Tumor-derived inducible heat-shock protein 70 (HSP70) is an essential component of anti-tumor immunity.

The anti-apoptotic function and tumor-associated expression of heat-shock protein 70 (HSP70) is consistent with HSP70 functioning as a survival factor to promote tumorigenesis. However, its immunomodulatory activities to induce anti-tumor immunity predict the suppression of tumor growth. Using the Hsp70.1/3(-/-)(Hsp70(-/-)) mouse model, we observed that tumor-derived HSP70 was neither required for cellular transformation nor for in vivo tumor growth. Hsp70(-/-) murine embryonic fibroblasts (MEFs) were transformed by E1A/Ras and generated tumors in immunodeficient hosts as efficiently as wild-type (WT) transformants. Comparison of Bcr-Abl-mediated transformation of WT and Hsp70(-/-) bone marrow and progression of B-cell leukemogenesis in vivo revealed no differences in disease onset or survival rates, and Eµ-Myc-driven lymphoma in Hsp70(-/-) mice was phenotypically indistinguishable from that in WT Eµ-Myc mice. However, Hsp70(-/-) E1A/Ras MEFs generated significantly larger tumors than their WT counterparts in C57BL/6 J immune-competent hosts. Concurrent with this was a reduction in intra-tumoral infiltration of innate and adaptive immune cells, including macrophages and CD8(+) T cells. Evaluation of several potential mechanisms revealed an HSP70-chemokine-like activity to promote cellular migration. These observations support a role for tumor-derived HSP70 in facilitating anti-tumor immunity to limit tumor growth and highlight the potential consequences of anti-HSP70 therapy as an efficacious anti-cancer strategy.

Assessing whole body vibration exposure for use in epidemiological studies of back injuries: measurements, observations and self-reports.

Improved assessment of whole body vibration exposure is needed for epidemiological studies investigating the causes of low back disorders. Vibration was measured on 54 worker-days in five heavy industries, with data collected on observed and self-reported driving conditions, demographics, and vehicle characteristics. Variables significant at p < 0.1 in simple linear regressions (20 of 34) were retained for mixed effects multiple regressions to determine the best prediction of rms vibration level and 8-h equivalent vibration exposure. Vibration was measured, on average, for 205 min per work shift (SD 105). Means and standard deviations in m · s⁻² were: x-axis 0.35 (0.19); y-axis 0.34 (0.28); z-axis 0.54 (0.23); vector sum 0.90 (0.49); and 8-h equivalent vector sum 0.70 (0.37). The final three regression models retained only 2 or 3 of the 34 variables (driving speed (<20 km/h and/or 20-40 km/h) and industry and/or vehicle type and explained up to 60% of the variance (R² = 0.26-0.6). PRACTITIONER SUMMARY: The purpose of the project was to create a model that can predict whole body vibration exposure from a number of observed or self-reported variables. This could eliminate the need for costly and time-consuming field measurements of WBV in epidemiological studies. Despite a large number of variables included in the model (34) and 54 worker-days of WBV measurement, the final models contained only two or three variables, and explained 60% of the variance. While this is an improvement over use of job title in epidemiological studies, it still leaves a considerable amount of WBV variance unexplained.

The effect of cyclic GMP on rabbit corporal smooth muscle tone and its modulation by cyclo-oxygenase products.

Corporal smooth muscle (CSM) tone is maintained by a finite balance between relaxant and contractile neurotransmitters. The aim of these experiments was to ascertain the degree to which cyclic GMP is involved in these interactions. We also sought to elucidate the pharmacological mechanism of action of MB in rabbit corpus cavernosum (RCC), an important tool in nitric oxide research. Using an organ chamber technique, strips of RCC were treated with the guanylate cyclase inhibitors Methylene Blue (MB) and LY83583; 100 microM MB led to increases in resting tension which were antagonized by indomethacin, nifedipine, phentolamine, but not superoxide dismutase (SOD). Contractile responses to noradrenaline (NA) were increased and relaxation to ACh was impaired by both MB and LY83583 and reversed with indomethacin, but not SOD. Pyrogallol had no effect on agonist-induced responses. The pharmacological action of MB in RCC does not depend on the generation of superoxide anions. Endothelium-dependent relaxation in RCC results in activation of soluble guanylate cyclase and release of a stable endothelium derived contracting factor(s), which is likely to be a constrictor prostanoid(s). Tonic production of cGMP in RCC inhibits the presynaptic release and contractile effects of NA and can be modulated by cyclo-oxygenase inhibition, demonstrating the important interaction and functional antagonism between cGMP and prostaglandins in the control of CSM tone.

Static respiratory muscle work during immersion with positive and negative respiratory loading.

Upright immersion imposes a pressure imbalance across the thorax. This study examined the effects of air-delivery pressure on inspiratory muscle work during upright immersion. Eight subjects performed respiratory pressure-volume relaxation maneuvers while seated in air (control) and during immersion. Hydrostatic, respiratory elastic (lung and chest wall), and resultant static respiratory muscle work components were computed. During immersion, the effects of four air-delivery pressures were evaluated: mouth pressure (uncompensated); the pressure at the lung centroid (PL,c); and at PL,c +/-0.98 kPa. When breathing at pressures less than the PL,c, subjects generally defended an expiratory reserve volume (ERV) greater than the immersed relaxation volume, minus residual volume, resulting in additional inspiratory muscle work. The resultant static inspiratory muscle work, computed over a 1-liter tidal volume above the ERV, increased from 0.23 J. l(-1), when subjects were breathing at PL,c, to 0.83 J. l(-1) at PL,c -0.98 kPa (P < 0.05), and to 1.79 J. l(-1) at mouth pressure (P < 0.05). Under the control state, and during the above experimental conditions, static expiratory work was minimal. When breathing at PL,c +0.98 kPa, subjects adopted an ERV less than the immersed relaxation volume, minus residual volume, resulting in 0.36 J. l(-1) of expiratory muscle work. Thus static inspiratory muscle work varied with respiratory loading, whereas PL,c air supply minimized this work during upright immersion, restoring lung-tissue, chest-wall, and static muscle work to levels obtained in the control state.

Effectiveness of rest pauses and cooling in alleviation of heat stress during simulated fire-fighting activity.

This study examined whether cooling a fire-fighter with a high velocity fan, during 10 min rest pauses between, and following, 10 min work periods, decreases heat stress during repetitive fire-fighting activity. Twelve professional fire-fighters (mean age 31.8 +/- 6.7 years) completed two, 40 min work/recovery trials in an environmental chamber at 40 degrees C and 70% relative humidity (RH). One trial was termed an enhanced recovery (ER) trial and the other was termed a normal recovery (NR) trial. In both conditions subjects wore full protective clothing and breathing apparatus during the work. In the ER trial a subject removed his protective coat and sat in front of a fan during each recovery period. In the NR trial a subject merely unbuckled his coat and was not cooled by a fan during either recovery period. The group mean metabolic cost (VO2), and the exercise and recovery heart rates were significantly lower (p < or = 0.05) during the ER trial than in the NR condition. Group mean rectal temperature increased by 1.5 degrees C in the NR trial but by only 0.8 degree C during the ER trial. The latter group's more effective cooling indicates the potential of fan cooling to reduce physiological strain and decrease the risk of heat exhaustion during repetitive fire-fighting activity. The results suggest that a fire-fighter's short 10 min exposure to heavy work in a hot environment of 40 degrees C and 70% RH produces minimal heat stress in a healthy fire-fighter. However, a period of fire-fighting exposure greater than 10 min without adequate rest and cooling may lead to a significant accumulation of heat stress and fatigue during further fire-fighting activity, irrespective of physical prowess.

Femoral forces during limb lengthening in children.

A system was designed to measure forces during femoral lengthening using force transducers on an Ilizarov femoral frame. Measurements were made in three teenaged subjects overnight and during weight bearing. A progressive increase in axial load secondary to distraction was seen, forces peaking at 428, 447, and 673 N for the three subjects. Little change in force transmitted by the frame was observed during weight bearing. Measurements taken before and after each individual lengthening showed no change in axial force or bending moment (p > 0.01). A diurnal variation of axial load was found (p < 0.01). Forces at midnight were greater than in the morning in all the subjects, with a mean difference of 113 N (p < 0.01). Distraction forces measured in the femur during distraction are greater than those previously measured in the tibia. Evidence exists that the callus is stiff and may be the origin of these forces.

Static and dynamic pulmonary compliance during upright immersion.

Elastic properties of the lung are typically assessed using the static pressure-volume relaxation manoeuvre. Although dynamic methods have produced equivalent results in normal healthy subjects, their use under obstructive pulmonary disease states and during certain conditions has been questioned. Static (Cst(1)) and dynamic (Cdyn(1)) pulmonary compliance were measured in eight subjects in air (control) and during immersion. Cdyn(1) decreased from 2.94 to 1.61 l kPa-1 following immersion, during which subjects breathed air supplied at mouth pressure (P < 0.05), while Cst(1) remained approximately equivalent (3.16 and 4.07 l kPa-1 respectively, P > 0.05). When immersed subjects were supplied with breathing gas at lung centroid pressure (PLC), Cdyn(1) returned to control status (2.89 l kPa-1; P > 0.05), while Cst(1) remained stable at 3.60 l kPa-1 (P > 0.05). The difference between Cst(1) and Cdynm(1) may imply that flow-resistive properties are included within the latter measurement. It is recommended that Cdyn(1), under these conditions, be interpreted as an index of peripheral airway patency, rather than as an assessment of lung elasticity.

Biomechanical comparison of carpet-stretching devices.

Peak impact forces, measured from seven male carpetlayers using a knee-kicker over 39 trials were 2933 N (SD 397), taking 9.5 ms (SD +/- 1.1) to reach peak. The knee-kicking cycle involved high knee decelerations of 880 m.s-2 (SD +/- 271). Angles at peak force for the knee (63 degrees SD +/- 10 degrees) and hip (80 degrees SD +/- 35 degrees) showed considerable variation between individuals. Kneeling forces on the non-kicking leg during the kick cycle were 894 N: comparative forces were 368 N and 476 N measured during use of the power stretcher and crab re-stretcher, respectively. Under dynamic conditions the effective mechanical advantage of the knee-kicker was less than 1.0. In comparison, the mechanical advantage of the power stretcher was approximately 14 times greater over the stretch action. When tested with a crab re-stretcher, the breaking strength of the smooth-edge to which the carpet attaches averaged 2384 N (SD +/- 245). Design guidelines for an improved carpet stretching device are provided.

A computer-aided socket design procedure for above-knee prostheses.

A computer-aided socket design procedure (CASD) has been developed whereby an above-knee socket shape can be created based on anthropometric measurements taken from an amputee. The anthroometric measurements are used to select a subset of three reference shapes from a Reference Shape Library stored in the computer in the form of three-dimensional numerical data. Transformation procedures then scale the reference shapes at each cross-sectional level to match the amputee's cross-sectional areas. Blending of the three shapes is determined by tissue mass weighting factors, to yield a single custom socket configuration, known as the "basic socket shape." Subsequent graphical procedures in the CASD system allows further sculpting of the shape in the form of interactive adjustments of the numerical data to reach the socket shape desired by the prosthetist. The resultant shape data can then be transferred to a computer numerically controlled (CNC) milling machine to carve a model of the socket shape.

Brain tissue pH and ventilatory acclimatization to high altitude.

31P nuclear magnetic resonance spectroscopy (31P-NMRS) was performed on brain cross sections of four human subjects before and after 7 days in a hypobaric chamber at 447 Torr to test the hypothesis that brain intracellular acidosis develops during acclimatization to high altitude and accounts for the progressively increasing ventilation that develops (ventilatory acclimatization). Arterial blood gas measurements confirmed increased ventilation. At the end of 1 wk of hypobaria, brain intracellular pH was 7.023 +/- 0.046 (SD), unchanged from preexposure pH of 6.998 +/- 0.029. After return to sea level, however, it decreased to 6.918 +/- 0.032 at 15 min (P less than 0.01) and 6.920 +/- 0.046 at 12 h (P less than 0.01). The ventilatory response to hypoxia increased [from 0.35 +/- 0.11 (l/min)/(-%O2 saturation) before exposure to 0.69 +/- 0.19 after, P = 0.06]. Brain intracellular acidosis is probably not a supplemental stimulus to ventilatory acclimatization to high altitude. However, brain intracellular acidosis develops on return to normoxia from chronic hypoxia, suggesting that brain pH may follow changes in blood and cerebrospinal fluid pH as they are altered by changes in ventilation.

Pulmonary flow-resistive work during hydrostatic loading.

This paper focuses upon flow-resistive pulmonary work during upright immersion, and during changes in the air delivery pressure. Nine male non-smokers (aged 26.2 +/- 3.5 years), with normal lung function history, performed spontaneous respiration while seated in air (control) and during total immersion. During the immersed state subjects were supplied with air at four hydrostatic pressures: mouth pressure (PM; simulating a mouth-held demand regulator), lung centroid pressure (PLC; + 1.33 kPa relative to the sternal notch), and 0.98 kPa (10 cmH2O) above and below the lung centroid pressure. Inspiratory, expiratory and total flow-resistive pulmonary work were computed from the integration of transpulmonary pressure (difference between oesophageal and mouth pressure) with respect to lung volume change. When breathing air delivered at mouth pressure, immersion significantly elevated all total flow-resistive pulmonary work components (P less than 0.05). Each increment in breathing pressure resulted in a progressive reduction in expiratory and total flow-resistive pulmonary work, so that when air was provided at lung centroid pressure and lung centroid pressure +0.98 kPa both components were similar to control values (P greater than 0.05). Inspiratory was always less than expiratory pulmonary work. During immersion inspiratory pulmonary work was significantly reduced when air supply pressure was increased above mouth pressure (P less than 0.05). Subsequent pressure increments failed to produce further changes in inspiratory pulmonary work. The difference in response between the inspiratory and expiratory components of total flow resistive pulmonary work was attributed primarily to the volume-dependence of the expiratory component.

Exercise breathing pattern during chronic altitude exposure.

Breathing pattern in response to maximal exercise was examined in four subjects during a 7-day acclimatisation to a simulated altitude of 4247 m (barometric pressure, PB = 59.5 kPa). Graded exercise tests to exhaustion were performed during normoxia (day 0), and on days 2 and 7 of hypoxia, respectively. Ventilation was significantly augmented in the hypoxic environment, as were both the mean inspiratory flow (VT/TI) and inspiratory duty cycle (TI/TTOT) components of it. VI/TI was increased due to a significant increase in tidal volume (VT) and a corresponding decrease in inspiratory time duration (TI). Throughout a range of exercise ventilation, TI/TTOT was increased due to an apparently greater decrease in expiratory time duration (TE) with respect to TI. In all cases, the relation between VT and TI displayed a typical range 2 behaviour, with evidence of a range 3 occurring at very high ventilatory rates. There was essentially no difference observed in the VT-TI relation during exercise between the normoxic and hypoxic conditions. No significant changes were observed in the breathing pattern in response to exercise within the exposure period (from day 2 to day 7), although there was a discernible tendency to a higher stage 3 plateau by day 7 of altitude exposure.

Lung volume changes in response to altered breathing gas pressure during upright immersion.

Since elastic and flow-resistive respiratory work are volume dependent, changes in lung volume during immersion affect respiratory effort. This investigation examined changes in lung volume with air delivery pressure modifications during upright immersion. Static pressure-volume relaxation relationships and lung volumes were obtained from ten immersed subjects breathing air at four delivery pressures: mouth pressure, lung centroid pressure (PLC), and 0.98 kPa above and below PLC. The PLC is the static lung pressure which returns the respiratory relaxation volume (VR) to normal and was previously determined to be +1.33 kPa relative to pressure at the sternal notch. Lung volume changes observed when breathing air at mouth pressure were reversed when air was supplied at PLC. The expiratory reserve volume (ERV) and VR were reduced by 58% and 87%, respectively, during uncompensated immersion. These differences indicated an active defence of ERV and implied that additional static respiratory work was required to overcome transrespiratory pressure gradients.

Effects of CO2 and N2 partial pressures on cognitive and psychomotor performance.

This study examined N2 and CO2 components of narcosis by comparing the effects of three levels of PETCO2 [low = 29 mmHg (SD = 4 mmHg), medium = 47 mmHg (SD = 1 mmHg), high = 57 mmHg (SD = 2 mmHg)] at 1 and 6 atm abs in 12 male volunteers. Cognitive and psychomotor performances were examined using a variety of tasks, including a modified Stroop test, an arithmetic test, number comparison, a figure copying test, and the Purdue pegboard test. Performance on all tasks demonstrated significant (P less than 0.05) decrements at 6 atm abs. High CO2 tensions significantly impaired cognitive and psychomotor performance at 1 atm abs and caused further decrements at 6 atm abs (P less than 0.05). However, no significant N2-CO2 interaction (P greater than 0.05) or global threshold for the onset of CO2 narcosis was indicated by the test scores. The pattern of intratest results were different for N2 and CO2. At high PETCO2, performance deficits were due to a slowing of performance rather than a disruption of the accuracy of processing. Nitrogen narcosis, conversely, produced significant impairment through both decreases in the speed and accuracy of processing on the majority of performance tests. It was concluded that within the PETCO2 ranges studied: a) PETCO2 and PIN2 are additive in their effects on impaired cognitive and psychomotor performance at depth; b) high PETCO2 and PIN2 induce distinctly different strategic responses on the speed accuracy trade-off function of the performance tests; c) decrements in cognitive and psychomotor performance under high PETCO2 do not conform to the predicted narcotic potency of CO2 according to the lipid solubility theory of narcosis.

Computer-aided design and manufacture of an above-knee amputee socket.

This paper describes the initial test results obtained from a newly developed computer-aided socket design (CASD) and manufacturing (CASM) process for above-knee amputees. Anthropometric measures taken from an amputee provided input information to a CASD system. Using these measurements, data from a reference shape library stored in the computer were selected and modified to create a unique socket shape reflecting the particular characteristics of the amputation stump. The resultant shape was produced as a 'primitive' test socket by a CASM process. Numerical shape data were then transferred to a CNC milling machine to construct a negative cast, from which the primitive socket was produced by a vacuum-forming procedure. The resultant primitive socket shape was fitted and the amputee was able to load the socket without discomfort. Some shape discrepancies were identified and the shape data were modified interactively by the CASD system to create a final socket shape. The final socket shape was manufactured and worn by the amputee during a 35 min walking trial. Subjective evaluation was that the socket provided comfort and control comparable with that of the conventional socket, and proved to be acceptable to the amputee. This was followed by a 2-month home trial which was also successful. The CASD socket shapes were compared numerically in area, shape and volume with data taken from the original socket worn by the amputee, a new socket made by conventional methods and a topographic model of the amputation stump. The final CASD socket shape compared favourably with that of a socket manufactured by conventional methods.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of breathing-gas pressure on pulmonary function and work capacity during immersion.

Upright immersion induces respiratory mechanical changes that may impair pulmonary function during hyperbaric exercise. To evaluate this, 10 divers performed an incremental cycling protocol while immersed upright at 1.02 and 6.05 atmospheres absolute (atm abs). Air was supplied at each of two hydrostatic pressures: mouth pressure (Pm: to stimulate a mouth-held demand regulator) and lung centroid pressure (PLC). Subjects perceived air delivery at PLC to be more comfortable at each level of exercise at both absolute pressures (P less than 0.05). At 6.05 atm abs subjects perceived narcosis to be greater for Pm than for PLC air delivery. Hypoventilation was encountered at 6.05 atm abs with PLC air delivery and was further exacerbated when air was delivered at Pm (P less than 0.05). It was concluded that hypoventilation and narcosis are reduced whereas respiratory comfort is increased when air is delivered at PLC. This change is possibly due to improved pulmonary mechanics accompanying PLC air supply pressure.