Carotid sinus baroafferent signals contribute to cerebral blood flow regulation during acute hypotension in young males: A randomized crossover study.

Cerebral autoregulation is an important factor in prevention of cerebral ischemic events. We tested a traditional but unproven hypothesis that carotid sinus baroafferent signals contribute to dynamic cerebral autoregulation. Middle cerebral artery mean blood velocity (MCA Vmean ) responses to thigh-cuff deflation-induced acute hypotension were compared between conditions using neck suction soon after cuff deflation, without or with a cushion wrapped around the upper neck, in nine healthy males (aged 25 ± 5 years). Neck suction was applied close to the hypotension. The MCA Vmean response was expected to differ between conditions because the cushion was presumed to prevent the carotid sinus distension by neck suction. The cushion hindered bradycardia and depressor responses during sole neck suction. Thigh-cuff deflation decreased mean arterial blood pressure (MAP) and MCA Vmean (Ps < 0.05) with an almost unchanged respiratory rate under both conditions. However, in the neck suction + cushion condition, subsequent MCA Vmean restoration was faster and greater (Ps ≤ 0.0131), despite similar changes in MAP in both conditions. Thus, carotid sinus baroafferent signals would accelerate dynamic cerebral autoregulation during rapid hypotension in healthy young males. Elucidating the mechanism underlying cerebral neural autoregulation could provide a new target for preventing cerebral ischemic events.

Arterial Stiffness, Assessed Using the Cardio-Ankle Vascular Index, before and 2 Years after Total Knee Arthroplasty in Patients with Knee Osteoarthritis.

Purpose: Cardiovascular disease (CVD) is a major risk factor for mortality in patients with osteoarthritis, and such comorbidities increase the risk of postoperative complications following total knee arthroplasty (TKA). Arteriosclerosis plays a major role in hemodynamic dysfunction and CVD; however, the postoperative changes in arteriosclerosis following TKA have not been evaluated. Therefore, we assessed the postoperative changes in arteriosclerosis using the cardio-ankle vascular index (CAVI) in patients undergoing TKA, and its relationships with preoperative patient characteristics. Methods: Arteriosclerosis was prospectively evaluated in 119 consecutive patients (140 knees) (15 males (17), 104 females (123); median age 73 years) with knee osteoarthritis who underwent TKA. CAVI was measured before and 2 years after TKA, and the relationships between CAVI and preoperative age, sex, BMI, physical activity status, comorbidities, clinical score, triglyceride concentration, cholesterol concentration, and smoking history were analyzed. Results: CAVI remained stable or improved in 54 joints (39%) and worsened in 86 joints (61%) 2 years post-operation. The median difference between pre- and postoperative CAVI was 0.2 (-0.3, 0.8), and the only preoperative factor associated with this change was preoperative CAVI (r = -0.469, p < 0.001). No other preoperative factor had a significant effect on postoperative arteriosclerosis. Conclusions: The results suggest that patients who undergo TKA subsequently show less severe arteriosclerosis, and the protective effect of TKA on arterial stiffness is greater in those with a higher preoperative CAVI. TKA may be an effective means of reducing the deterioration of arteriosclerosis associated with knee osteoarthritis, at least in the relatively short term.

Discovery of 7-Azanorbornane-Based Dual Agonists for the Delta and Kappa Opioid Receptors through an In Situ Screening Protocol.

In medicinal chemistry, the copper-catalyzed click reaction is used to prepare ligand candidates. This reaction is so clean that the bioactivities of the products can be determined without purification. Despite the advantages of this in situ screening protocol, the applicability of this method for transmembrane proteins has not been validated due to the incompatibility with copper catalysts. To address this point, we performed ligand screening for the µ, δ, and κ opioid receptors using this protocol. As we had previously reported the 7-azanorbornane skeleton as a privileged scaffold for the G protein-coupled receptors, we performed the click reactions between various 7-substituted 2-ethynyl-7-azanorbornanes and azides. Screening assays were performed without purification using the CellKeyTM system, and the putative hit compounds were re-synthesized and re-evaluated. Although the "hit" compounds for the µ and the δ receptors were totally inactive after purifications, three of the four "hits" for the κ receptor were true agonists for this receptor and also showed activities for the δ receptor. Although false positive/negative results exist as in other screening projects for soluble proteins, this in situ method is effective in identifying novel ligands for transmembrane proteins.

Differential relationship between decreased muscle oxygenation and blood pressure recovery during supraventricular and ventricular tachycardia.

Vasoconstriction during tachyarrhythmia contributes to maintenance of arterial pressure (AP) by decreasing peripheral blood flow. This cross-sectional observational study aimed to ascertain whether the relationship between peripheral blood flow and AP recovery occurs during both paroxysmal supraventricular (PSVT, n = 19) and ventricular tachycardias (VT, n = 17). Peripheral blood flow was evaluated using forearm tissue oxygen index (TOI), and mean AP (MAP) was measured using a catheter inserted in the brachial or femoral artery during an electrophysiological study. PSVT and VT rapidly decreased MAP with a comparable heart rate (P = 0.194). MAP recovered to the baseline level at 40 s from PSVT onset, but not VT. The forearm TOI decreased during both tachyarrhythmias (P ≤ 0.029). The TOI response was correlated with MAPrecovery (i.e., MAP recovery from the initial rapid decrease) at 20-60 s from PSVT onset (r = -- 0.652 to - 0.814, P ≤ 0.0298); however, this association was not observed during VT. These findings persisted even after excluding patients who had taken vasoactive drugs. Thus, restricting peripheral blood flow was associated with MAP recovery during PSVT, but not VT. This indicates that AP recovery depends on the type of tachyarrhythmia: different cardiac output and/or vasoconstriction ability during tachyarrhythmia.

Characteristics of Preoperative Arteriosclerosis Evaluated by Cardio-Ankle Vascular Index in Patients with Osteoarthritis before Total Knee Arthroplasty.

PURPOSE: Cardiovascular disease (CVD) is a major risk factor for mortality in patients with osteoarthritis, and comorbidities increase postoperative complications after total knee arthroplasty (TKA). Arteriosclerosis plays a main role in hemodynamic dysfunction and CVD; however, arteriosclerosis has not been preoperatively evaluated before TKA using the cardio-ankle vascular index (CAVI). In this study, we evaluated the degree of preoperative arteriosclerosis using the CAVI in patients undergoing TKA, as well as its correlations with several preoperative patient factors. METHODS: Arteriosclerosis was evaluated in 209 consecutive patients (251 knees) with osteoarthritis who underwent TKA at our institution between May 2011 and June 2022. The CAVI was measured in the supine position 1 day before TKA, and the correlations between the CAVI and several clinical factors were analyzed. RESULTS: The CAVI was normal in 62 knees (25%), borderline in 71 knees (28%), and abnormal in 118 knees (47%). Univariate analysis revealed a moderate positive correlation between preoperative CAVI and age (r = 0.451, p < 0.001) and a weak negative correlation between preoperative CAVI and body weight (r = -0.306, p < 0.001) and body mass index (BMI) (r = -0.319, p < 0.001). Multivariate analysis showed that age (ß = 0.349, p < 0.001) and BMI (ß = -0.235, p < 0.001) were significantly correlated with preoperative CAVI. CONCLUSION: Arteriosclerosis should be carefully managed intraoperatively and postoperatively in patients with osteoarthritis undergoing TKA, particularly in older patients and patients with a low BMI.

Patient factors impacting localization of popliteal artery before total knee arthroplasty.

PURPOSE: Intraoperative injury to the popliteal artery (PA) should be avoided during total knee arthroplasty (TKA). This study was performed to clarify the preoperative localization of the PA and the patient factors that impact its localization as a preventive measure. METHODS: Ninety-seven patients (110 knees; 18 men, 79 women) with osteoarthritis who underwent primary TKA were retrospectively reviewed. Preoperative sagittal magnetic resonance imaging was used to measure the distance between the PA and the closest point at three levels: the femoral epicondyle (DPF), the tibial articular surface (DPAS), and the posterior tibial cortex (DPT). All variables are expressed in millimeters as median (interquartile range). RESULTS: The median distance was 10.35 (7.90-12.34) mm for DPF, 6.32 (5.12-8.57) mm for DPAS, and 3.76 (2.28-5.26) mm for DPT. Body height and weight showed weak correlations with DPF (r = 0.324, p < 0.001 and r = 0.207, p = 0.03, respectively). DPF was smaller in women [9.82 (7.64-12.23) mm] than in men [11.27 (10.26-12.75) mm] (p = 0.004). A larger flexion angle and range of motion showed a weak negative correlation with DPT (r = - 0.282, p = 0.003 and r = - 0.236, p = 0.016, respectively). Multiple regression analysis revealed that DPF was related to body height (ß = 0.341, p < 0.001) and that DPT was related to the flexion angle (ß = - 0.264, p = 0.005). CONCLUSIONS: Special attention should be paid to women with a small physique on the femoral side and/or patients with a large flexion angle on the tibial side as a strategy to prevent PA-related complications.

Positive effect of total knee arthroplasty on progression of arteriosclerosis evaluated by cardio-ankle vascular index.

INTRODUCTION: Physical function is expected to improve with an increase in physical activity owing to improvement in knee joint pain after total knee arthroplasty (TKA). This study was performed to evaluate the impact of TKA on arteriosclerosis by measuring the cardio-ankle vascular index (CAVI) before and after surgery. MATERIALS AND METHODS: In total, 206 consecutive patients undergoing unilateral TKA were investigated. The CAVI, an index of the overall stiffness of the artery from the origin of the aorta to the ankle, was used to evaluate the degree of arteriosclerosis. The CAVI of the TKA side and non-TKA side was compared before and 1 year after TKA. RESULTS: There were no differences in the CAVI before and after TKA on the TKA side and non-TKA side, although these values should have worsened at 1 year compared with preoperative values. The CAVI, which did not differ between the two sides preoperatively, differed significantly between the two sides postoperatively (p = 0.013). A generalized linear model showed no interaction between each time point and the measured sides in terms of the CAVI. The relationship between the preoperative CAVI and the difference between the preoperative and postoperative CAVI were examined, showing that R = - 0.428 (p < 0.001) for the TKA side and R = - 0.416 (p < 0.001) for the non-TKA side (significant negative correlation). CONCLUSIONS: The lack of significant age-related deterioration over time on both sides suggests that TKA may slow the progression of arteriosclerosis, especially on the operated side. The effect of TKA was found to be greater with a higher CAVI (i.e., more advanced arteriosclerosis).

Central command suppresses pressor-evoked bradycardia at the onset of voluntary standing up in conscious cats.

NEW FINDINGS: What is the central question of this study? Standing up can cause hypotension and tachycardia. Accumulated evidence poses the simple question, does the cardiac baroreflex operate at the onset of standing up? If the cardiac baroreflex is suppressed, what mechanism is responsible for baroreflex inhibition? What is the main finding and its importance? In cats, we found blunting of cardiac baroreflex sensitivity in the pressor range at the onset of voluntary hindlimb standing, but not of passive hindlimb standing. This finding suggests that central command suppresses pressor-evoked bradycardia at the onset of standing up, probably in advance, to prevent or buffer orthostatic hypotension. ABSTRACT: It remains unclear whether cardiac baroreflex function is preserved or suppressed at the onset of standing up. To answer the question and, if cardiac baroreflex is suppressed, to investigate the mechanism responsible for the suppression, we compared the sensitivity of the arterial cardiac baroreflex at the onset of voluntary and passive hindlimb standing in conscious cats. Cardiac baroreflex sensitivity was estimated from the maximal slope of the baroreflex curve between the responses of systolic arterial blood pressure and heart rate to a brief occlusion of the abdominal aorta. The systolic arterial blood pressure response to standing up without aortic occlusion was greater in the voluntary case than in the passive case. Cardiac baroreflex sensitivity was clearly decreased at the onset of voluntary standing up compared with rest (P = 0.005) and the onset of passive standing up (P = 0.007). The cardiac baroreflex sensitivity at the onset of passive standing up was similar to that at rest (P = 0.909). The findings suggest that central command would transmit a modulatory signal to the cardiac baroreflex system during the voluntary initiation of standing up. Furthermore, the present data tempt speculation on a close relationship between central inhibition of the cardiac baroreflex and the centrally induced tachycardiac response to standing up.

Comparison of the Tibial Posterior Slope Angle Between the Tibial Mechanical Axis and Various Diaphyseal Tibial Axes After Total Knee Arthroplasty.

Background: The posterior tibial slope angle (PTS) is crucial for sagittal alignment after total knee arthroplasty (TKA). This study aimed to determine which PTS based on the lateral view of standard knee radiographs (LSKRs; 36 × 43 cm) reflects the PTS based on a full-length lateral tibial radiograph (FLTR). Methods: A total of 290 patients (355 knees) who underwent primary TKA were retrospectively recruited. Cross-sectional views from the 3-dimensional digital model of the tibial prosthesis and bone complex in the sagittal plane were used as FLTRs and LSKRs. Considering the region 21.5 cm proximal to the site of FLTR as the spot for LSKR to determine the 5 tibial diaphyseal axes, the axis that simulates the PTS as determined by the tibial mechanical axis between the center of the tibial component and the ankle plafond in LSKR was determined and compared. Results: PTS (α5) defined by the line connecting the midpoints of tibial width between the region 10-cm distal to the knee joint and the distal end of the tibia based on LSKR revealed the least mean difference (0.13° ± 1.00°) and the strongest correlation (P < .001, r = 0.948) with PTS based on FLTR (α0). The number of knees in α5, indicating a difference of <2° from α0, was 333 of 355 (93.8%). The equivalence test results indicated that α0 and α5 were statistically equivalent within a difference of 2° (P < .001). Conclusions: PTS (α5) can be used as a clinically reliable substitution of the true PTS on an FLTR for evaluating sagittal alignment after TKA.

Comparison of Operative Times in Primary Bilateral Total Knee Arthroplasty Performed by a Single Surgeon.

Purpose: Prolonged operative time (OT) is associated with adverse complications after total knee arthroplasty (TKA). The purpose of this study was to determine whether preoperative factors, such as sex, age, body mass index, body weight (BW), body height, American Society of Anesthesiologists grade, tibiofemoral angle, hospital for special surgery scores, surgical side, surgical order, and calendar year of surgery, affect OT. Methods: One hundred and nineteen patients (238 knees) with osteoarthritis who underwent staged bilateral primary TKA performed by a single surgeon were evaluated. The medical records of 15 males and 104 females were retrospectively reviewed. All variables were expressed as median (interquartile range). Results: The OT for all TKAs was 57 min (51, 65). The OT on the left side (59 min (52−67)) was longer than that on the right side (55 min (50−62)) (p = 0.015). Multiple regression analysis revealed that longer OT was related to BW (ß = 0.488, p < 0.001), calendar year of surgery (ß = −0.218, p< 0.001), and operative side (ß = −0.151, p = 0.007). The Jonckheere−Terpstra test showed a trend toward decreasing OT with calendar year on the left side (p = 0.037) (surgeon's non-dominant side), but not on the right (p = 0.795). Body height, BW, and body mass index showed weak correlations (r = 0.212, p = 0.001; r = 0.352, p < 0.001; r = 0.290, p < 0.001, respectively) with OT. Conclusion: Patients with a large physique, and especially obesity, with an affected knee on the surgeon's non-dominant side may require a longer OT; OT decreased over time.

Central modulation of cardiac baroreflex moment-to-moment sensitivity during treadmill exercise in conscious cats.

It remains undetermined whether the cardiac component of the entire arterial baroreflex is blunted even at the onset of low-intensity exercise. We sought to examine the moment-to-moment sensitivity of the cardiac baroreflex during walking at different speeds and the presumed mechanisms responsible for baroreflex modulation in conscious cats. Arterial baroreflex sensitivity for heart rate was estimated from the baroreflex ratio between changes in systolic arterial blood pressure and heart rate and from the slope of the baroreflex curve between the cardiovascular responses to brief occlusion of the abdominal aorta. Treadmill walking was performed for 1 min at three levels of speed (low: 20-30 m/min, moderate: 40 m/min, and high: 50-60 m/min) or for 3 min at the stepwise change of speed (low to high to low transition). Cardiac baroreflex sensitivity was blunted at the onset of walking, irrespective of speed. Thereafter, the blunted cardiac baroreflex sensitivity was restored around 15 s of walking at any speed, while the blunting occurred again at 45 s of high-speed walking. The inhibition of cardiac baroreflex sensitivity also occurred (1) during the speed transition from low to high and (2) at 45 s of high-speed exercise of the stepwise exercise. The blunted cardiac baroreflex sensitivity was restored immediately to the resting level during the speed transition from high to low, despite sustained pressor and tachycardiac responses. Therefore, moment-to-moment modulation of the cardiac baroreflex during exercise would occur in association with motor intention (i.e., exercise onset) and effort (i.e., treadmill speed).

Regional difference in prefrontal oxygenation before and during overground walking in humans: a wearable multichannel NIRS study.

Using wireless multichannel near-infrared spectroscopy, regional difference in cortical activity over the prefrontal cortex (PFC) was examined before and during overground walking and in response to changes in speed and cognitive demand. Oxygenated-hemoglobin concentration (Oxy-Hb) as index of cortical activity in ventrolateral PFC (VLPFC), dorsolateral PFC (DLPFC), and frontopolar cortex (FPC) was measured in 14 subjects, whereas heart rate was measured as estimation of exercise intensity in six subjects. The impact of mental imagery on prefrontal Oxy-Hb was also explored. On both sides, Oxy-Hb in VLPFC, DLPFC, and lateral FPC was increased before the onset of normal-speed walking, whereas Oxy-Hb in medial FPC did not respond before walking onset. During the walking, Oxy-Hb further increased in bilateral VLPFC, whereas Oxy-Hb was decreased in DLPFC and lateral and medial FPC. Increasing walking speed did not alter the increase in Oxy-Hb in VLPFC but counteracted the decrease in Oxy-Hb in DLPFC (but not in lateral and medial FPC). Treadmill running evoked a greater Oxy-Hb increase in DLPFC (n = 5 subjects). Furthermore, increasing cognitive demand during walking, by deprivation of visual feedback, counteracted the decrease in Oxy-Hb in DLPFC and lateral and medial FPC, but it did not affect the increase in Oxy-Hb in VLPFC. Taken together, the profound and localized Oxy-Hb increase is a unique response for the VLPFC. The regional heterogeneity of the prefrontal Oxy-Hb responses to natural overground walking was accentuated by increasing walking speed or cognitive demand, suggesting functional distinction within the PFC.

Preoperative bone assessment by bone mineral density and bone turnover in patients undergoing total knee arthroplasty.

BACKGROUND: The preoperative overall bone quality in patients undergoing total knee arthroplasty (TKA) might influence the development of postoperative bone-derived complications. This study was performed to simultaneously evaluate the baseline bone mineral density (BMD) and bone turnover in these patients. METHODS: We prospectively measured the lumbar spine, total hip, and femoral neck BMD using dual-energy X-ray absorptiometry (DXA) in 214 patients (239 knees; women, 199 knees; men, 40 knees) 1 day preoperatively. Women were stratified into three age groups: <70 years (60s), <80 years (70s), and ≥80 years (80s). We assessed bone turnover using the urinary level of N-telopeptide (NTx) normalized to creatinine (NTx/Cre). RESULTS: The prevalence of osteoporosis as assessed by DXA (T-score of ≤ -2.5) was 22% in women and 5% in men. A decline in BMD with aging was found in the hip but not in the lumbar spine with significant differences among ages. Women showed a higher NTx/Cre level than men (p = 0.033). An NTx/Cre level suggesting a high fracture risk (>56.5 mmol BCE/mmol Cre) was present in 54% of women and 35% of men (p = 0.037). No significant differences were found in this prevalence among age groups in women. Seventeen percent of women and 0% of men had both osteoporosis and a high fracture risk simultaneously (p = 0.002). The proportion of women in this category was lower in the 60s than 70s age group (p = 0.019). CONCLUSIONS: Preoperative bone health screening before TKA might be necessary for women aged ≥70 years to prevent complications caused by perioperative poor bone condition.

Preoperative characteristics and intraoperative factors do not correlate with accomplishments of active straight-leg raising, standing up, and walking after primary total knee arthroplasty.

BACKGROUND: The correlations between patient characteristics and early postoperative functional performances after total knee arthroplasty have not been adequately studied. The purpose of this study was to clarify the effects of preoperative characteristics (sex, age, body mass index, American Society of Anesthesiologists grade, hospital for special surgery score) and intraoperative factors (duration of surgery and tourniquet use) on the time required to accomplish active straight-leg-raising, standing up, and walking as the objective performances for the initiation of early postoperative rehabilitation. METHODS: This cross-sectional retrospective study included 307 patients (384 primary total knee arthroplasties). Postoperative times required until each activity was accomplished were measured. Various preoperative characteristics and intraoperative factors that might affect three objective performances were evaluated. RESULTS: The postoperative times required before each activity was accomplished were 1.5 ± 0.5 days for active straight-leg-raising, 1.2 ± 0.5 days for standing up, and 1.4 ± 0.7 days for walking. There were no significant correlations between any factor (age, body mass index, hospital for special surgery score, duration of surgery, and tourniquet use) and the three objective performances using Spearman's correlation coefficient. There were no differences in sex or American Society of Anesthesiologists grade for three objective functional assessments by Wilcoxon rank sum test. CONCLUSIONS: Differences in patient preoperative characteristics and intraoperative factors are unlikely to affect three objective functional performances in the early postoperative period. Therefore, there is no need to consider differences between patients when initiating early postoperative rehabilitation.

Central command-related increases in blood velocity of anterior cerebral artery and prefrontal oxygenation at the onset of voluntary tapping.

The anterior cerebral artery (ACA) supplies blood predominantly to the frontal lobe including the prefrontal cortex. Our laboratory reported that prefrontal oxygenated-hemoglobin concentration (Oxy-Hb) increased before and at exercise onset, as long as exercise is arbitrarily started. Moreover, the increased prefrontal oxygenation seems independent of both exercise intensity and muscle mass. If so, mean blood velocity of the ACA (ACABV) should increase with "very light motor effort," concomitantly with the preexercise and initial increase in prefrontal Oxy-Hb. This study aimed to examine the responses in ACABV and vascular conductance index (ACAVCI) of the ACA as well as prefrontal Oxy-Hb during arbitrary or cued finger tapping in 12 subjects, an activity with a Borg scale perceived exertion rating of 7 (median). With arbitrary start, ACABV increased at tapping onset (14 ± 9%) via an elevation in ACAVCI. Likewise, prefrontal Oxy-Hb increased at the onset of tapping with a time course resembling that of ACABV. A positive cross correlation between the initial changes in ACABV and prefrontal Oxy-Hb was found significant in 67% of subjects, having a time lag of 2 s, whereas a positive linear regression between them was significant in 75% of subjects. When tapping was forced to start by cue, the initial increases in ACABV, ACAVCI, and prefrontal Oxy-Hb were delayed and blunted as compared with an arbitrary start. Thus, active vasodilatation of the ACA vascular bed occurs at tapping onset, as long as tapping is arbitrarily started, and contributes to immediate increases in blood flow and prefrontal oxygenation.NEW & NOTEWORTHY Anterior cerebral artery blood velocity and vascular conductance index along with prefrontal oxygenated-hemoglobin concentration all increased at the onset of finger tapping, peaking immediately after tapping onset, as long as tapping was arbitrarily started. Positive cross correlation and linear regression between the increases in ACABV and prefrontal Oxy-Hb were significant in 67%-75% of subjects. Active vasodilatation of the ACA vascular bed occurs with arbitrary tapping onset and contributes to increased ACABV and prefrontal oxygenation.

Alignment evaluation using different distal reference points after total knee arthroplasty.

BACKGROUND: To assess alignment for total knee arthroplasty, the center of the ankle has been used as the main reference point for the distal tibia; however, the true load-bearing mechanical axis should be determined as a line from the center of the femoral head to the lowest point of calcaneus. Thus, the purpose of this study was to compare the differences in alignment. METHODS: Patients with medial osteoarthritis who underwent primary total knee arthroplasty (Group A, center of ankle reference, or Group C, calcaneal contact reference) were recruited. We determined (1) the total number with calcaneal contact point lateral to the center of ankle and compared (2) percentage of displacement of the load-bearing axis at the level of the knee, (3) anatomical axis angle, (4) mechanical axis angle, and (5) tibial component angle. RESULTS: The study included 94 patients (128 knees), with the calcaneal contact reference point located lateral relative to the center of the ankle in 88.3% (113/128 knees). Using calcaneal contact point references, displacement of the load-bearing axis at the knee was greater (p < 0.0001, 38.7% vs 34.0%), and angles demonstrated significantly valgus alignment (p < 0.0001, 5.6° vs. 4.8° for anatomical axis angle, -3.0° vs. -4.2° for mechanical axis angle, and 89.9° vs. 88.6°for tibial component angle). CONCLUSIONS: Varus alignment measured by the ankle reference method might correspond to the neutral alignment by the amount of valgus alignment indicated by the calcaneal reference. Surgeons should take this into account when preoperative planning, performing intraoperative procedures, and during postoperative evaluation.

Increased prefrontal oxygenation prior to and at the onset of over-ground locomotion in humans.

Our laboratory has reported with near-infrared spectroscopy (NIRS) that prefrontal oxygenated-hemoglobin concentration (Oxy-Hb), measured as index of regional cerebral blood flow, increased before and at the onset of arbitrary (i.e., noncued) ergometer exercise in a laboratory environment. In the current study, we hypothesized that naturally occurring over-ground locomotion, despite "very light" motor effort, as indicated by a Borg scale of 8.0 ± 0.3, likewise causes preexercise activation of the prefrontal cortex. Using wireless NIRS, we examined in this study how early and to what extent prefrontal activity changed before the onset of arbitrary walking in 13 subjects. Prefrontal Oxy-Hb increased 2 s before the onset of arbitrary walking, and the increased Oxy-Hb reached a peak at 5 s from walking onset. The preexercise and initial increase in prefrontal Oxy-Hb was absent when over-ground walking was forced to start by cue. The difference in the Oxy-Hb response between arbitrary and cued start, which was considered to be related to central command, became significant 2 s before walking onset, preceding the difference in the heart rate (HR) response by 8 s. This demonstrated a positive relationship with the HR difference in 69% of subjects. Imagery of arbitrary walking was, likewise, able to increase prefrontal oxygenation to the same extent as actual walking. Thus, it is likely that prefrontal oxygenation increases before the onset of naturally occurring walking in daily life, despite "very light" effort. The increased prefrontal oxygenation may contribute at least partly to cardiac adjustment, synchronized with the beginning of motor performance.NEW & NOTEWORTHY We found using wireless near-infrared spectroscopy that prefrontal oxygenation increased before the onset of arbitrary over-ground walking, whereas the preexercise increase was absent when walking was suddenly started by cue. The difference in prefrontal oxygenation between start modes (considered related to central command) preceded heart rate response variances and demonstrated a positive relationship with the difference in heart rate. The central command-related prefrontal activity may contribute to cardiac adjustment, synchronized with the beginning of over-ground walking.

Increased oxygenation in the non-contracting forearm muscle during contralateral skilful hand movement.

NEW FINDINGS: What is the central question of this study? When performing skilful hand movement, motor command descends especially towards distal arm muscles. Does central command evoke a vascular response selectively in the distal arm muscles during skilful hand movement? What is the main finding and its importance? We found, using near-infrared spectroscopy, that unilateral skilful hand movement evoked a greater increase in oxygenation of the contralateral forearm muscle compared with that of the upper arm muscles. Mental imagery of the hand movement also increased oxygenation of the forearm muscle. These findings suggest that central command might contribute to the vasodilator response in the non-contracting forearm muscle during contralateral skilful hand movement. ABSTRACT: The human hand is a special organ to perform skilful movement in daily life. To meet metabolic demands of the working distal arm muscles, central command might evoke neurogenic vasodilatation in the muscles. Based on our previous demonstration that a centrally generated vasodilator signal is transmitted bilaterally to skeletal muscles during exercise, centrally induced vasodilatation might occur in the non-contracting distal arm muscles during contralateral skilful hand movement. To examine this possibility, we used near-infrared spectroscopy to measure the relative concentrations of oxygenated haemoglobin (Oxy-Hb; as an index of regional blood flow) in the non-contracting arm muscles during skilful hand movement (two-ball rotation) in 22 subjects. Two-ball rotation increased Oxy-Hb of both forearm and upper arm muscles, with little changes in perfusion pressure and cardiac output. The increased Oxy-Hb was greater in the forearm muscle than in the upper arm muscles. The increased Oxy-Hb of the forearm muscle during two-ball rotation was greater than that during one-armed cranking performed with no load. Mental imagery of two-ball rotation increased Oxy-Hb of the forearm and biceps muscles. The increases in Oxy-Hb of both forearm and upper arm muscles during two-ball rotation were reduced by decreasing the level of task difficulty. Intravenous administration of atropine attenuated the increases in Oxy-Hb of the arm muscles during two-ball rotation. It is likely that contralateral skilful hand movement evokes a selective increase in Oxy-Hb of the non-contracting forearm muscle via a sympathetic cholinergic mechanism and that the increase in oxygenation might be mediated, at least in part, by central command.

Pivotal role of the ventral tegmental area in spontaneous motor activity and concomitant cardiovascular responses in decerebrate rats.

Central command, a feedforward signal from higher brain centers, regulates the cardiovascular system in association with exercise. Previous evidence suggests that nucleus (or nuclei) around the midbrain may contribute to generating spontaneous motor activity and concomitant cardiovascular responses. To examine which area within the midbrain is important for the spontaneous and synchronized responses, 18 rats were decerebrated at three levels (pre-midbrain, rostroventral midbrain, and caudal midbrain levels) and paralyzed with a neuromuscular blocker. Individual brain sections showed decerebration rostral to the pre-collicular level in the pre-midbrain preparation and, additionally, removal of the periaqueductal gray in the rostroventral midbrain preparation, and decerebration around the midcollicular level in the caudal midbrain preparation. Spontaneous motor activity occurred at frequency of 69 ± 27 times/h and accompanied increases in heart rate (by 15 ± 4 beats/min) and mean arterial blood pressure (by 54 ± 4 mmHg) in the pre-midbrain preparation. Similar motor and cardiovascular responses took place in the rostroventral midbrain preparation, while such responses hardly occurred in the caudal midbrain preparation. We next examined whether injection of a GABAergic receptor agonist (muscimol) in the ventral tegmental area (VTA) inhibits the spontaneous motor and cardiovascular responses in 6 pre-midbrain preparations. The occurrence of spontaneous motor activity and concomitant cardiovascular responses was inhibited clearly (P < 0.05) by injection of muscimol, but not saline. It is concluded that the VTA plays a pivotal role in the spontaneous and synchronized activation of the motor and cardiovascular systems in decerebrate rats.

Pertuzumab in the treatment of HER2-positive breast cancer: an evidence-based review of its safety, efficacy, and place in therapy.

Human epidermal growth factor receptor 2 (HER2)-positive breast cancer is a distinct subset of breast cancer that results from overexpression of HER2 protein. Pertuzumab-a recombinant humanized monoclonal antibody that binds to the extracellular dimerization domain II of HER2-was recently approved for adjuvant therapy and neoadjuvant therapy of HER2-positive early breast cancer. As pertuzumab and trastuzumab bind to different domains of the extracellular dimerization domain of HER2, a combination therapy of pertuzumab and trastuzumab is beneficial for the treatment of metastatic cancer, advanced local cancer, or early cancer by dual HER2 blockage. Many clinical trials have been performed using pertuzumab for breast cancer patients; these include the CLEOPATRA trial for palliative therapy, the APHINITY trial for adjuvant therapy, and the NeoSphere and the TRYPHAENA trials for neoadjuvant therapy. These trials revealed pertuzumab to be a safe and effective drug regardless of the patient age and hormone receptor status. Notably, pertuzumab use was associated with severe cardiac toxicity in some cases; however, the risk of pertuzumab-induced cardiac dysfunction was low. The most common adverse effect associated with pertuzumab-use was diarrhea, but most cases were not severe. Several different chemotherapeutic agents have been investigated to determine optimal chemotherapeutic combinations for dual HER2 blockage. Some exploratory analyses indicate that pertuzumab treatment offered little benefit to patients with node-negative and small primary tumors; pertuzumab treatment was also found not be cost-effective. Further research will reveal the appropriate usage of pertuzumab for treating a subset of eligible patients.