Anatomical study of the articular branches innervated the hip and knee joint with reference to mechanism of referral pain in hip joint disease patients

Introduction : Referred pain in the anterior knee joint is the most common symptom in hip disease patients. The development of referred pain is considered to be related to dichotomizing peripheral sensory fibers. However, no gross anatomical findings identify any dichotomizing fibers innervating both the hip and knee joints. We dissected the femoral and obturator nerves in human cadavers to investigate the distribution of the articular branches in the hip and knee joints. Fourteen embalmed left lower limbs from 14 Japanese adult cadavers (five from females, nine from males, average age 73.8 ± 14.1 years) were observed macroscopically. The articular branches of the femoral and obturator nerves were dissected at the anterior margin of the groin toward the thigh region. After dissections of the articular nerves of the hip joints, the femoral and obturator nerves were exposed from proximally to distally to identify the articular nerves of the knee joints. The branching pattern of the articular branches in the hip and knee joints was recorded. In six of 14 limbs (42.9%), the femoral nerve supplied articular branches to the anteromedial aspect of both the hip and knee joints. These articular branches were derived from the same bundle of femoral nerve. These gross anatomical findings suggested that dichotomizing peripheral sensory fibers innervate the hip and knee joints and these could relate to the referred pain confirmed in the anterior knee joints of patients with hip disease. Clin. Anat. 31:705–709, 2018. © 2018 Wiley Periodicals, Inc.     

Abnormal interaction between cognitive control network and affective network in patients with end-stage renal disease

End-stage renal disease (ESRD) is a common complicated disorder that is generally associated with an altered central nervous system and cognitive impairment. Neuroimaging studies have recorded aberrant brain circuits in patients with ESRD that were closely associated with abnormal clinical manifestations. However, whether the altered interaction was within and/or between these circuits is largely unclear. We investigated brain topological organization and/or module interaction by employing resting-state functional magnetic resonance imaging (rs-fMRI) and modularity network analysis in 24 patients with ESRD and 20 age- and gender-matched healthy control (HC) subjects. Stroop task was used to evaluate the performance of cognitive control in all subjects. At the global level, ESRD patients exhibited significantly decreased global and local efficiency which were mainly related to abnormal functional connectivity of the amygdala and inferior frontal gyrus (IFG). Stepwise regression analysis was applied to estimate the relationships between network efficiency and blood biochemistry level (urea, creatine, phosphate, Ca²⁺, hematocrit, cystatin, hemoglobin levels, parathyroid hormone, K⁺ and Na⁺), and only the hematocrit level was significantly associated with global efficiency in patients with ESRD. At the modular level, we discovered an aberrant brain interaction between the amygdala- and IFG-related circuits in the ESRD group, and the regional efficiency of the amygdala was observably relative to the performance of cognitive control in patients with ESRD. Our results suggested that ESRD exhibited aberrant brain functional topological organization and module-level interaction between the affective and cognitive control circuits, providing crucial insights into the pathophysiological mechanism of ESRD patients.     

Vascular endothelial growth factor receptor-1 regulates postnatal angiogenesis through inhibition of the excessive activation of Akt

Vascular endothelial growth factor (VEGF) binds both VEGF receptor-1 (VEGFR-1) and VEGF receptor-2 (VEGFR-2). Activation of VEGFR-2 is thought to play a major role in the regulation of endothelial function by VEGF. Recently, specific ligands for VEGFR-1 have been reported to have beneficial effects when used to treat ischemic diseases. However, the role of VEGFR-1 in angiogenesis is not fully understood. In this study, we showed that VEGFR-1 performs "fine tuning" of VEGF signaling to induce neovascularization. We examined the effects of retroviral vectors expressing a small interference RNA that targeted either the VEGFR-1 gene or the VEGFR-2 gene. Deletion of either VEGFR-1 or VEGFR-2 reduced the ability of endothelial cells to form capillaries. Deletion of VEGFR-1 markedly reduced endothelial cell proliferation and induced premature senescence of endothelial cells. In contrast, deletion of VEGFR-2 significantly impaired endothelial cell survival. When VEGFR-1 expression was blocked, VEGF constitutively activated Akt signals and thus induced endothelial cell senescence via a p53-dependent pathway. VEGFR-1(+/-) mice exhibited an increase of endothelial Akt activity and showed an impaired neovascularization in response to ischemia, and this impairment was ameliorated in VEGFR-1(+/-) Akt1(+/-) mice. These results suggest that VEGFR-1 plays a critical role in the maintenance of endothelial integrity by modulating the VEGF/Akt signaling pathway.     

Zn deficiency aggravates hypertension in spontaneously hypertensive rats: possible role of Cu/Zn-superoxide dismutase

Using spontaneously hypertensive rats (SHR) fed a standard or a Zn-deficient diet for 4 weeks, we examined whether Zn deficiency affects systemic blood pressure (BP) levels in a genetically hypertensive state through a fall in the activity of Cu/Zn-superoxide dismutase (SOD). SHR fed a Zn-deficient diet had a progressive increase in systolic BP during the dietary conditioning. Consequently, SHR fed a Zn-deficient diet exhibited significantly increased levels of systolic BP by 2 weeks after the start of dietary treatment when compared with SHR fed a standard diet. Similarly, levels of basal mean arterial pressure (MAP) observed at the end of dietary treatment were SHR fed a Zn-deficient diet > SHR fed a standard diet. Administration of the nitric oxide synthase (NOS) inhibitor, L-NAME, caused an increase in MAP levels in the two groups of rats, demonstrating the involvement of the vasodilator, nitric oxide (NO), in the regulation of systemic BP in a genetically hypertensive state. The expression of endothelial (e) NOS mRNA and protein in the thoracic aorta paralleled basal MAP levels in the two groups of rats, suggesting the counter-regulation of eNOS against the developed hypertensive state in SHR fed a Zn-deficient diet. On the other hand, administration of the superoxide scavenger, tempol (a SOD mimetic compound), led to a decrease in MAP levels in the two groups of rats, indicating the participation of the oxygen free radical, superoxide, in an increase in systemic BP in a genetically hypertensive state. As reported recently, the mechanism involved is due likely to a decrease in the action of the vasodilator, NO, based on the formation of peroxynitrite coming from the non-enzymatic reaction of superoxide and NO. In addition, tempol treatment completely restored MAP levels in SHR fed a Zn-deficient diet to levels comparable to those observed in SHR fed a standard diet, indicating that a further increase in systemic BP levels seen in SHR fed a Zn-deficient vs. a standard diet is presumably brought by a reduction in the action of the vasodilator, NO, resulting from an increase in the action of superoxide. The activity of the superoxide scavenger, Cu/Zn-SOD, in the thoracic aorta was significantly decreased in SHR fed a Zn-deficient diet relative to SHR fed a standard diet. It appears that a decrease in the activity of Cu/Zn-SOD observed in the thoracic aorta of SHR fed a Zn-deficient diet at least in part plays a role in an increase in the action of superoxide in this model. Thus, Zn deficiency may be a factor to develop genetic hypertension presumably through the oxidative stress caused by superoxide.     

Circadian dynamics of heart rate and physical activity in patients with heart failure

The present study was designed to develop a method to continuously measure Holter electrocardiogram (ECG) and physical activity in terms of metabolic costs to examine circadian dynamics of RR intervals and physical activity in patients with heart failure. A total of 7 healthy subjects and 3 heart failure patients performed cardiopulmonary exercise test using four-stage graded treadmill walking at 0% grade to examine whether the acceleration signals in the vertical direction could reflect actual body energy expenditure during physical activity. Then, using this new method, 24-hr monitorings of ECG and physical activity were performed in 24 inpatients with heart failure while they were allowed to walk around freely. Our results showed the integral of rectified acceleration signals was closely correlated with actual metabolic cost in all subjects. Instantaneous changes in heart rate were quite concordant with physical activity. As compared with the asymptomatic patients (n = 12), the symptomatic patients (n = 12) had lower energy expenditure during 8-hr daytime periods but higher mean heart rate. Furthermore, a more prominent ultradian rhythm of circadian changes in heart rate and physical activity was found in 50% of all subjects studied. The simultaneous analysis of Holter ECG and physical activity as the same time series revealed that in patients with heart failure, sympathovagal balance shifted toward sympathotonic conditions and their physical activity could become subject to intrinsic ultradian dynamics of body's homeostasis.     

Interaction between ACE and ADD1 gene polymorphisms in the progression of IgA nephropathy in Japanese patients

An interaction effect between the angiotensin-converting enzyme insertion/deletion (ACE I/D) and alpha-adducin (ADD1) Gly460Trp polymorphisms (G460W) on blood pressure regulation has recently been suggested, although its significance in the prognosis of renal function in IgA nephropathy (IgAN) has not been fully investigated. Therefore, we evaluated the clinical manifestations and renal prognosis in 276 Japanese patients with histologically proven IgAN with respect to their ACE I/D and ADD1 G460W polymorphisms. The prognosis of renal function was analyzed by Kaplan-Meier survival curves and multivariate Cox proportional-hazards regression models. Baseline data, including blood pressures, proteinuria, renal function, and incidence of hypertension, were similar for the different genotypes of ACE and ADD1. The individual genotypes taken alone were not associated with the progression of renal dysfunction. However, renal survival of patients with the 460WW polymorphism of ADD1 was significantly worse within the group with the II genotype of ACE (Kaplan-Meier, log rank test; chi2=6.062, P=0.0138) but not for those with other ACE genotypes. In the Cox proportional-hazards regression model with adjustment for clinical risk factors, including hypertension, proteinuria, and no administration of an angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, the 460WW variant of ADD1 was a highly significant and independent risk factor only for patients with the ACE II genotype, with a hazard ratio of 3.65 (P=0.0016), but not for those with other ACE genotypes (hazard ratio=0.65, P=0.2902). These findings suggest an interaction between ACE and ADD1 polymorphisms not only on blood pressure regulation but also on the progression of renal dysfunction in patients with IgAN.