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Introduction: Renal cell carcinoma is often discovered at an early stage due to the increased use of imaging studies in the current era; therefore, its presentation as a gigantic renal cell carcinoma is rarely encountered., Case Presentation: A 59-year-old male presented to our hospital due to dizziness, fatigue, and increasing abdominal distension. A computed tomography scan showed an extremely large mass occupying most of the abdomen and pelvis. Surgical resection of the mass was performed. The largely cavitary mass with fibrous capsule was 43 cm and 13.0 kg, and contained a large amount of necrotic tissue. A portion of the left kidney was identified at the periphery of the mass, indicating that the tumor was arising from the left kidney. The final pathologic diagnosis was type 1 papillary renal cell carcinoma., Conclusion: To the best of our knowledge, this tumor is the world's largest malignant renal tumor., Competing Interests: The authors declare no conflict of interest., (© 2020 The Authors. IJU Case Reports published by John Wiley & Sons Australia, Ltd on behalf of Japanese Urological Association.)

Obstructive sleep apnea (OSA) patients are at risk for increased blood pressure and carotid intima-media thickness (IMT), with pulmonary hypertension and right-sided heart failure potentially developing as well. Chronic intermittent hypoxia (IH) has been used as an OSA model in animals, but its effects on vascular beds have not been evaluated using objective unbiased tools. Previously published and current experimental data in mice exposed to IH were evaluated for IMT in aorta and pulmonary artery (PA) after IH with or without normoxic recovery using software for meta-analysis, Review Manager 5. Because IMT data reports on PA were extremely scarce, atherosclerotic area percentage from lumen data was also evaluated. IH significantly increased IMT parameters in both aorta and PA as illustrated by Forest plots ( P < 0.01), which also confirmed that IMT values after normoxic recovery were within the normal range in both vascular beds. One-sided scarce lower areas in Funnel Plots were seen for both aorta and PA indicating the likelihood of significant publication bias. Forest and Funnel plots, which provide unbiased assessments of published and current data, suggest that IH exposures may induce IMT thickening that may be reversed by normoxic recovery in both aorta and PA. In light of the potential likelihood of publication bias, future studies are needed to confirm or refute the findings. In conclusion, OSA may induce IMT thickening (e.g., aorta and/or PA), but the treatment (e.g., nasal continuous positive airway pressure) will likely lead to improvements in such findings., (Copyright © 2020 Umeda, Miyagawa, Mochida, Takeda, Takeda, Okada and Gozal.)

Background and Objective: After cerebral hemorrhage, cognitive functions and activities of daily living (ADL) are affected by various factors, including hematoma volume and patient age. In the present study, we investigated the effect of age and hematoma volume on cognitive functions and on ADL., Methods: The sample comprised 274 patients (183 men and 91 women; mean age 58.2 ± 12.5 years) with putaminal hemorrhage who were hospitalized in a convalescent rehabilitation ward. Hematoma volume was estimated from computed tomography imaging at stroke onset. Cognitive functions were evaluated using Raven's Colored Progressive Matrices test (RCPM) and the Mini-Mental State Examination (MMSE) at hospital admission, while ADL score was assessed at discharge using the Functional Independence Measure motor subscale (FIM-M). In the present study, we classified the patients into six groups according to whether they were non-elderly or elderly (cutoff age, 60 years) and whether their hematoma was small, medium, or large (cutoff volumes, 20 and 40 mL, respectively). Subsequently, the scores on the RCPM, MMSE, and FIM-M were compared among the groups., Results: In both age groups, patients with a larger hematoma volume had lower RCPM and MMSE scores. Patients <60 years old exhibited different trends in their RCPM and MMSE scores, such that the RCPM score showed a step-wise decrease according to hematoma volume, while a difference in the MMSE score was only observed at the 20 mL boundary. Most of the younger patients (<60 years of age) attained high FIM-M scores at discharge, as long as their hematoma volume was either medium or small (<40 mL). This age group had higher RCPM scores on admission, which may have contributed to their higher FIM-M scores on discharge., Conclusions: In the present study, we demonstrated that advancing age increases the effect of hematoma volume on RCPM and MMSE scores and identified differences in the effects observed on these two scores. Thus, it may be important to use the RCPM alongside the MMSE for patient assessment., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Seizures are induced when subjects are exposed to severe hypoxia. It is followed by ventilatory fall-off and eventual respiratory arrest, which may underlie the pathophysiology of death in patients with epilepsy and severe respiratory disorders. However, the mechanisms of hypoxia-induced seizures have not been fully understood. Because astrocytes are involved in various neurological disorders, we aimed to investigate whether astrocytes are operational in seizure generation and respiratory arrest in a severe hypoxic condition. We examined the effects of astrocytic activation blockade on responses of EEG and ventilation to severe hypoxia. Adult mice were divided into two groups; in one group (n = 24) only vehicle was injected, and in the other group (n = 24) arundic acid, an inhibitory modulator of astrocytic activation, was administered before initiation of recording. After recording EEG and ventilation by whole body plethysmography in room air, the gas in the recording chamber was switched to 5% oxygen (nitrogen balanced) until a seizure and ventilatory depression occurred, followed by prompt switch back to room air. Severe hypoxia initially increased ventilation, followed by a seizure and ventilatory suppression in all mice examined. Fourteen mice without arundic acid showed respiratory arrest during loading of hypoxia. However, 22 mice pretreated with arundic acid did not suffer from respiratory arrest. Time from the onset of hypoxia to the occurrence of seizures was significantly longer in the group with arundic acid than that in the group without arundic acid. We suggest that blockade of astrocytic activation delays the occurrence of seizures and prevents respiratory arrest., (© 2019 Wiley Periodicals, Inc.)

Purpose: Computed tomography (CT) is used for initial assessment of patients with suspected stroke. Motor outcome prediction using the initial CT image is important for clinical rehabilitation. However, there is inconsistency in the results reported by the few publications on hematoma volume and motor outcomes in patients with putaminal hemorrhage. To clarify the direction of hematoma and relationship between the hematoma volume and motor outcomes in patients with putaminal hemorrhage using an initial CT image, we evaluated the volume of direction of hematoma in 170 patients in the subacute phase after putaminal hemorrhage using CT at stroke onset., Methods: The patients were divided into 5 groups according to the direction of the hematoma. For each group, Spearman's correlation coefficients were calculated to investigate the relationship between hematoma volume and motor outcomes. Motor outcomes were assessed using the motor items of Stroke Impairment Assessment Set, which are impairment indexes for the distal and proximal functions of the upper and lower extremities after stroke., Results: Hematoma volume was significantly correlated with all the motor items in the group whose hematoma extended to the posterior limb of the internal capsule alone (Bonferroni corrected P <.05). On the other hand, significant correlations between hematoma volume and motor outcomes could not be found in almost all the other groups., Conclusions: Motor outcome after putaminal hemorrhage can be predicted by evaluating the progression of hematoma to the corticospinal tract and its volume using CT images at stroke onset., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: This study sought to identify the prefrontal cortex hemodynamic response that is dependent on cognitive performance in patients with bulimic disorders (BD), and investigate its association with personality characteristics., Methods: Nineteen female patients with BD and 23 healthy women were recruited. Their personality characteristics related to eating disorders were examined using a self-reporting questionnaire, namely the eating disorder inventory-2 (EDI-2). Cerebral blood flow response in the prefrontal cortex during the digit span backward task (DSBT) was measured using near-infrared spectroscopy (NIRS). Change in oxygenated hemoglobin concentration (ΔoxyHb), obtained using NIRS, were used as an index of brain activity. Further, the relationship between prefrontal cortical activity and personality characteristics was investigated in patients with BD., Results: The cognitive performance of patients with BD was significantly lower in the DSBT compared with healthy subjects. There was no difference between the groups in ΔoxyHb during the task. Task scores of patients with BD correlated with asceticism and perfectionism. Moreover, the asceticism score was negatively correlated with ΔoxyHb of the bilateral prefrontal cortex in patients with BD., Conclusion: The results suggest that cognitive performance and brain activity induced during DSBT might be affected by asceticism in BD patients., Level of Evidence: III, case-control study.

This study explored gender differences in correct response rates and response times on a task involving left or right arrow selection and another involving the transformation of mental rotation of the hand. We recruited 15 healthy, right-handed men (age 24.5 ± 6.4) and 15 healthy, right-handed women (age 21.3 ± 4.9). For the tasks, we used pictures of left and right arrows and 32 hand pictures (left and right, palm and back) placed in cons (each at 45° from 0° to 315°). Hand and arrow pictures alternated and were shown at random. Participants decided as quickly as possible whether each picture was left or right. To compare the time taken for the transformation of mental rotation of the hand, we subtracted the average arrow response time from that for the left and right hand pictures for each participant. Correct response rates did not differ significantly between men and women or left and right for either arrow or hand pictures. Regardless of gender, the response time was longer for the left arrow picture than right arrow picture. The response time for the hand picture was longest for both men and women for pictures at rotation angles that were most difficult to align with participants' hands. While there was no difference between men's responses for left and right hand pictures, the responses of women were longer for left than right hand pictures and also than those of men. These findings suggest that both men and women mainly perform the hand mental rotation task with implicit motor imagery. On the other hand, the gender difference in performance might be explained by the difference in balance with other strategies, such as visual imagery, and by cognitive, neurophysiological, and morphological differences., Competing Interests: The authors have declared that no competing interests exist.

A hand mental rotation task (HMRT) is a task wherein a person judges whether an image of a rotated hand is of the right or left hand. Two performance strategies are expected to come into play when performing these tasks: a visual imagery (VI) strategy, in which an image is mentally rotated, and a motor imagery (MI) strategy, in which the movement of a person's own hand is simulated. Although elderly people generally take some time to perform these tasks, ability differs greatly between individuals. The present study hypothesizes that there is a relationship between differences in task performance strategy and performance ability, and it compares performance strategy among elderly people divided into groups with a short mental rotation time and a long mental rotation time. In response to images of the palm, both groups displayed a medial-lateral effect in which responses were faster for images where the third finger was rotated toward the midline of the body than images rotated in the opposite direction, and we inferred that an MI strategy was primarily employed. Meanwhile, in response to images of the back of the hand, a medial-lateral effect was also observed in the group with a long mental rotation time and not in the group with the shortest mental rotation time (VI strategy). These results suggest that different strategies for performing HMRT task are used by elderly people with a short mental rotation time and those with a long mental rotation time.

The integration of multiple sensory modalities allows us to adapt to the environment of the outside world. It is widely known that visual stimuli interfere with the processing of auditory information, which is involved in the ability to pay attention. Additionally, visuospatial attention has the characteristic of laterality. It is unclear whether this laterality of visuospatial attention affects the processing of auditory stimuli. The sensorimotor gating system is a neurological process, which filters out unnecessary stimuli from environmental stimuli in the brain. Prepulse inhibition (PPI) is an operational measure of the sensorimotor gating system, which a weaker prestimulus (prepulse), such as a visual stimulus, inhibits the startle reflex elicited by a subsequent robust startling stimulus (pulse) such as a tone. Therefore, we investigated whether the visual stimulus from the left or right visual space affects the sensorimotor gating system in a "rest" task (low attentional condition) and a "selective attention" task (high attentional condition). In the selective attention task, we found that the target prepulse presented in the left and bilateral visual fields suppressed the startle reflex more than that presented in the right visual field. By contrast, there was no laterality of PPI in the no-target prepulse condition, and there was no laterality of PPI in the rest task. These results suggest that the laterality of visuospatial attention affects the sensorimotor gating system depending on the attentional condition. Moreover, the process of visual information processing may differ between the left and right brain.

Objective To assess quantitatively the efficacy of oral baclofen for spasticity poststroke. Methods The participants were 29 persons poststroke with increased resistance to passive ankle dorsiflexion and ankle clonus on clinical assessment. Baclofen was administered at 20 mg/day for 1 week. The ankle joint was passively dorsiflexed at either 5°/s (slow stretch) or 90°/s (fast stretch) by a custom-built device. The ankle joint angle and resistive torque were measured during the ramp-and-hold stretch, with gastrocnemius electromyogram. The main outcome measures were the numbers of ankle clonus during hold, and the torques at 10° of ankle dorsiflexion in slow stretch (T-slow) and fast stretch (T-fast). Moreover, the velocity-dependent torque (ΔT = T-fast - T-slow) was compared between before and after oral baclofen. Results The numbers of ankle clonus, T-slow, T-fast, and ΔT for all participants did not exhibit significant differences between before and after baclofen administration. However, reduction in the number of ankle clonus of five or more was accompanied with a reduction in ΔT (4.0 ± 1.8 Nm) in three participants (the responders). Conclusion Although the responder rate was low, some participants responded to oral baclofen. Thus, a short-term trial of oral baclofen, and quantitative and electrophysiological assessments of muscle tone and ankle clonus are recommended.

A 50-year-old man was diagnosed with multiple myeloma complicating AL amyloidosis. Splenic rupture was complicated during autologous stem cell transplantation (auto-SCT). Granulocyte colony-stimulating factor (G-CSF) was not administered. A pathological examination of the spleen revealed that CD34-positive cells were concentrated in the ruptured part of the splenic capsule. Hematopoietic cells were engrafted in the small gap between the capsule and amyloid protein deposition area of the spleen, which might have caused the splenic rupture in the absence of G-CSF administration. Special attention is thus required for amyloidosis patients undergoing auto-SCT, even when G-CSF is not administered.

Background Individuals exhibiting hemiplegia and increased ankle plantar flexors muscle tone following stroke are frequently prescribed an ankle-foot orthosis (AFO) to regain functional ambulation. The effect of muscle tone on ankle kinetics when walking with an AFO remains unknown. Objectives To investigate the effect of plantar flexion (PF) muscle tone on ankle plantar flexion torque during walking with an ankle-foot orthosis Methods The study included 80 participants with first-ever stroke whose manual muscle testing (MMT) of ankle DF 0-4, and 10 healthy subjects. Participants were instructed to walk on a treadmill, at a comfortable speed, wearing an instrumented AFO. Minimum PF torque during the last half of swing was extracted as an outcome measure. Resistive PF torques during passive slow and fast stretches were measured with a custom-built device, with torques at 10° DF (T10°-slow and T10°-fast) extracted as defining parameters for stiffness and muscle tone, respectively. Results Correlations between both T10°-slow and T10°-fast variables with minimum PF torque were fair among ankle DF MMT 0-3 groups (r = 0.71 -0.74, p < 0.01), with no correlation observed among the MMT 4 group and healthy subjects. Conclusions Effects of muscle tone on ankle kinetics during swing phase, with an AFO, were observed in persons with severe ankle DF paresis. Quantitative evaluation of ankle kinetics during gait with an AFO in addition to evaluation of muscle tone at rest is contributory to objective assessment of a muscle tone, not subjective rating scale at rest, or visual inspection of walking.

Neuromuscular electrical stimulation (NMES), specifically functional electrical stimulation (FES) that compensates for voluntary motion, and therapeutic electrical stimulation (TES) aimed at muscle strengthening and recovery from paralysis are widely used in stroke rehabilitation. The electrical stimulation of muscle contraction should be synchronized with intended motion to restore paralysis. Therefore, NMES devices, which monitor electromyogram (EMG) or electroencephalogram (EEG) changes with motor intention and use them as a trigger, have been developed. Devices that modify the current intensity of NMES, based on EMG or EEG, have also been proposed. Given the diversity in devices and stimulation methods of NMES, the aim of the current review was to introduce some commercial FES and TES devices and application methods, which depend on the condition of the patient with stroke, including the degree of paralysis., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Objective: The aim of this study was to investigate whether anodal transcranial direct current stimulation over the left temporoparietal area improved audioverbal memory performance in stroke patients., Design: Twelve stroke patients with audioverbal memory impairment participated in a single-masked, crossover, and sham-controlled experiment. The anodal or sham transcranial direct current stimulation was applied during the Rey Auditory Verbal Learning Test, which evaluates the ability to recall a list of 15 heard words over five trials. The number of correctly recalled words was compared between the anodal and sham conditions and the influence of transcranial direct current stimulation on serial position effect of the 15 words was also examined., Results: The increase in the number of correctly recalled words from the first to the fifth trial was significantly greater in the anodal condition than in the sham condition (P < 0.01). There was a significant difference (P < 0.01) between the anodal and sham conditions in the number of correctly recalled words within the first five words (primacy region) over the second to fifth trial trials, but not in the middle (next five words) or recency (last five words) regions., Conclusions: Anodal transcranial direct current stimulation over the left temporoparietal area improved audioverbal memory performance and induced the primacy effect in stroke patients.

Fear conditioning is a valuable behavioral paradigm for studying the neural basis of emotional learning and memory. The present study examined the involvement of extracellular signal-regulated kinase 1/2 (ERK) signaling on the serotonin (5-HT) 7 receptor-mediated fear conditioning. Conditioning was performed in a trial in which a tone was followed by an electrical foot-shock. Context- and tone-dependent fear were examined in tests conducted 24 and 48h after conditioning, respectively. The selective 5-HT 7 receptor antagonist 2a-[4-(4-phenyl-1,2,3,6-tetrahydropyridyl)butyl]-2a,3,4,-tetrahydrobenzo(c,d)indol-2-(1H)-one (DR4004) (5mg/kg), when administered intraperitoneally (i.p.) immediately after conditioning, caused a significant decrease in both context- and tone-dependent fear responses (freezing behavior). A significant increase in ERK activity was observed in the amygdala of mice that displayed context- or tone-dependent fear responses, and these changes were also inhibited by the administration of DR4004 (5mg/kg, i.p.) immediately after conditioning. In contrast, the increase in hippocampal ERK activity in mice that displayed context-dependent fear responses was further enhanced by the administration of DR4004 (5mg/kg, i.p.). These results suggest that 5-HT 7 receptor-mediated ERK signaling may play a significant role in the processes of emotional learning and memory., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Mild hypoxia increases ventilation, but severe hypoxia depresses it. The mechanism of hypoxic ventilatory depression, in particular, the functional role of the cerebrum, is not fully understood. Recent progress in glial physiology has provided evidence that astrocytes play active roles in information processing in various brain functions. We investigated the hypothesis that astrocytic activation is necessary to maintain the cerebral function and ventilation in hypoxia, by examining the responses of EEG and ventilation to severe hypoxia before and after administration of a modulator of astrocytic function, arundic acid, in unanesthetized mice. Ventilatory parameters were measured by whole body plethysmography. When hypoxic ventilatory depression occurred, gamma frequency band of EEG was suppressed. Arundic acid further suppressed ventilation, and the EEG power was suppressed in a dose-dependent manner. Arundic acid also suppressed hypoxia-induced c-Fos expression in the hypothalamus. We conclude that severe hypoxia suppresses the cerebral function which could reduce the stimulus to the brainstem resulting in ventilatory depression. Astrocytic activation in hypoxia may counteract both cerebral and ventilatory suppression., (Copyright © 2015. Published by Elsevier B.V.)

Background: Quantification of increased muscle tone for patients with spasticity has been performed to date using various devices to replace the manual scales, such as the modified Ashworth scale or the Tardieu scale. We developed a device that could measure resistive plantar flexion (PF) torque of the ankle during passive dorsiflexion (DF) as an indicator of muscle tone of ankle plantar flexors., Methods: The primary objective was to explore the test-retest intrarater reliability of a custom-built device. Participants were 11 healthy subjects (7 men, 4 women; mean age 47.0 years) and 22 patients with poststroke hemiplegia (11 hemorrhagic, 11 ischemic; 14 men, 8 women; mean age 57.2 years). The device was affixed to the ankle. Subjects were seated with knees either flexed or extended. The ankle was passively dorsiflexed from 20° of PF to more than 10° of DF at 5°/second (slow stretch) or 90°/second (fast stretch). Angle and torque were measured twice during the stretches. The intraclass correlation coefficients (ICCs) of torque at 10° of DF (T10) in the 4 conditions-slow and fast stretches with knee flexed or extended-were calculated., Results: The T10 ICCs of the 4 conditions were .95-.99 in both groups. The healthy subjects showed significantly higher T10 of knee extension than of knee flexion during slow and fast stretches. The patients showed increased velocity-dependent torque during fast stretches., Conclusions: Excellent reliability was observed. The device is suitable for measuring resistive PF torque during passive stretch in a flexed knee condition., (Copyright © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Condyloma acuminatum (CA) is a common sexually transmitted disease caused by human papilloma virus infection. Not all individuals develop persistent, progressive disease, but careful follow up is required with moderate-to-severe dysplasia to prevent progression to malignancy. Standard therapies include surgical treatments (trans-anal resection and trans-anal endoscopic microsurgery) and immunotherapeutic and topical methods (topical imiquimod); however, local recurrence remains a considerable problem. Here, we report a case with superficial CA of the anal canal, treated with endoscopic submucosal dissection (ESD). A 28-year-old man presented with a chief complaint of hematochezia. Digital exam did not detect a tumor. Screening colonoscopy revealed 10-mm long, whitish condyles extending from the anal canal to the lower rectum. The lesion covered almost the whole circumference, and only a small amount of normal mucosa remained. Magnifying endoscopy with narrow band imaging showed brownish hairpin-shaped, coiled capillaries. Although histopathological diagnosis by biopsy revealed CA, accurate histological differentiation between CA, papilloma, and squamous cell carcinoma can be difficult with a small specimen. Therefore, we performed diagnostic ESD, which provides a complete specimen for precise histopathological evaluation. The pathological diagnosis was CA, with moderate dysplasia (anal intraepithelial neoplasia 2). There was no recurrence at 16 mo after the initial ESD. Compared to surgical treatment, endoscopic diagnosis and resection could be performed simultaneously and the tumor margin observed clearly with a magnifying chromocolonoscopy, resulting in less recurrence. These findings suggest that endoscopic resection may be an alternative method for CA that prevents recurrence.

Dimethyl sulfoxide (DMSO) is commonly used as a solvent for hydrophobic substances, but the compound's innate bioactivity is an area of limited understanding. In this investigation we seek to determine the analgesic potential of DMSO. We addressed the issue by assessing the perception of thermal pain stimulus, using a 55 °C hotplate design, in conscious mice. The latency of withdrawal behaviors over a range of incremental accumulative intraperitoneal DMSO doses (0.5-15.5 g/kg) in the same mouse was taken as a measure of thermal endurance. The findings were that the latency, on average, amounted to 15-30 s and it differed inappreciably between the sequential DMSO conditions. Nor was it different from the pre-DMSO control conditions. Thus, DMSO did not influence the cutaneous thermal pain perception. The findings do not lend support to those literature reports that point to the plausible antinociceptive potential of DMSO as one of a plethora of its innate bioactivities. However, the findings concern the mouse's footpad nociceptors which have specific morphology and stimulus transduction pathways, which cannot exclude DMSO's antinociceptive influence on other types of pain or in other types of skin. Complex and as yet unresolved neural mechanisms of perception of cutaneous noxious heat stimulus should be further explored with alternative experimental designs.

Dimethyl sulfoxide (DMSO) is one of the most commonly used solvents for hydrophobic substances in biological experiments. In addition, the compound exhibits a plethora of bioactivities, which makes it of potential pharmacological use of its own. The influence on respiration, and thus on arterial blood oxygenation, of DMSO is unclear, contentious, and an area of limited study. Thus, in the present investigation we set out to determine the influence on lung ventilation of cumulated doses of DMSO in the amount of 0.5, 1.5, 3.5, 7.5, and 15.5 g/kg; each dose given intraperitoneally at 1 h interval in conscious mice. Ventilation and its responses to 7 % hypoxia (N(2) balanced) were recorded in a whole body plethsymograph. We demonstrate a dose-dependent inhibitory effect of DMSO on lung ventilation and its hypoxic responsiveness, driven mostly by changes in the tidal component. The maximum safe dose of DMSO devoid of meaningful consequences for respiratory function was 3.5 g/kg. The dose of 7.5 g/kg of DMSO significantly dampened respiration, with yet well preserved hyperventilatory response to hypoxia. The highest dose of 15.5 g/kg severely impaired ventilation and its responses. The study delineates the safety profile of DMSO regarding the respiratory function which is essential for maintaining proper tissue oxygenation. Caution should be exercised concerning dose concentration of DMSO.

This review tackles the unresolved issue of the existence of oxygen sensor in the body. The sensor that would respond to changes in tissue oxygen content, possibly along the hypoxia-normoxia-hyperoxia spectrum, rather than to a given level of oxygen, and would translate the response into lung ventilation changes, the major adaptive process. Studies on oxygen sensing, for decades, concentrated around the hypoxic ventilatory response generated mostly by carotid body chemoreceptor cells. Despite gaining a substantial insight into the cellular transduction pathways in carotid chemoreceptors, the exact molecular mechanisms of the chemoreflex have never been conclusively verified. The article briefly sums up the older studies and presents novel theories on oxygen, notably, hypoxia sensing. These theories have to do with the role of transient receptor potential cation TRPA1 channels and brain astrocytes in hypoxia sensing. Although both play a substantial role in shaping the ventilatory response to hypoxia, neither can yet be considered the ultimate sensor of hypoxia. The enigma of oxygen sensing in tissue still remains to be resolved.

Background Context: During quiet standing, the gravity line (GL) can be located according to the sum of the ground reaction forces (GRFs) measured with a force platform. C7 plumb line (C7PL) is an easy method to estimate sagittal trunk balance, but discordance between C7PL and the GL is widely recognized. However, the prevalence of occiput-trunk (O-T) discordance (GL-C7PL>3 cm) and the factors affecting this type of discordance have not yet been determined., Purpose: The purpose of this study was to report the prevalence of O-T discordance in adult spinal deformity (ASD) patients and identify the factors affecting this type of discordance., Study Design: This was a retrospective consecutive case series of ASD., Patient Sample: This retrospective case series included 300 consecutive ASD patients. The inclusion criteria were age more than 50 years, Cobb angle of the main curve more than 20°, and C7PL more than 5 cm. The exclusion criteria consisted of inappropriate radiography; syndromic, neuromuscular, or other pathologic conditions; and previous joint replacement., Outcome Measures: The outcome measures included self-reported (Scoliosis Research Society 22 and Oswestry disability index [ODI]) and radiographic measures., Methods: In a retrospective consecutive case series, demographic and radiographic patient data were reviewed. Demographic data included age, gender, curve type, SRS22, and ODI. Radiographic data included GL, C7PL, C2-C7, T2-T5, T5-T12, T10-L2, T2 tilt, lumbar lordosis (LL), sacrum slope (SS), pelvic tilt (PT), and pelvic incidence (PI). Global sagittal and spinopelvic alignments were also reviewed. Patients were categorized in either a O-T concordance (C group, GL-C7PL<3 cm) or a O-T discordance (D group, GL-C7PL more than +3 cm) group, and the demographic, radiographic, and clinical outcome data were compared between these groups. One-way analysis of variance, correlation coefficient tests, and multiple regression and logistic regression analyses were performed for statistical analysis. p Value less than .01 was considered statistically significant. Force platform analysis was performed to assess the relationship among GRF, GL, and C7PL., Results: Among 300 consecutive ASD patients, 72 (24%) were categorized in the D group. There was no significant difference in terms of demographic data between the C and D groups. The SRS and ODI of patients with GL more than 10 cm were significantly lower than those of patients with GL less than 10 cm. Comparisons of regional sagittal alignment showed significantly higher T5-T12 values in the D group, and multiple regression analysis revealed significant correlations among T2-T5, T5-T12, and GL-C7PL. In contrast, the analysis of global sagittal alignment revealed a significantly large T2 sagittal tilt in the D group compared with the C group. Force platform analysis showed concordance between GRF and GL, whereas discordance was observed between GRF and C7PL. The D group could be classified into 2 groups based on the global sagittal alignment: 10 patients were classified as the hypo-compensation type (small SVA, small CL, small TK, and normal-to-small LL), whereas 62 were classified as the forward-leaning type (large sagittal vertical axis, large cervical lordosis, large thoracic kyphosis, and small LL)., Conclusions: The prevalence of discordance between GL and C7PL in ASD patients was 24%, and thoracic kyphosis and global sagittal alignment were significantly correlated with this discordance. The concordance of GRF and GL and the discordance of GRF and C7PL highlight the importance and necessity of accounting for GL when considering surgical treatment., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Yokukansan, a traditional Japanese herbal medicine, has been used for the management of neurodegenerative disorders and for the treatment of neurosis, insomnia, and behavioral and psychological symptoms of dementia. Recently, several studies have shown that yokukansan has a neuroprotective effect. The aim of this study was to examine the neuroprotective effect of yokukansan on hippocampal neurons from embryonic mouse brain against the effects of corticosterone, which is considered to be a stress hormone and to be cytotoxic toward neurons. The cell survival rates were measured by the WST-8 assay and LDH assay. Twenty-four hours after treatment with corticosterone, cell numbers were significantly decreased compared with the control or treatment with vehicle in a dose-dependent manner. When cells were treated with 30 μM corticosterone, the decrease in the number of cells was significantly recovered by treatment with yokukansan (100-1,000 μg/ml) in a dose-dependent manner. However, yokukansan did not suppress the decrease in cell numbers that was induced by treatment with 100 μM corticosterone. In the LDH assay, treatment with yokukansan at a high concentration (500-1,000 μg/ml) suppressed the LDH concentration induced by treatment with both 30 μM and 100 μM corticosterone compared to treatment with corticosterone alone, respectively. These results suggest that yokukansan protects against the cytotoxic effect of a low concentration of corticosterone on hippocampal neurons., (Copyright © 2014 Elsevier GmbH. All rights reserved.)

Prolyl hydroxylase domain (PHD) proteins catalyze oxygen-dependent prolyl hydroxylation of hypoxia-inducible factor 1α and 2α, tagging them for pVHL-dependent polyubiquitination and proteasomal degradation. In this study, albumin Cre (Alb(Cre))-mediated, hepatocyte-specific triple disruption of Phd1, Phd2, and Phd3 (Phd(1/2/3)hKO) promoted liver erythropoietin (EPO) expression 1246-fold, whereas renal EPO was down-regulated to 6.7% of normal levels. In Phd(1/2/3)hKO mice, hematocrit levels reached 82.4%, accompanied by severe vascular malformation and steatosis in the liver. In mice double-deficient for hepatic PHD2 and PHD3 (Phd(2/3)hKO), liver EPO increase and renal EPO loss both occurred but were much less dramatic than in Phd(1/2/3)hKO mice. Hematocrit levels, vascular organization, and liver lipid contents all appeared normal in Phd(2/3)hKO mice. In a chronic renal failure model, Phd(2/3)hKO mice maintained normal hematocrit levels throughout the 8-week time course, whereas floxed controls developed severe anemia. Maintenance of normal hematocrit levels in Phd(2/3)hKO mice was accomplished by sensitized induction of liver EPO expression. Consistent with such a mechanism, liver HIF-2α accumulated to higher levels in Phd(2/3)hKO mice in response to conditions causing modest systemic hypoxia. Besides promoting erythropoiesis, EPO is also known to modulate retinal vascular integrity and neovascularization. In Phd(1/2/3)hKO mice, however, neonatal retinas remained sensitive to oxygen-induced retinopathy, suggesting that local EPO may be more important than hepatic and/or renal EPO in mediating protective effects in the retina., (Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Deficiencies in prolyl hydroxylase domain proteins (PHDs) may lead to the accumulation of hypoxia-inducible factor-α proteins, the latter of which activate local angiogenic responses by paracrine mechanisms. Here, we investigate whether a keratinocyte-specific PHD deficiency may promote vascular survival and growth in a distantly located ischemic tissue by a remote signaling mechanism. We generated mice that carry a keratinocyte-specific Phd2 knockout (kPhd2KO) and performed femoral artery ligation. Relative to wild-type controls, kPhd2KO mice displayed improved vascular survival and arteriogenesis in ischemic hind limbs, leading to the accelerated recovery of hindlimb perfusion and superior muscle regeneration. Similar protective effects were also seen in type 1 and type 2 diabetic mice. Molecularly, both abundance of hypoxia-inducible factor-1α protein and expression of vascular endothelial growth factor-A were increased in epidermal tissues of kPhd2KO mice, accompanied by increased plasma concentration of vascular endothelial growth factor-A. Contrary to kPhd2KO mice, which are PHD2 deficient in all skin tissues, localized kPhd2KO in hindlimb skin tissues did not have similar effects, excluding paracrine signaling as a major mechanism. Confirming the existence of remote effects, hepatocyte-specific Phd2 knockout also protected hind limbs from ischemia injury. These data indicate that vascular survival and growth in ischemia-injured tissue may be stimulated by suppressing PHD2 in a remotely located tissue and may provide highly effective angiogenesis therapies without the need for directly accessing target tissues., (Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

The aim of the present study was to examine the effect of yokukansan, a traditional Japanese herbal medicine that is composed of Atractylodis lanceae Rhizoma, Poria, Cnidii Rhizoma, Uncariae Uncis cum Ramulus, Angelicae Radix, Bupleuri Radix and Glycyrrhizae Radix, on the emotional abnormality induced by maladaptation to stress in mice. Mice were exposed to repeated restraint stress for 60 or 240 min/day for 14 days. From the 3rd day of stress exposure, mice were given yokukansan orally (p.o.) or the 5-HT1A receptor agonist flesinoxan intraperitoneally (i.p.) immediately after the daily exposure to restraint stress. After the final exposure to restraint stress, the emotionality of mice was evaluated using an automatic hole-board apparatus. A single exposure to restraint stress for 60 min induced a decrease in head-dipping behavior in the hole-board test. This emotional stress response disappeared in mice that had been exposed to repeated restraint stress for 60 min/day for 14 days, which confirmed the development of stress adaptation. In contrast, mice that were exposed to restraint stress for 240 min/day for 14 days did not develop this stress adaptation, and still showed a decrease in head-dipping behavior. The decreased emotionality observed in stress-maladaptive mice was significantly recovered by chronic treatment with yokukansan (1000 mg/kg, p.o.) as well as flesinoxan (0.25 and 0.5 mg/kg, i.p.) immediately after daily exposure to stress. These findings suggest that yokukansan may have a beneficial effect on stress adaptation and alleviate the emotional abnormality under conditions of excessive stress., (Copyright © 2013 Elsevier GmbH. All rights reserved.)

Cancer is a major cause of death, and the development of new anticancer drugs is urgently needed. Invasion and metastasis are the primary causes of death due to cancer rather than growth of the primary tumor. In the current study, we examined the anti-invasive effects of p-dodecylaminophenol (1), which was developed based on N-(4-hydroxyphenyl)retinamide (2), a synthetic amide of all-trans-retinoic acid (3). In HT1080 cells 1 inhibited growth, induced apoptosis and arrested the cell cycle in S phase in a dose-dependent manner. In addition, 1 significantly suppressed cell invasion, and the activity and mRNA expression of matrix metalloproteinase-9 (MMP-9). Furthermore, the expression of the reversion-inducing cysteine-rich protein with Kazal motifs (RECK), which is a negative regulator of MMP-9, was increased by treatment with 1. These results suggest that 1 could be an effective anti-cancer agent that suppresses cell growth through apoptosis induction and cell cycle arrest, which also inhibits cell invasion by decreasing MMP-9 expression due to an increase in RECK. Compound 1 might be useful clinically as a new and potent anticancer agent that could overcome adverse side effects of the retinoids., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

An electromyogram (EMG)-driven neuromuscular stimulator for upper limb functional recovery (Muraoka et al., 1998) can stimulate target muscles in proportion to the amount of voluntary EMG of the identical target muscles. Furthermore, it can facilitate the contraction of paralyzed muscles by electrical stimulation at subthreshold intensity level. Although it has been suggested that to use the stimulator for as long a time as possible might be needed for more effective treatment, the utilization time was limited by the size of the stimulator, which involved a laptop personal computer. To use in daily life, the device was improved to be a smaller size of 95×65×40 mm (including batteries) which was equivalent to a mobile phone (in 2002). The stimulator was called the Integrated Volitional-control Electrical Stimulator (IVES). IVES has already been manufactured and its use has spread in Japan since 2008. Nowadays, therapy using IVES is an effective therapy to improve the motor function of the upper limb in post-stroke patients with hemiparesis. However, the signal processing and internal structure of IVES has not yet been reported. In this study the device specification of IVES is described, especially its electrical circuits and signal processing that detect voluntary EMG and stimulate from the same electrodes. IVES uses two DIACs for detecting voluntary EMG from stimulating electrodes. The DIACs switch passively between the stimulation circuit and the EMG amplifier circuit. Furthermore, the signal processing of the time-shifted difference of the 2-cycle EMG signal following identical stimulation pulses eliminates stimulation artifacts and evoked potentials, and extracts voluntary EMG.

Background: We developed an electroencephalogram-based brain computer interface system to modulate functional electrical stimulation (FES) to the affected tibialis anterior muscle in a stroke patient. The intensity of FES current increased in a stepwise manner when the event-related desynchronization (ERD) reflecting motor intent was continuously detected from the primary cortical motor area., Methods: We tested the feasibility of the ERD-modulated FES system in comparison with FES without ERD modulation. The stroke patient who presented with severe hemiparesis attempted to perform dorsiflexion of the paralyzed ankle during which FES was applied either with or without ERD modulation., Results: After 20 minutes of training, the range of movement at the ankle joint and the electromyography amplitude of the affected tibialis anterior muscle were significantly increased following the ERD-modulated FES compared with the FES alone., Conclusions: The proposed rehabilitation technique using ERD-modulated FES for stroke patients was feasible. The system holds potentials to improve the limb function and to benefit stroke patients.

Recently there has been an increase in the number of stroke patients with motor paralysis. Appropriate re-afferent sensory feedback synchronized with a voluntary motor intention would be effective for promoting neural plasticity in the stroke rehabilitation. Therefore, BCI technology is considered to be a promising approach in the neuro-rehabilitation. To estimate human motor intention, an event-related desynchronization (ERD), a feature of electroencephalogram (EEG) evoked by motor execution or motor imagery is usually used. However, there exists various factors that affect ERD production, and its neural mechanism is still an open question. As a preliminary stage, we evaluate mutual effects of intrinsic (voluntary motor imagery) and extrinsic (visual and somatosensory stimuli) factors on the ERD production. Experimental results indicate that these three factors are not always additively interacting with each other and affecting the ERD production.

Retinopathy of prematurity is a major side effect of oxygen therapy for preterm infants, and is a leading cause of blindness in children. To date, it remains unclear whether the initial microvascular obliteration is triggered by degradation of hypoxia inducible factor (HIF) α proteins or by other mechanisms such as oxidative stress. Here we show that prolyl hydroxylase domain protein 2 (PHD2), an enzyme mostly responsible for oxygen-induced degradation of HIF-α proteins, plays a major role in oxygen-induced retinopathy in mice. In neonatal mice expressing normal amounts of PHD2, exposure to 75% oxygen caused significant degradation of retinal HIF-α proteins, accompanied by massive losses of retinal microvessels. PHD2 deficiency significantly stabilized HIF-1α, and to some extent HIF-2α, in neonatal retinal tissues, and protected retinal microvessels from oxygen-induced obliteration. After hyperoxia-treated neonatal mice were returned to ambient room air, retinal vasculature in PHD2-deficient mice remained mostly intact and showed very little neoangiogenesis. These findings demonstrate a close association between PHD2-dependent HIF-α degradation and oxygen-induced retinal microvascular obliteration, and imply that PHD2 may be a promising therapeutic target to prevent oxygen-induced retinopathy., (Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Sensory disturbance is very common following stroke and may exacerbate a patient's functional impairment, even if the patient has good motor function. For instance, patients with sensory disturbances will often grip an object with excessive or underestimated pinch pressure, because they do not receive the appropriate sensory feedback and must rely only on visual feedback. In this study, we developed a sensory feedback system that used cutaneous electrical stimulation for patients with sensory loss. In the system, electrical stimulation is modulated by the strength of pinch pressure and the patients are able to identify their fingertip pinch pressure. To evaluate the efficacy of the system, a clinical case study was conducted in a stroke patient with severe sensory loss. The fluctuation in force control during grasping was gradually decreased as the training progressed and the patient was able to maintain a stable pinch pressure during grasping even without the system following 2 months of intervention. We conclude that the system described in this study may be a useful contribution towards the rehabilitation of patients with sensory loss., (© 2011 IEEE)

Objective: Prolyl hydroxylase domain-containing proteins (PHDs) play pivotal roles in oxygen-sensing system through the regulation of alpha-subunit of hypoxia-inducible factor (HIF), a key transcription factor governing a large set of gene expression to adapt hypoxia. Although tissue hypoxia plays an essential role in maintaining inflammation, the role of PHDs in the inflammatory responses has not been clearly determined. Here, we investigated the role of PHDs in lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNF-alpha) induction in macrophages., Methods and Results: Northern blot analysis and ELISA revealed that LPS-induced TNF-alpha upregulation was strongly suppressed by PHD inhibitors, dimethyloxallyl glycine (DMOG), and TM6008 in RAW264.7 macrophages. DMOG suppressed LPS-induced TNF-alpha upregulation in HIF-1alpha-depleted cells and HIF-1alpha overexpression failed to suppress the induction of TNF-alpha. DMOG rather suppressed LPS-induced NF-kappaB transcriptional activity. Downregulation of Phd1 or Phd2 mRNA by RNA interference partially attenuated LPS-induced TNF-alpha induction. DMOG also inhibited LPS-induced TNF-alpha production in peritoneal macrophages as well as human macrophages., Conclusions: PHD inhibition by DMOG or RNA interference inhibited LPS-induced TNF-alpha upregulation in macrophages possibly through NF-kappaB inhibition, which is independent of HIF-1alpha accumulation. This study suggests that PHDs are positive regulators of LPS-induced inflammatory process, and therefore inhibition of PHD may be a novel strategy for the treatment of inflammatory diseases.

Telmisartan, an angiotensin II type 1 receptor antagonist, was reported to be a partial agonist of peroxisome proliferator-activated receptor-gamma. Although peroxisome proliferator-activated receptor-gamma activators have been shown to have an anti-inflammatory effect, such as inhibition of cytokine production, it has not been determined whether telmisartan has such effects. We examined whether telmisartan inhibits expression of interleukin-6 (IL-6), a proinflammatory cytokine, in vascular smooth muscle cells. Telmisartan, but not valsartan, attenuated IL-6 mRNA expression induced by tumor necrosis factor-alpha (TNF-alpha). Telmisartan decreased TNF-alpha-induced IL-6 mRNA and protein expression in a dose-dependent manner. Because suppression of IL-6 mRNA expression was prevented by pretreatment with GW9662, a specific peroxisome proliferator-activated receptor-gamma antagonist, peroxisome proliferator-activated receptor-gamma may be involved in the process. Telmisartan suppressed IL-6 gene promoter activity induced by TNF-alpha. Deletion analysis suggested that the DNA segment between -150 bp and -27 bp of the IL-6 gene promoter that contains nuclear factor kappaB and CCAAT/enhancer-binding protein-beta sites was responsible for telmisartan suppression. Telmisartan attenuated TNF-alpha-induced nuclear factor kappaB- and CCAAT/enhancer-binding protein-beta-dependent gene transcription and DNA binding. Telmisartan also attenuated serum IL-6 level in TNF-alpha-infused mice and IL-6 production from rat aorta stimulated with TNF-alpha ex vivo. These data suggest that telmisartan may attenuate inflammatory process induced by TNF-alpha in addition to the blockade of angiotensin II type 1 receptor. Because both TNF-alpha and angiotensin II play important roles in atherogenesis through enhancement of vascular inflammation, telmisartan may be beneficial for treatment of not only hypertension but also vascular inflammatory change.

Polycythemia is often associated with erythropoietin (EPO) overexpression and defective oxygen sensing. In normal cells, intracellular oxygen concentrations are directly sensed by prolyl hydroxylase domain (PHD)-containing proteins, which tag hypoxia-inducible factor (HIF) alpha subunits for polyubiquitination and proteasomal degradation by oxygen-dependent prolyl hydroxylation. Here we show that different PHD isoforms differentially regulate HIF-alpha stability in the adult liver and kidney and suppress Epo expression and erythropoiesis through distinct mechanisms. Although Phd1(-/-) or Phd3(-/-) mice had no apparent defects, double knockout of Phd1 and Phd3 led to moderate erythrocytosis. HIF-2alpha, which is known to activate Epo expression, accumulated in the liver. In adult mice deficient for PHD2, the prototypic Epo transcriptional activator HIF-1alpha accumulated in both the kidney and liver. Elevated HIF-1alpha levels were associated with dramatically increased concentrations of both Epo mRNA in the kidney and Epo protein in the serum, which led to severe erythrocytosis. In contrast, heterozygous mutation of Phd2 had no detectable effects on blood homeostasis. These findings suggest that PHD1/3 double deficiency leads to erythrocytosis partly by activating the hepatic HIF-2alpha/Epo pathway, whereas PHD2 deficiency leads to erythrocytosis by activating the renal Epo pathway.

Motor functional recovery after stroke may be attributable to cerebral reorganization. We used near-infrared spectroscopy, which measures non-invasively the changes in oxy- and deoxy-hemoglobin concentrations in response to neural activation, for monitoring cerebral activation in stroke patients, and investigated the longitudinal changes in functional laterality of activations in the primary sensorimotor cortex during unilateral audio-paced (1 Hz) hand movement. We examined five ischemic stroke patients (4 females and 1 male, 52-67 years old) with mild to moderate hemiparesis at acute stages and chronic stages at least 1 month later. Normal subjects (3 females and 2 males, 47-63 years old) were also included. Unilateral hand movement activated predominantly the contralateral primary sensorimotor cortex in the normal subjects and the stroke patients when they moved unaffected hand. Affected hand movements activated bilateral sensorimotor cortices early after stroke (< 25 days of stroke onset), whereas the activation pattern returned toward normal at later periods (> 35 days). The contralaterality index (0.34 +/- 0.12 in normal control) was reduced at early periods (0.00 +/- 0.03, p < 0.01) after stroke, and returned to normal (0.35 +/- 0.24) as motor function recovered. These findings suggest that a transient increase in motor activation in the ipsilateral intact hemisphere within 1 month may play an important role in the recovery from motor dysfunction after stroke.

PHD1, PHD2, and PHD3 are prolyl hydroxylase domain proteins that regulate the stability of hypoxia-inducible factor alpha subunits (HIF-alpha). To determine the roles of individual PHDs during mouse development, we disrupted all three Phd genes and found that Phd2(-/-) embryos died between embryonic days 12.5 and 14.5 whereas Phd1(-/-) or Phd3(-/-) mice were apparently normal. In Phd2(-/-) mice, severe placental and heart defects preceded embryonic death. Placental defects included significantly reduced labyrinthine branching morphogenesis, widespread penetration of the labyrinth by spongiotrophoblasts, and abnormal distribution of trophoblast giant cells. The expression of several trophoblast markers was also altered, including an increase in the spongiotrophoblast marker Mash2 and decreases in the labyrinthine markers Tfeb and Gcm1. In the heart, trabeculae were poorly developed, the myocardium was remarkably thinner, and interventricular septum was incompletely formed. Surprisingly, while there were significant global increases in HIF-alpha protein levels in the placenta and the embryo proper, there was no specific HIF-alpha increase in the heart. Taken together, these data indicate that among all three PHD proteins, PHD2 is uniquely essential during mouse embryogenesis.

We reported previously an important role of cyclic AMP-response element (CRE) for the induction of interleukin-6 gene expression by angiotensin II (AngII). We examined signaling pathways that are responsible for AngII-induced phosphorylation of CRE-binding protein (CREB) at serine 133 that is a critical marker for the activation in rat vascular smooth muscle cells (VSMC). AngII time dependently induced phosphorylation of CREB with a peak at 5 min. The AngII-induced phosphorylation of CREB was blocked by CV11974, an AngII type I receptor antagonist, suggesting that AngII type I receptor may mediate the phosphorylation of CREB. Inhibition of extracellular signal-regulated protein kinase (ERK) by PD98059 or inhibition of p38 mitogen-activated protein kinase (MAPK) by SB203580 partially inhibited AngII-induced CREB phosphorylation. A protein kinase A inhibitor, H89, also partially suppressed AngII-induced CREB phosphorylation. Inhibition of epidermal growth factor-receptor by AG1478 suppressed the AngII-induced CREB phosphorylation as well as activation of ERK and p38MAPK. Overexpression of the dominant negative form of CREB by an adenovirus vector suppressed AngII-induced c-fos expression and incorporation of [(3)H]leucine to VSMC. These findings suggest that AngII may activate multiple signaling pathways involving two MAPK pathways and protein kinase A, all of which contribute to the activation of CREB. Transactivation of epidermal growth factor-receptor is also critical for AngII-induced CREB phosphorylation. Activation of CREB may be important for the regulation of gene expression and hypertrophy of VSMC induced by AngII.