Fibroblasts activation by embryonic signal switching: A novel mechanism of placental growth factor-induced cardiac remodeling.

INTRODUCTION: Cardiac remodeling is defined as cellular interstitial changes that lead dysfunction of the heart after injury. Placental growth factor (PlGF), a member of the VEGF family, has been reported to regulate cardiac hypertrophy in hemodynamic state. We therefore analyze the function of PlGF during cardiac remodeling using cardiac cells and fibroblasts, under Angiotensin II (AngII) stimulation. METHODS: PlGF overexpressed mouse embryonic fibroblasts derived from C57BL/6 mice, were made by deficient retrovirus vector, designated as C57/PlGF. Only retrovirus vector introduced C57 cells (C57/EV) were used as control. After AngII stimulation, wound scratching assay and MTT proliferation assay with or without p38 MAPK inhibitor, SB205580 were performed in retrovirally-introduced C57 cells. Reactive oxygen species (ROS) production, NF-kB activation, IL-6 and TNF-α production were also measured. Then we assessed AngII-induced cell proliferation of mouse cardiac fibroblasts (CFs) and rat primary cardiomyocytes incubating with C57/PlGF conditioned-medium. RESULTS: The PlGF production in C57/PlGF were confirmed by ELISA (1093.48 ± 3.5 pg/ml, ±SE). AngII-induced cell migration, proliferation and H2O2 production were increased in C57/PlGF compared with C57/EV. SB205580 inhibited the AngII-induced cell proliferation in C57/PlGF. In C57/PlGF cells, NF-kB activation was higher, followed by up-regulation of IL-6 and TNF-α production. CFs and cardiomyocytes proliferation increased when stimulated with C57/PlGF conditioned-medium. DISCUSSION: The activation of fibroblast is stimulated by PlGF signaling via p38 MAPK/NF-kB pathway accompanied by elevation of ROS and inflammatory response. Furthermore, these signals stimulate the activation of CFs and cardiomyocytes, indicating that high circulating level of PlGF have a potential to regulate cardiac remodeling.

"Honey pot"-like lesion formation: Impact of catheter contact angle on lesion formation by novel diamond-embedded temperature-controlled ablation catheter in a porcine experimental model.

BACKGROUND: Novel diamond-embedded catheter enables precise temperature-controlled ablation. However, the effects of contact angle on lesion formation of this catheter are poorly understood. OBJECTIVE: The purpose of this study was to evaluate lesion formation using the temperature-controlled ablation catheter embedded with diamond at different angles in a porcine experimental model. METHODS: Freshly sacrificed porcine hearts were used. Radiofrequency catheter ablation was performed at 50 W for 15 seconds at an upper temperature setting of 60°C. The contact force (5g, 10g, 30g) and catheter contact angles (30°, 45°, 90°) were changed in each set (n = 13 each). Surface width, maximum lesion width, lesion depth, surface area, distance from the distal edge to the widest area, and impedance drop were evaluated. RESULTS: Surface width and maximum lesion width were longer at 30° than at 90° (P <.05). There were no significant differences in the lesion depth by catheter angle except at 30g. Surface area was larger at 30° than at 90° (P <.05). Distance from the distal edge to the widest area was longer at 30° than at 90° (P <.05). There were no significant differences in impedance drop according to catheter angle. CONCLUSION: With diamond-embedded temperature-controlled ablation catheters, lesion width increased at a shallower contact angle, whereas lesion depth did not. Surface area also increased at a shallower contact angle. This catheter created a large ablation lesion on the proximal side of the catheter, which looked like a "honey pot."

Prognostic impact of oral anticoagulation therapy and atrial fibrillation in patients with type B acute aortic dissection.

Background: The prognostic impact of atrial fibrillation (AF) and oral anticoagulation (OAC) therapy in patients with type B acute aortic dissection (AAD) remains unclear. Therefore, we investigated the prognostic impact of AF and OAC therapy in patients with type B AAD. Methods: Consecutive patients diagnosed with AAD were included in this single-center, retrospective study. Patients with type B AAD were selected from the study population and divided into three groups: AF(+)/OAC(+), AF(+)/OAC(-), and AF(-)/OAC(-). The primary end point was major adverse cardiovascular and cerebrovascular events (MACCE), including all-cause death, progressive aortic events, cerebral infarction, and organ malperfusion. Results: In total, 139 patients diagnosed with type B AAD were analyzed. AF was observed in 27 patients (19%). Among them, 13 patients (9%) received OAC therapy for AF. MACCE occurred in 32 patients (23%) during the observation period: all-cause death in four patients, progressive aortic events in 24 patients, cerebral infarction events in two patients, and malperfusion events in two patients. The incidence of MACCE was higher in the AF(+)/OAC(+) group than in the AF(+)/OAC(-) group (hazard ratio[HR]: 3.875; 95% confidence interval [CI]: 1.153-17.496). In contrast, there was no significant difference in the incidence of MACCE between the AF(+)/OAC(-) and AF(-)/OAC(-) groups (HR: 1.001, 95% CI: 0.509-1.802). Conclusion: Among patients with type B AAD, the use of OAC for AF was associated with a higher risk of MACCE.

Analysis of Quadriceps Muscle Tightness as a Risk Factor for Osgood-Schlatter Disease: A Prospective Cohort Study.

Background: The prevalence of Osgood-Schlatter disease (OSD) is unknown. Tightness of the quadriceps femoris has been reported to be a risk factor for OSD. Hypothesis: Quadriceps muscle tightness would not contribute to the development of OSD. Study Design: Cohort study; Level of evidence, 2. Methods: We enrolled 150 Japanese male junior high school soccer players (N = 300 knees), with a mean age at first examination of 12.5 years (range, 12-13 years). All players were assessed annually and evaluated for 2 years. Ten players (n = 14 knees) had a history of OSD before the first medical examination. After excluding these 10 players (n = 20 knees), the remaining 140 players (n = 280 knees) were included in this prospective analysis. Age at the time of starting soccer, history of injury (including OSD and time missed), height, weight, annual increase in height, body mass index (BMI), straight-leg raise angle, heel-buttock distance (HBD), and ultrasound images of the tibial tuberosity (maturity and morphology) were compared between players who developed OSD and those who did not. Results: OSD was identified in 8 knees of 6 players, with an incidence of 2.9% of knees (8/280) and 4.3% of players (6/140). Univariate analysis revealed significant differences between the OSD and non-OSD groups regarding BMI (17.1 ± 1 kg/m2 vs 18.5 ± 1.6 kg/m2, respectively; P = .018), HBD (1.5 ± 1.6 cm vs 4.8 ± 4.5 cm; P < .001), and stage of tibial tuberosity maturity (P < .001). The maturity of the tibial tuberosity was the only independent risk factor for the development of OSD in multivariate logistic regression analysis (odds ratio, 9.848 [95% CI, 3.297-29.41]; P < .001). Conclusion: Study findings indicated that quadriceps muscle tightness did not contribute to the development of OSD.

Quadratus lumborum muscle strain in a youth soccer player: a case report.

Case: We report a case of quadratus lumborum muscle strain that occurred in a 16-year-old soccer player during a game. According to a video recording of the game, the injury occurred when the leg landed just after kicking the ball with the same leg while dribbling. The mechanism was suspected to be right lateral flexion of the trunk while the pelvis was simultaneously forced to tilt backward. The injury healed and he was able to return to competition 3 weeks later.Conclusion: This is the first report of a sports-related quadratus lumborum muscle strain.

Lesion size index-guided cavotricuspid isthmus linear ablation.

BACKGROUND: The lesion size index (LSI) predicts radiofrequency (RF) ablation lesion size and is an established parameter for pulmonary vein isolation. However, the effectiveness and safety of LSI for cavotricuspid isthmus (CTI) linear ablation remain unclear. METHODS: This single-center retrospective study included 50 of patients (67 ± 10 years, 68% male) who underwent de novo CTI linear ablation between July 2020 and December 2020. The LSI target was set at 5.0 and 4.0 for the anterior 2/3 and posterior 1/3 segments, respectively. Acute procedural parameters of ablation were evaluated. RESULTS: Acute bidirectional CTI block was achieved in all patients with an RF application time of 4.0 min (3.1-5.0 min), RF application number of 15 ± 7, and length of CTI of 36.9 ± 9.3 mm. First-pass bidirectional conduction block of the CTI was achieved in 39/50 (78%) patients. No major complications were observed. The contact force (CF) per application was significantly lower in the gap tag group than in the non-gap tag group (7 g [7-8 g] vs. 10 g [7-12 g], P = 0.0284). CONCLUSIONS: LSI-guided CTI linear ablation is an effective and safe treatment approach. CF affects gap formation, even when the target LSI is the same.

Age-related differences in glenohumeral internal rotation deficit, humeral retrotorsion angle, and posterior shoulder tightness in baseball players.

BACKGROUND: Glenohumeral internal rotation deficit is generally recognized as a risk factor for throwing disability in baseball players. However, the pathology, timing of onset, role in the onset of humeral retrotorsion angle (HTA) and soft tissue extensibility (STE), and the relationship with age remain unclear. Therefore, the purpose of this cross-sectional study was to investigate age-related glenohumeral internal rotation deficit, HTA, and STE in Japanese baseball players and determine whether these factors correlate with throwing disability. METHODS: Participants were 172 male baseball players divided into a symptomatic group (n = 68) and an asymptomatic group (n = 104). The mean age at examination was 15.4 ± 3.2 (range, 8-22) years. Measurement items were range of motion of bilateral internal and external rotation at 90° abduction (2ndIR and 2ndER, respectively), bilateral HTA, and posterior shoulder muscle elasticity. Correlations of age, symptom, and dominance with these measurements were investigated, and significant bilateral differences in HTA and STE by age and symptom were analyzed. RESULTS: HTA and 2ndER of the dominant side were significantly greater than those of the nondominant side in those over the age of 13 years in both the asymptomatic and symptomatic groups. In contrast, 2ndIR of the dominant side was significantly smaller than that of the nondominant side in those over the age of 13 years in both the asymptomatic and symptomatic groups. The difference in HTA between the dominant and nondominant sides increased and then plateaued at 12° after the age of 16 years. STE was observed only in the symptomatic group, and the value of STE was significantly greater in players aged >16 years compared with that in players aged <12 years (P = .001). Muscle elasticity did not differ significantly between sides and showed no correlation with STE. CONCLUSIONS: The difference in HTA between the dominant and nondominant sides increased with age until 16 years old regardless of symptoms. STE in the dominant side was observed only in symptomatic baseball players after the age of 13 years and increased with age, plateauing around the age of 16 years. Posterior shoulder muscle elasticity was not indicated as a cause of STE.

Coupling of hippocampal theta and ripples with pontogeniculooccipital waves.

The hippocampus has a major role in encoding and consolidating long-term memories, and undergoes plastic changes during sleep1. These changes require precise homeostatic control by subcortical neuromodulatory structures2. The underlying mechanisms of this phenomenon, however, remain unknown. Here, using multi-structure recordings in macaque monkeys, we show that the brainstem transiently modulates hippocampal network events through phasic pontine waves known as pontogeniculooccipital waves (PGO waves). Two physiologically distinct types of PGO wave appear to occur sequentially, selectively influencing high-frequency ripples and low-frequency theta events, respectively. The two types of PGO wave are associated with opposite hippocampal spike-field coupling, prompting periods of high neural synchrony of neural populations during periods of ripple and theta instances. The coupling between PGO waves and ripples, classically associated with distinct sleep stages, supports the notion that a global coordination mechanism of hippocampal sleep dynamics by cholinergic pontine transients may promote systems and synaptic memory consolidation as well as synaptic homeostasis.

Hippocampal Sharp-Wave Ripples Influence Selective Activation of the Default Mode Network.

The default mode network (DMN) is a commonly observed resting-state network (RSN) that includes medial temporal, parietal, and prefrontal regions involved in episodic memory [1-3]. The behavioral relevance of endogenous DMN activity remains elusive, despite an emerging literature correlating resting fMRI fluctuations with memory performance [4, 5]-particularly in DMN regions [6-8]. Mechanistic support for the DMN's role in memory consolidation might come from investigation of large deflections (sharp-waves) in the hippocampal local field potential that co-occur with high-frequency (>80 Hz) oscillations called ripples-both during sleep [9, 10] and awake deliberative periods [11-13]. Ripples are ideally suited for memory consolidation [14, 15], since the reactivation of hippocampal place cell ensembles occurs during ripples [16-19]. Moreover, the number of ripples after learning predicts subsequent memory performance in rodents [20-22] and humans [23], whereas electrical stimulation of the hippocampus after learning interferes with memory consolidation [24-26]. A recent study in macaques showed diffuse fMRI neocortical activation and subcortical deactivation specifically after ripples [27]. Yet it is unclear whether ripples and other hippocampal neural events influence endogenous fluctuations in specific RSNs-like the DMN-unitarily. Here, we examine fMRI datasets from anesthetized monkeys with simultaneous hippocampal electrophysiology recordings, where we observe a dramatic increase in the DMN fMRI signal following ripples, but not following other hippocampal electrophysiological events. Crucially, we find increases in ongoing DMN activity after ripples, but not in other RSNs. Our results relate endogenous DMN fluctuations to hippocampal ripples, thereby linking network-level resting fMRI fluctuations with behaviorally relevant circuit-level neural dynamics.

Binocular flash suppression in the primary visual cortex of anesthetized and awake macaques.

Primary visual cortex (V1) was implicated as an important candidate for the site of perceptual suppression in numerous psychophysical and imaging studies. However, neurophysiological results in awake monkeys provided evidence for competition mainly between neurons in areas beyond V1. In particular, only a moderate percentage of neurons in V1 were found to modulate in parallel with perception with magnitude substantially smaller than the physical preference of these neurons. It is yet unclear whether these small modulations are rooted from local circuits in V1 or influenced by higher cognitive states. To address this question we recorded multi-unit spiking activity and local field potentials in area V1 of awake and anesthetized macaque monkeys during the paradigm of binocular flash suppression. We found that a small but significant modulation was present in both the anesthetized and awake states during the flash suppression presentation. Furthermore, the relative amplitudes of the perceptual modulations were not significantly different in the two states. We suggest that these early effects of perceptual suppression might occur locally in V1, in prior processing stages or within early visual cortical areas in the absence of top-down feedback from higher cognitive stages that are suppressed under anesthesia.

Temporal jitter of the BOLD signal reveals a reliable initial dip and improved spatial resolution.

fMRI, one of the most important noninvasive brain imaging methods, relies on the blood oxygen level-dependent (BOLD) signal, whose precise underpinnings are still not fully understood. It is a widespread assumption that the components of the hemodynamic response function (HRF) are fixed relative to each other in time, leading most studies as well as analysis tools to focus on trial-averaged responses, thus using or estimating a condition- or location-specific "canonical HRF". In the current study, we examined the nature of the variability of the BOLD response and asked in particular whether the positive BOLD peak is subject to trial-to-trial temporal jitter. Our results show that the positive peak of the stimulus-evoked BOLD signal exhibits a trial-to-trial temporal jitter on the order of seconds. Moreover, the trial-to-trial variability can be exploited to uncover the initial dip in the majority of voxels by pooling trial responses with large peak latencies. Initial dips exposed by this procedure possess higher spatial resolution compared to the positive BOLD signal in the human visual cortex. These findings allow for the reliable observation of fMRI signals that are physiologically closer to neural activity, leading to improvements in both temporal and spatial resolution.

Antioxidant characteristics of extracts from cereal residues by their subcritical water treatment.

Subcritical water treatment of cereal residues including okara, defatted rice bran, desalted soy sauce lees, sake lees, corn kernel hull, and defatted rapeseed was conducted at 260°C for 5 min to obtain the antioxidative extracts. The antioxidative activities of the extracts were evaluated using DPPH radical, peroxyl radical, hydroxyl radical, hypochlorite ion, and peroxynitrite ion. The results show that the extracts from the sake lees, corn kernel hull, and defatted rapeseed had differently the antioxidative activities against all radicals and ions. However, the okara, defatted rice bran and desalted soy sauce lees had no activity against the hypochlorite ion.

Unravelling cerebellar pathways with high temporal precision targeting motor and extensive sensory and parietal networks.

Increasing evidence has implicated the cerebellum in providing forward models of motor plants predicting the sensory consequences of actions. Assuming that cerebellar input to the cerebral cortex contributes to the cerebro-cortical processing by adding forward model signals, we would expect to find projections emphasising motor and sensory cortical areas. However, this expectation is only partially met by studies of cerebello-cerebral connections. Here we show that by electrically stimulating the cerebellar output and imaging responses with functional magnetic resonance imaging, evoked blood oxygen level-dependant activity is observed not only in the classical cerebellar projection target, the primary motor cortex, but also in a number of additional areas in insular, parietal and occipital cortex, including sensory cortical representations. Further probing of the responses reveals a projection system that has been optimized to mediate fast and temporarily precise information. In conclusion, both the topography of the stimulation effects and its emphasis on temporal precision are in full accordance with the concept of cerebellar forward model information modulating cerebro-cortical processing.

Improved decoding of neural activity from fMRI signals using non-separable spatiotemporal deconvolutions.

The goal of most functional Magnetic Resonance Imaging (fMRI) analyses is to investigate neural activity. Many fMRI analysis methods assume that the temporal dynamics of the hemodynamic response function (HRF) to neural activation is separable from its spatial dynamics. Although there is empirical evidence that the HRF is more complex than suggested by space-time separable canonical HRF models, it is difficult to assess how much information about neural activity is lost when assuming space-time separability. In this study we directly test whether spatiotemporal variability in the HRF that is not captured by separable models contains information about neural signals. We predict intracranially measured neural activity from simultaneously recorded fMRI data using separable and non-separable spatiotemporal deconvolutions of voxel time series around the recording electrode. Our results show that abandoning the spatiotemporal separability assumption consistently improves the decoding accuracy of neural signals from fMRI data. We compare our findings with results from optical imaging and fMRI studies and discuss potential implications for classical fMRI analyses without invasive electrophysiological recordings.

The amplitude and timing of the BOLD signal reflects the relationship between local field potential power at different frequencies.

There is growing evidence that several components of the mass neural activity contributing to the local field potential (LFP) can be partly separated by decomposing the LFP into nonoverlapping frequency bands. Although the blood oxygen level-dependent (BOLD) signal has been found to correlate preferentially with specific frequency bands of the LFP, it is still unclear whether the BOLD signal relates to the activity expressed by each LFP band independently of the others or if, instead, it also reflects specific relationships among different bands. We investigated these issues by recording, simultaneously and with high spatiotemporal resolution, BOLD signal and LFP during spontaneous activity in early visual cortices of anesthetized monkeys (Macaca mulatta). We used information theory to characterize the statistical dependency between BOLD and LFP. We found that the alpha (8-12 Hz), beta (18-30 Hz), and gamma (40-100 Hz) LFP bands were informative about the BOLD signal. In agreement with previous studies, gamma was the most informative band. Both increases and decreases in BOLD signal reliably followed increases and decreases in gamma power. However, both alpha and beta power signals carried information about BOLD that was largely complementary to that carried by gamma power. In particular, the relationship between alpha and gamma power was reflected in the amplitude of the BOLD signal, while the relationship between beta and gamma bands was reflected in the latency of BOLD with respect to significant changes in gamma power. These results lay the basis for identifying contributions of different neural pathways to cortical processing using fMRI.

Tracing of noradrenergic projections using manganese-enhanced MRI.

We examined the applicability of manganese-enhanced MRI (MEMRI) to the in vivo tracing of diffuse neuromodulatory projections by means of simultaneous iontophoretic injections of an extremely low, non-toxic concentration of MnCl(2) (10mM) and fluorescent dextran in the locus coeruleus (LC) in the rat. We validated the use of the iontophoretic injection by reproducing previously reported results from pressure injections of MnCl(2) in primary somatosensory cortex. Twenty fourhours after injection in LC, Mn(2+) labeling was detected in major cortical and subcortical targets of LC projections including predominantly ipsilateral primary motor and somatosensory cortices, hippocampus and amygdala. Although the injections were in most cases centered in the core of LC, the pattern of Mn(2+) labeling greatly varied across rats. In addition, despite a certain degree of overlap of the labeling obtained with both MEMRI and classical tracing, MEMRI tracing consistently failed to reliably label not only several minor but also major targets of LC, notably the thalamus. The lack of Mn(2+) labeling in thalamus possibly reflected a weaker functional connectivity within coeruleothalamic projections that could not be predicted by anatomical tracing. Inversely, a number of brain regions, particularly contralateral motor cortex, that were not or only sparsely labeled with fluorescent dextran were strongly labeled by Mn(2+). This discrepancy could be partly due to both the activity-dependent and transsynaptic nature of Mn(2+) transport. The overall labeling produced using MEMRI with iontophoretic injections in LC indicates that the Mn(2+) imaging of highly diffuse projections is in principle feasible. However, the labeling pattern of each individual case needs to be carefully interpreted particularly before submitting data for group analysis or in the case of longitudinal examination of discrete changes in functional connectivity under various physiological or behavioral conditions.

Attention but not awareness modulates the BOLD signal in the human V1 during binocular suppression.

Although recent psychophysical studies indicate that visual awareness and top-down attention are two distinct processes, it is not clear how they are neurally dissociated in the visual system. Using a two-by-two factorial functional magnetic resonance imaging design with binocular suppression, we found that the visibility or invisibility of a visual target led to only nonsignificant blood oxygenation level-dependent (BOLD) effects in the human primary visual cortex (V1). Directing attention toward and away from the target had much larger and robust effects across all study participants. The difference in the lower-level limit of BOLD activation between attention and awareness illustrates dissociated neural correlates of the two processes. Our results agree with previously reported V1 BOLD effects on attention, while they invite a reconsideration of the functional role of V1 in visual awareness.

Activation of SC during electrical stimulation of LGN: retinal antidromic stimulation or corticocollicular activation?

We have recently used combined electrostimulation, neurophysiology, microinjection and functional magnetic resonance imaging (fMRI) to study the cortical activity patterns elicited during stimulation of cortical afferents in monkeys. We found that stimulation of a site in lateral geniculate nucleus (LGN) increases the fMRI signal in the regions of primary visual cortex receiving input from that site, but suppresses it in the retinotopically matched regions of extrastriate cortex. Intracortical injection experiments showed that such suppression is due to synaptic inhibition. During these experiments, we have consistently observed activation of superior colliculus (SC) following LGN stimulation. Since LGN does not directly project to SC, the current study investigated the origin of SC activation. By examining experimental manipulations inactivating the primary visual cortex, we present here evidence that the robust SC activation, which follows the stimulation of LGN, is due to the activation of corticocollicular pathway.

esfMRI of the upper STS: further evidence for the lack of electrically induced polysynaptic propagation of activity in the neocortex.

Combining electrical stimulation with fMRI (esfMRI) has proven to be an important tool to study the global effects of electrical stimulation on neural networks in the brain. Here we extend our previous studies to stimulating the upper superior temporal sulcus (STS) in the anesthetized monkey. Our results show that stimulating area V5/MT and surrounding areas leads to positive BOLD responses in the majority of cortical areas known to receive direct/monosynaptic connections from the stimulation site. We confirm our previous results from stimulating primary visual cortex that the propagation of electrically induced activity is limited in its transsynaptic propagation to the first synapse also for extrastriate areas.