Microcirculation of skeletal muscle adapts differently to a resistive exercise intervention with and without superimposed whole‐body vibrations

Whole‐body vibration (WBV) training is commonly practiced and may enhance peripheral blood flow. Here, we investigated muscle morphology and acute microcirculatory responses before and after a 6‐week resistive exercise training intervention without (RE) or with (RVE) simultaneous whole‐body vibrations (20 Hz, 6 mm peak‐to‐peak amplitude) in 26 healthy men in a randomized, controlled parallel‐design study. Total haemoglobin (tHb) and tissue oxygenation index (TOI) were measured in gastrocnemius muscle (GM) with near‐infrared spectroscopy (NIRS). Whole‐body oxygen consumption (VO₂) was measured via spirometry, and skeletal muscle morphology was determined in soleus (SOL) muscle biopsies. Our data reveal that exercise‐induced muscle deoxygenation both before and after 6 weeks training was similar in RE and RVE (P = 0·76), although VO₂ was 20% higher in the RVE group (P<0·001). The RVE group showed a 14%‐point increase in reactive hyperaemia (P = 0·007) and a 27% increase in blood volume (P<0·01) in GM after 6 weeks of training. The number of capillaries around fibres was increased by 15% after 6 weeks training in both groups (P<0·001) with no specific effect of superimposed WBV (P = 0·61). Neither of the training regimens induced fibre hypertrophy in SOL. The present findings suggest an increased blood volume and vasodilator response in GM as an adaptation to long‐term RVE, which was not observed after RE alone. We conclude that RVE training enhances vasodilation of small arterioles and possibly capillaries. This effect might be advantageous for muscle thermoregulation and the delivery of oxygen and nutrients to exercising muscle and removal of carbon dioxide and metabolites.     

A canadian study of the total medical costs for patients with systemic lupus erythematosus and the predictors of costs

Objective. We conducted a cost identification analysis on 164 consecutive patients with systemic lupus erythematosus (SLE) who entered the Montreal General Hospital Lupus Registry between January 1977 and January 1990, compared their costs to the population of Quebec, and determined the predictors of cost. Methods. In January 1990 and 1991, participants completed questionnaires on health services utilization and on employment history over the preceding 6 months, as well as on functional, psychological, and social well-being. The societal burden of SLE was determined in terms of direct costs (all resources consumed in patient care) and indirect costs (wages lost due to lack of work force participation because of morbidity). Results. The mean total annual cost for 1989, as assessed in January 1990 and expressed in 1990 Canadian dollars, was $13,094. Although only 44% of the patients were fully employed, indirect costs were responsible for 54% of this total ($7,071). Ambulatory costs, primarily diagnostic procedures, medications, and visits to health care professionals, comprised 55% of direct costs ($3,331). The results of the 1990 cost determination were similar. On average, hospitalizations among SLE patients were 4 times more frequent than among the general population of Quebec (matched for age and sex), and the number of ambulatory visits to physicians was double that for the average resident of Quebec. Higher 1989 values of creatinine and a poorer level of physical functioning were the best predictors of higher 1990 direct costs (R² = 0.29). A poorer SLE well-being score, a combination of education and employment status, and a weaker level of social support were the best predictors of higher indirect costs (R² = 0.29). Conclusion. The direct and indirect costs for patients with SLE are substantial, and their respective predictors are distinct. Direct costs arise from organic complications which induce functional disability. Predictors of indirect costs are potentially amenable to psychological or social interventions and may be more easily modified than the determinants of direct costs, thereby improving patient outcome while simultaneously reducing disease costs.     

Immunohistochemical detection of proluteinizing hormone-releasing hormone peptides in neurons in the human hypothalamus.

To determine the presence of LHRH prohormone products in the human hypothalamus, antisera raised against LHRH and GnRH-associated peptide (GAP) were used to search for the presence of the corresponding antigens in the human adult and fetal hypothalamus by an immunohistochemical approach. The comparison of immunostaining on adjacent sections shows that all of the cells labeled with LHRH antiserum are also labeled with GAP antiserum and vice versa. Labeled cells are detectable during the 9th week of fetal life, this being the earliest time evaluated. At this time, the LHRH/GAP-positive cells frequently have a neuroblastic appearance. The first detectable fibers appear during the 11th week, and these were observed in the lamina terminalis cinerea and median eminence. In the adult brain, fibers and endings labeled with LHRH or GAP antiserum in the median eminence demonstrate the same topography and morphological characteristics, which are distinct from fibers labeled with other neuropeptide antisera. These results show that the LHRH precursor molecule is produced throughout life in the human hypothalamus, including the earliest stages of development of the peptidergic neurons. Moreover, the detection of LHRH- and GAP-positive fibers in the median eminence by the 11th week of fetal life suggests the possibility of an early role of LHRH and, possibly, other LHRH prohormone-derived peptides in the development of anterior pituitary function during the fetal period.     

Plasmin modulates vascular endothelial growth factor-A-mediated angiogenesis during wound repair

Plasmin-catalyzed cleavage of the vascular endothelial growth factor (VEGF)-A isoform VEGF165 results in loss of its carboxyl-terminal heparin-binding domain and significant loss in its bioactivity. Little is known about the in vivo significance of this process. To investigate the biological relevance of the protease sensitivity of VEGF165 in wound healing we assessed the activity of a VEGF165 mutant resistant to plasmin proteolysis (VEGF165(A111P)) in a genetic mouse model of impaired wound healing (db/db mouse). In the present study we demonstrate that in this mouse model plasmin activity is increased at the wound site. The stability of the mutant VEGF165 was substantially increased in wound tissue lysates in comparison to wild-type VEGF165, thus indicating a prolonged activity of the plasmin-resistant VEGF165 mutant. The db/db delayed healing phenotype could be reversed by topical application of wild-type VEGF165 or VEGF165(A111P). However, resistance of VEGF165 to plasmin cleavage resulted in the increased stability of vascular structures during the late phase of healing due to increased recruitment of perivascular cells and delayed and reduced endothelial cell apoptosis. Our data provide the first indication that plasmin-catalyzed cleavage regulates VEGF165-mediated angiogenesis in vivo. Inactivation of the plasmin cleavage site Arg110/Ala111 may preserve the biological function of VEGF165 in therapeutic angiogenesis under conditions in which proteases are highly active, such as wound repair and inflammation.     

Endpoint force fluctuations reveal flexible rather than synergistic patterns of muscle cooperation

We developed a new approach to investigate how the nervous system activates multiple redundant muscles by studying the endpoint force fluctuations during isometric force generation at a multi-degree-of-freedom joint. We hypothesized that, due to signal-dependent muscle force noise, endpoint force fluctuations would depend on the target direction of index finger force and that this dependence could be used to distinguish flexible from synergistic activation of the musculature. We made high-gain measurements of isometric forces generated to different target magnitudes and directions, in the plane of index finger metacarpophalangeal joint abduction-adduction/flexion-extension. Force fluctuations from each target were used to calculate a covariance ellipse, the shape of which varied as a function of target direction. Directions with narrow ellipses were approximately aligned with the estimated mechanical actions of key muscles. For example, targets directed along the mechanical action of the first dorsal interosseous (FDI) yielded narrow ellipses, with 88% of the variance directed along those target directions. It follows the FDI is likely a prime mover in this target direction and that, at most, 12% of the force variance could be explained by synergistic coupling with other muscles. In contrast, other target directions exhibited broader covariance ellipses with as little as 30% of force variance directed along those target directions. This is the result of cooperation among multiple muscles, based on independent electromyographic recordings. However, the pattern of cooperation across target directions indicates that muscles are recruited flexibly in accordance with their mechanical action, rather than in fixed groupings.     

Structural Activation of Pro-inflammatory Human Cytokine IL-23 by Cognate IL-23 Receptor Enables Recruitment of the Shared Receptor IL-12Rβ1

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Dosimetric accuracy of Kodak EDR2 film for IMRT verifications

Patient-specific intensity-modulated radiotherapy (IMRT) verifications require an accurate two-dimensional dosimeter that is not labor-intensive. We assessed the precision and reproducibility of film calibrations over time, measured the elemental composition of the film, measured the intermittency effect, and measured the dosimetric accuracy and reproducibility of calibrated Kodak EDR2 film for single-beam verifications in a solid water phantom and for full-plan verifications in a Rexolite phantom. Repeated measurements of the film sensitometric curve in a single experiment yielded overall uncertainties in dose of 2.1% local and 0.8% relative to 300 cGy. 547 film calibrations over an 18-month period, exposed to a range of doses from 0 to a maximum of 240 MU or 360 MU and using 6 MV or 18 MV energies, had optical density (OD) standard deviations that were 7%-15% of their average values. This indicates that daily film calibrations are essential when EDR2 film is used to obtain absolute dose results. An elemental analysis of EDR2 film revealed that it contains 60% as much silver and 20% as much bromine as Kodak XV2 film. EDR2 film also has an unusual 1.69:1 silver:halide molar ratio, compared with the XV2 film's 1.02:1 ratio, which may affect its chemical reactions. To test EDR2's intermittency effect, the OD generated by a single 300 MU exposure was compared to the ODs generated by exposing the film 1 MU, 2 MU, and 4 MU at a time to a total of 300 MU. An ion chamber recorded the relative dose of all intermittency measurements to account for machine output variations. Using small MU bursts to expose the film resulted in delivery times of 4 to 14 minutes and lowered the film's OD by approximately 2% for both 6 and 18 MV beams. This effect may result in EDR2 film underestimating absolute doses for patient verifications that require long delivery times. After using a calibration to convert EDR2 film's OD to dose values, film measurements agreed within 2% relative difference and 2 mm criteria to ion chamber measurements for both sliding window and step-and-shoot fluence map verifications. Calibrated film results agreed with ion chamber measurements to within 5 % /2 mm criteria for transverse-plane full-plan verifications, but were consistently low. When properly calibrated, EDR2 film can be an adequate two-dimensional dosimeter for IMRT verifications, although it may underestimate doses in regions with long exposure times.     

Whole-body fluorescence lifetime imaging of a tumor-targeted near-infrared molecular probe in mice

Fluorescence lifetime imaging can provide valuable diagnostic information relating to the functional status of diseases. In this study, a near-infrared (NIR) dye-labeled hexapeptide (abbreviated Cyp-GRD) was synthesized. In vitro, Cyp-GRD internalized in nonsmall cell lung cancer cells (A549) without observable cytotoxic or proliferative effects to the cells at a concentration up to 1x10(-4) M. Time-domain fluorescence intensity and lifetime imaging of Cyp-GRD injected into A549 tumor-bearing mice revealed that the probe preferentially accumulated in the tumor and the major excretion organs. The fluorescence lifetime of the conjugate at the tumor site was mapped, showing the spatial distribution of the lifetime related to its environment. Additionally, fluorescence intensity image reconstruction obtained by integrating the time-resolved intensities enabled the contrast ratios of tumor-to-kidney or liver in slices at different depths to be displayed. The mean lifetime was 1.03 ns for the tumor and 0.80 ns for the liver when averaging those pixels exhibiting adequate signal-to-noise ratio, showing the tumor had a higher lifetime average and reflecting the altered physiopathology of the tumor. This study clearly demonstrated the feasibility of whole-body NIR fluorescence lifetime imaging for tumor localization and its spatial functional status in living small animals.