The effect of increasing work rate amplitudes from a common metabolic baseline on the kinetic response of V̇o2p, blood flow, and muscle deoxygenation.

A step-transition in external work rate (WR) increases pulmonary O2 uptake (V̇o2p) in a monoexponential fashion. Although the rate of this increase, quantified by the time constant (τ), has frequently been shown to be similar between multiple different WR amplitudes (ΔWR), the adjustment of O2 delivery to the muscle (via blood flow; BF), a potential regulator of V̇o2p kinetics, has not been extensively studied. To investigate the role of BF on V̇o2p kinetics, 10 participants performed step-transitions on a knee-extension ergometer from a common baseline WR (3 W) to: 24, 33, 45, 54, and 66 W. Each transition lasted 8 min and was repeated four to six times. Volume turbinometry and mass spectrometry, Doppler ultrasound, and near-infrared spectroscopy were used to measure V̇o2p, BF, and muscle deoxygenation (deoxy[Hb + Mb]), respectively. Similar transitions were ensemble-averaged, and phase II V̇o2p, BF, and deoxy[Hb + Mb] were fit with a monoexponential nonlinear least squares regression equation. With increasing ΔWR, τV̇o2p became larger at the higher ΔWRs (P < 0.05), while τBF did not change significantly, and the mean response time (MRT) of deoxy[Hb + Mb] became smaller. These findings that V̇o2p kinetics become slower with increasing ΔWR, while BF kinetics are not influenced by ΔWR, suggest that O2 delivery could not limit V̇o2p in this situation. However, the speeding of deoxy[Hb + Mb] kinetics with increasing ΔWR does imply that the O2 delivery-to-O2 utilization of the microvasculature decreases at higher ΔWRs. This suggests that the contribution of O2 delivery and O2 extraction to V̇O2 in the muscle changes with increasing ΔWR.NEW & NOTEWORTHY A step increase in work rate produces a monoexponential increase in V̇o2p and blood flow to a new steady-state. We found that step transitions from a common metabolic baseline to increasing work rate amplitudes produced a slowing of V̇o2p kinetics, no change in blood flow kinetics, and a speeding of muscle deoxygenation kinetics. As work rate amplitude increased, the ratio of blood flow to V̇o2p became smaller, while the amplitude of muscle deoxygenation became greater. The gain in vascular conductance became smaller, while kinetics tended to become slower at higher work rate amplitudes.

Chronic abdominal pain leads to discovery of congenital anomaly.

A 43-year-old female with no history of a cholecystectomy presented with chronic right sided abdominal pain that became worse after fatty food intake. This led to an extensive workup for gallbladder disease for the patient's source of her pain. She had an initial ultrasound, which showed a collapsed gallbladder around gallstones, which signified chronic cholecystitis. This was confirmed with a hepatobiliary iminodiacetic acid scan with Choletec and morphine as there was no visualization of the gallbladder. Due to the patient's persistent abdominal pain with associated symptoms and radiographic evidence of cholecystitis, she was taken to the operating theater for a laparoscopic cholecystectomy and the absence of a gallbladder was discovered. The goal of this clinical case report is to highlight this rare anomaly and how it presents in a clinical setting.

Data analysis technique influences blood flow kinetics parameter estimates for moderate- and heavy-intensity exercise transitions.

NEW FINDINGS: What is the central question of this study? During exercise, there are fluctuations in conduit artery blood flow (BF) caused by both cardiac and muscle contraction-relaxation cycles. What is the optimal method to process Doppler ultrasound-measured BF for the purpose of characterizing the dynamic response of BF during step-transitions in exercise? What is the main finding and its importance? Continuous BF data were processed in relation to either cardiac or muscle contraction-relaxation cycles and computed based on 'binned' or 'rolling' averages over one, two or five consecutive cycles. Kinetics characterization revealed no data processing technique-specific differences in steady-state BF, but variability in the rapidity at which BF attained steady-state (i.e., mean response time) was observed. ABSTRACT: The overall rate of blood flow (BF) adjustment (i.e., kinetics) from the onset of an exercise transition can be quantified by the mean response time (MRT). However, the BF response profile can be distorted during rhythmic, dynamic exercise consequent to variations caused by the cardiac cycle (HR) and the muscle contraction-relaxation (CR) cycle. We examined the extent to which distortions imposed by HR and CR cycles affected BF kinetics. Eight healthy, young men (27 (4) years; mean (SD)) performed transitions of alternate-leg knee-extension exercise from 3 W to either a moderate- (MOD) or heavy-intensity (HVY) power output. Femoral artery BF was continuously measured by Doppler ultrasound and averaged over one, two or five 'binned' (e.g., HR2b, etc.) or 'rolling' (e.g., CR5r, etc.) HR and CR cycles. Among analysis techniques, there were no differences for steady-state BF values at the 3 W baseline. In MOD, MRT using contraction-relaxation cycle (CR1) was smaller than most other analysis techniques. For both MOD and HVY, the 95% confidence interval for MRT was generally larger when using HR- compared to CR-related methods, and monoexponential fits based on 'rolling' averages (HR2r, HR5r, CR2r, CR5r) had a poorer ability to estimate the true end-exercise BF in HVY than in MOD. When modelling BF kinetics, we conclude that the CR1 method is a good option because of its ability to accurately estimate the 'data-determined' end-exercise BF value from the 'model-derived' response, maintain a relatively high density of data points during the transition and yield a relatively small 95% CI.

Scalp mass: an atypical presentation of multiple myeloma.

A 64-year-old male with no history of trauma presented to the general surgery clinic with a 6-month history of an asymptomatic left parietal scalp mass. The differential included benign etiologies such as lipoma or sebaceous cyst. At surgery, a hemorrhagic soft tissue mass with underlying defect in the parietal calvarium was noted. The initial attempt at resection was abandoned and neurosurgical consultation was requested. Magnetic resonance imaging demonstrated an enhancing scalp mass with a lytic lesion of the parietal calvarium with no intradural extension. Craniectomy with mass resection and mesh cranioplasty were performed. Pathology confirmed plasma cell neoplasm; serum protein electrophoresis and lytic skull lesions confirmed multiple myeloma. This rare presentation of multiple myeloma serves as a call for providers to maintain a broad differential when evaluating a seemingly benign mass, consider rare etiologies when appropriate and maintain vigilance for abnormal findings during any procedure.

Effect of heavy-intensity 'priming' exercise on oxygen uptake and muscle deoxygenation kinetics during moderate-intensity step-transitions initiated from an elevated work rate.

We examined the effect of heavy-intensity 'priming' exercise on the rate of adjustment of pulmonary O2 uptake (τV˙O2p) initiated from elevated intensities. Fourteen men (separated into two groups: τV˙O2p≤25s [Fast] or τV˙O2p>25s [Slow]) completed step-transitions from 20W to 45% lactate threshold (LT; lower-step, LS) and 45% to 90%LT (upper-step, US) performed (i) without; and (ii) with US preceded by heavy-intensity exercise (HUS). Breath-by-breath V˙O2p and near-infrared spectroscopy-derived muscle deoxygenation ([HHb+Mb]) were measured. Compared to LS, τV˙O2p was greater (p<0.05) in US in both Fast (LS, 19±4s; US, 30±4s) and Slow (LS, 25±5s; US, 40±11s) with τV˙O2p in US being lower (p<0.05) in Fast. In HUS, τV˙O2p in Slow was reduced (28±8s, p<0.05) and was not different (p>0.05) from LS or Fast group US. In Slow, τ[HHb+Mb] increased (p<0.05) in US relative to HUS; this finding coupled with a reduced τV˙O2p indicates a priming-induced improvement in matching of muscle O2 delivery-to-O2 utilization during transitions from elevated intensities in those with Slow but not Fast V˙O2p kinetics.

Influence of muscle metabolic heterogeneity in determining the V̇o2p kinetic response to ramp-incremental exercise.

The pulmonary O2 uptake (V̇o2p) response to ramp-incremental (RI) exercise increases linearly with work rate (WR) after an early exponential phase, implying that a single time constant (τ) and gain (G) describe the response. However, variability in τ and G of V̇o2p kinetics to different step increments in WR is documented. We hypothesized that the "linear" V̇o2p-WR relationship during RI exercise results from the conflation between WR-dependent changes in τ and G. Nine men performed three or four repeats of RI exercise (30 W/min) and two step-incremental protocols consisting of four 60-W increments beginning from 20 W or 50 W. During testing, breath-by-breath V̇o2p was measured by mass spectrometry and volume turbine. For each individual, the V̇o2p RI response was characterized with exponential functions containing either constant or variable τ and G values. A relationship between τ and G vs. WR was determined from the step-incremental protocols to derive the variable model parameters. τ and G increased from 21 ± 5 to 98 ± 20 s and from 8.7 ± 0.6 to 12.0 ± 1.9 ml·min(-1)·W(-1) for WRs of 20-230 W, respectively, and were best described by a second-order (τ) and a first-order (G) polynomial function of WR (lowest Akaike information criterion score). The sum of squared residuals was not different (P > 0.05) when the V̇o2p RI response was characterized with either the constant or variable models, indicating that they described the response equally well. Results suggest that τ and G increase progressively with WR during RI exercise. Importantly, these relationships may conflate to produce a linear V̇o2p-WR response, emphasizing the influence of metabolic heterogeneity in determining the apparent V̇o2p-WR relationship during RI exercise.

The relationship between human skeletal muscle pyruvate dehydrogenase phosphatase activity and muscle aerobic capacity.

Pyruvate dehydrogenase (PDH) is a mitochondrial enzyme responsible for regulating the conversion of pyruvate to acetyl-CoA for use in the tricarboxylic acid cycle. PDH is regulated through phosphorylation and inactivation by PDH kinase (PDK) and dephosphorylation and activation by PDH phosphatase (PDP). The effect of endurance training on PDK in humans has been investigated; however, to date no study has examined the effect of endurance training on PDP in humans. Therefore, the purpose of this study was to examine differences in PDP activity and PDP1 protein content in human skeletal muscle across a range of muscle aerobic capacities. This association is important as higher PDP activity and protein content will allow for increased activation of PDH, and carbohydrate oxidation. The main findings of this study were that 1) PDP activity (r(2) = 0.399, P = 0.001) and PDP1 protein expression (r(2) = 0.153, P = 0.039) were positively correlated with citrate synthase (CS) activity as a marker for muscle aerobic capacity; 2) E1α (r(2) = 0.310, P = 0.002) and PDK2 protein (r(2) = 0.229, P =0.012) are positively correlated with muscle CS activity; and 3) although it is the most abundant isoform, PDP1 protein content only explained ∼ 18% of the variance in PDP activity (r(2) = 0.184, P = 0.033). In addition, PDP1 in combination with E1α explained ∼ 38% of the variance in PDP activity (r(2) = 0.383, P = 0.005), suggesting that there may be alternative regulatory mechanisms of this enzyme other than protein content. These data suggest that with higher muscle aerobic capacity (CS activity) there is a greater capacity for carbohydrate oxidation (E1α), in concert with higher potential for PDH activation (PDP activity).

Active therapy for chronic low back pain: part 3. Factors influencing self-rated disability and its change following therapy.

DESIGN: Cross-sectional analysis of the factors influencing self-rated disability associated with chronic low back pain and prospective study of the relationship between changes in each of these factors and in disability following active therapy. OBJECTIVES: To examine the relative influences of pain, psychological factors, and physiological factors on self-rated disability. SUMMARY OF BACKGROUND DATA: In chronic LBP, the interrelationship between physical impairment, pain, and disability is particularly complicated, due to the influence of various psychological factors and the lack of unequivocal methods for assessing impairment. Investigations using new "belief" questionnaires and "sophisticated" performance tests, which have shown promise as discriminating measures of impairment, may assist in clarifying the situation. Previous studies have rarely investigated all these factors simultaneously. METHODS: One hundred forty-eight patients with cLBP completed questionnaires and underwent tests of mobility, strength, muscle activation, and fatigability, and (in a subgroup) erector spinae size and fiber size/type distribution. All measures were repeated after 3 months active therapy. Relationships between each factor and self-rated disability (Roland and Morris questionnaire) at baseline, and between the changes in each factor and changes in disability following therapy, were examined. RESULTS: Stepwise linear regression showed that the most significant predictors of disability at baseline were, in decreasing order of importance: pain; psychological distress; fear-avoidance beliefs; muscle activation levels; lumbar range of motion; gender. Only changes in pain, psychological distress, and fear-avoidance beliefs significantly accounted for the changes in disability following therapy. CONCLUSION: A combination of pain, psychological and physiological factors was best able to predict baseline disability, although its decrease following therapy was determined only by reductions in pain and psychological variables. The active therapy program-in addition to improving physical function-appeared capable of modifying important psychological factors, possibly as a result of the positive experience of completing the prescribed exercises without undue harm.

Invasive properties of murine squamous carcinoma cells: secretion of matrix-degrading cathepsins is attributable to a deficiency in the mannose 6-phosphate/insulin-like growth factor II receptor.

Penetration of basement membrane layers is a hallmark feature of metastatic tumor cells. The invasive propensity of murine SCC-VII squamous carcinoma cells is in part attributable to the extracellular action of the lysosomal cysteine proteinase cathepsin B. Although most noncancerous cells store this enzyme in the lysosomes, we found that SCC-VII cells release a large fraction (42%) of their newly synthesized procathepsin B into the culture medium. Procathepsins D and L, the precursors of other major lysosomal proteinases, are also secreted in significant amounts (24 and 75%, respectively). In contrast, normal murine 3T3-L1 fibroblasts exocytose only minor amounts of their newly synthesized procathepsins B (10%), D (<1%), and L (16%). Western blotting analysis revealed that SCC-VII cells are deficient in the 300 kDa mannose 6-phosphate/insulin-like growth factor-II receptor (M6P/IGF2R), a tumor suppressor with a central role in the intracellular transport of lysosomal enzymes. Consistent with the absence of M6P/IGF2R, SCC-VII cells lack dense lysosomes, with the bulk of intracellular acid hydrolases residing in late endosomes/ prelysosomes. On the other hand, the synthesis of the M6P recognition marker on lysosomal enzymes is not impaired in SCC-VII cells, because [33P]Pi is incorporated into the carbohydrate moieties of procathepsins B, D, and L. Furthermore, 69% of the phosphorylated N-linked oligosaccharides synthesized by SCC-VII cells carry phosphomonoester groups and as such constitute high-affinity ligands for M6P receptors. SCC-VII cells express the 46 kDa cation-dependent M6P receptor (MPR46), but intracellular retention of procathepsins B, D, and L is not affected by ammonium chloride and chloroquine, agents known to perturb the M6P receptor system. Our results indicate that failure to express the 300 kDa M6P/IGF2R may enhance the metastatic capacity of tumor cells by inducing the secretion of procathepsins B, D, and L.