance or shearing properties of the wave (or both) may dissociate a multimolecular complex, thereby disrupting the complex's function. This review focuses on recent studies that have reported cellular and molecular effects of therapeutic ultrasound and presents a mechanical mechanism that may lead to a better understanding of how the nonthermal effects of ultrasound may be therapeutic. Moreover, a better understanding of ultrasound's mechanical mechanism could lead to a better understanding of how and when ultrasound should be employed as a therapeutic modality.