Plasma FGF23 levels and heart rate variability in patients with stage 5 CKD.

UNLABELLED: Fibroblast growth factor 23(FGF23) is a bone-derived hormone which regulates mineral homeostasis but may also have a role in cardiovascular disease. Here, we found that higher plasma FGF23 was independently associated with decreased heart rate variability in stage 5 CKD patients and parathyroidectomy may reverse these abnormal indicators. INTRODUCTION: Lower heart rate variability (HRV) in patients with chronic kidney disease (CKD) compared with healthy controls is associated with increased risk of cardiovascular disease (CVD). Higher levels of plasma FGF23 also predict higher risk of CVD. Here, we aimed to evaluate the relationship between plasma FGF23 levels and HRV in patients with stage 5 CKD and to investigate longitudinal changes of them together with the correlation between their changes in two severe secondary hyperparathyroidism (SHPT) subgroups with successful parathyroidectomy (PTX) and persistent SHPT. METHODS: This cross-sectional study included 100 stage 5 CKD patients, 78 controls, and a prospective study in two PTX subgroups classified as successful PTX (n = 24) and persistent SHPT (n = 4) follow-up. Blood examination and 24-h Holter monitoring for HRV were measured. RESULTS: Most HRV indices were lower in stage 5 CKD patients than in healthy controls, and plasma FGF23 levels were higher. In multivariate stepwise regression models, levels of plasma FGF23 and serum parathyroid hormone (PTH) were correlated with HRV. The successful PTX subgroup had significant improvements over baseline in HRV indices. Persistent SHPT subgroup had numerically similar changes in HRV indices. However, plasma FGF23 levels decreased in both subgroups. CONCLUSIONS: Plasma FGF23 levels were higher in CKD patients than in controls, much higher in patients with severe SHPT. FGF23 was independently associated with decreased HRV in stage 5 CKD. Successful PTX may reverse these abnormal indicators and contribute to decreases in the risk of cardiovascular disease.

Total parathyroidectomy with autotransplantation for a rare disease derived from uremic secondary hyperparathyroidism, the uremic leontiasis ossea.

SUMMARY: We described six uremic leontiasis ossea (ULO) patients who underwent total parathyroidectomy with autotransplantation. ULO demonstrated more a systemic disease than a simple craniofacial deformation. The surgery seemed an effective treatment to alleviate secondary hyperparathyroidism and to improve patients' quality of life. ULO may have a high postoperative recurrence tendency. INTRODUCTION: ULO is a rare disease derived from uremic secondary hyperparathyroidism (SHPT). Previous studies mostly focused on the craniofacial deformations. This study aims to investigate the systemic features of the disease and the surgical outcomes. METHODS: The present study retrospectively assessed six ULO patients who underwent total parathyroidectomy (TPTX) with autotransplantation (AT). Follow-up data were recorded. The follow-up status was considered as "effectiveness" if serum intact parathyroid hormone (iPTH) levels were <150 pg/mL in the first 3 days after surgery, or as "recurrence" if serum iPTH gradually increased >300 pg/mL during follow-up in patients whose status was initially considered as "effectiveness". RESULTS: Craniofacial deformations, short stature, thoracocyllosis, spine malformations, osteodynia, and muscle weakness were observed in all patients. Abnormal pulmonary functions were observed in five patients. After surgery, one patient died from respiratory failure. Surgery was effective in the remaining five patients with relieved osteodynia and stopped craniofacial deformation. A mean follow-up of 7.6 (4 to 12) months was available. Three patients suffered from recurrence of hyperparathyroidism originating from autografts. CONCLUSIONS: Our data suggests that ULO is not only a simple disease with craniofacial malformations but is a severe systemic disease leading to increased surgical risks. TPTX with AT seems an effective treatment to relieve SHPT and to improve quality of life. ULO may have a high postoperative recurrence tendency.

Three distinct motifs within the C-terminus of acid-sensing ion channel 1a regulate its surface trafficking.

Various protein motifs play a key role in regulating protein biogenesis and trafficking. Here, we discovered that three distinct motifs regulate the trafficking of acid-sensing ion channel 1a (ASIC1a), the primary neuronal proton receptor which plays critical roles in neurological diseases including stroke, multiple sclerosis and seizures. Mutating the PDZ binding motif of ASIC1a increased its surface expression and current density. In contrast, mutating either a RRGK motif or a KEAKR motif reduced ASIC1a surface expression and acid-activated current density. Mutating or deleting the RRGK motif also reduced pH sensitivity and the rate of desensitization of ASIC1a. These changes were likely due to a change in ASIC1a biogenesis; mutating either the RRGK or KEAKR motif reduced N-glycosylation of ASIC1a while mutating the PDZ binding motif had the opposite effect. Our results demonstrate that these C-terminal motifs are important for ASIC1a trafficking and channel function. In addition, in contrast to multiple previous studies, which all show that K/R containing motifs lead to endoplasmic reticulum (ER) retention, our findings indicate that these motifs can also be required for efficient trafficking.

The dynamic change of circulating tumour cells in patients with operable breast cancer before and after chemotherapy based on a multimarker QPCR platform.

BACKGROUND: The possible presence of early tumour dissemination is the rationale behind the use of systemic adjuvant chemotherapy in patients with operable breast cancer. Circulating tumour cells (CTC) in peripheral blood may represent the possible presence of early tumour dissemination. However, relatively few studies were designed to investigate the relationship between the change of CTC status and the efficacy of adjuvant chemotherapy in operable breast cancer patients. METHODS: In a prospective study, we established a multimarker real-time quantitative PCR platform to detect CTC in peripheral blood of breast cancer patients. By using this platform, we detected CTC in peripheral blood of 94 operable breast cancer patients. Control group consisted of 20 patients with benign breast disease and 20 healthy volunteers. For 72 patients who underwent systemic adjuvant chemotherapy, the dynamic CTC status at three different time points (1 day before initiation of chemotherapy, 1 week after three cycles of chemotherapy and 1 week after all cycles of chemotherapy) was observed. RESULTS: Circulating tumour cells were detected in 56% (53 out of 94) of patients with operable breast cancer. The specificity was 95%. Seventy-two patients who received systemic adjuvant chemotherapy were followed up. After three cycles of chemotherapy, 47% (18 out of 38) of patients who were CTC-positive before chemotherapy changed into negative status. In addition, another 5% (2 out of 38) of patients had changed into negative status after all cycles of chemotherapy. CONCLUSION: Systemic adjuvant chemotherapy had a significant impact on CTC status, and this effect could be observed after three cycles of chemotherapy. Circulating tumour cells detection had the potential to be used to evaluate the efficacy of systemic adjuvant chemotherapy immediately after the chemotherapy was finished in operable breast cancer patients.

BDNF synthesis in spiral ganglion neurons is constitutive and CREB-dependent.

Brain-derived neurotrophic factor (BDNF), which supports spiral ganglion neuron (SGN) survival in vivo and in vitro, is synthesized by SGNs. The BDNF gene generates multiple different transcripts, each from its own promoter region. Using reverse transcriptase-polymerase chain reaction (RT-PCR), we find that SGNs express only the downstream transcripts III and IV in vivo and in vitro. Using RT-PCR assays of BDNF transcripts and transfection of BDNF promoter-reporter constructs, we tested the hypothesis, originally derived from studies of cortical neurons, that depolarization induces BDNF expression via a signaling pathway that includes Ca2+/calmodulin-dependent kinases (CaMKs) and the transcription factor, Ca2+/cyclic AMP response element binding protein (CREB). In contrast, we found that in SGNs in vivo BDNF expression is constitutive and is not increased by electrical activation. Similarly, BDNF expression in vitro is not increased by stimuli that activate CREB, including depolarization, cAMP, or transfection of activated CaMK mutants. However, transfection of dominant-negative CREB mutants did abrogate gene expression driven by BDNF promoters III and IV, indicating that CREB is necessary for constitutive BDNF expression. Thus, BDNF synthesis within SGNs makes possible an autocrine or paracrine mechanism that can contribute to support SGN survival but SGNs are distinctive in that this mechanism is constitutive and not activity-regulated.

Multiple distinct signal pathways, including an autocrine neurotrophic mechanism, contribute to the survival-promoting effect of depolarization on spiral ganglion neurons in vitro.

We have shown previously that BDNF, neurotrophin-3 (NT-3), chlorphenylthio-cAMP (cpt-cAMP) (a permeant cAMP analog), and membrane depolarization promote spiral ganglion neuron (SGN) survival in vitro in an additive manner, depolarization having the greatest efficacy. Expression of both BDNF and of NT-3 is detectable in cultured SGNs after plating in either depolarizing or nondepolarizing medium. These neurotrophins promote survival by an autocrine mechanism; TrkB-IgG or TrkC-IgG, which block neurotrophin binding to, respectively, TrkB and TrkC, partially inhibit the trophic effect of depolarization. The mitogen-activated protein kinase kinase inhibitor PD98059 and the phosphatidylinositol-3-OH kinase inhibitor LY294002 both abolish trophic support by neurotrophins but only partially inhibit support by depolarization. Inhibition by these compounds is not additive with inhibition by Trk-IgGs. The cAMP antagonist Rp-adenosine-3',5'-cyclic-phosphorothioate (Rp-cAMPS) abolishes survival attributable to cpt-cAMP but has no effect on that attributable to neurotrophins, nor do inhibitors of neurotrophin-dependent survival affect survival attributable to cpt-cAMP. However, Rp-cAMPS does partially inhibit depolarization-dependent survival, an inhibition that is additive with that by Trk-IgGs, PD98059, or LY294002. Moreover, Rp-cAMPS prevents depolarization-dependent survival of PC12 cells maintained in subthreshold levels of NGF. Inhibition of Ca(2+)/calmodulin-dependent protein kinases (CaMKs) with KN-62 reduces SGN survival independently of Rp-cAMPS, Trk-IgGs, and LY294002 and additively with them. Combined inhibition of Trk, cAMP, and CaMK signaling prevents depolarization-dependent survival. Thus, survival of SGNs under depolarizing conditions involves additivity among a depolarization-independent autocrine pathway, a cAMP-dependent pathway, and a CaMK-dependent pathway.

[Morphologic study of GABA-ergic neurons in dissociated cell culture of spinal cord and dorsal root ganglion].

gamma-Aminobutyric acid (GABA) is an important inhibitive neurotransmitter in central nervous system (CNS). Many studies have been made about the distribution of GABA-ergic neurons in the spinal cord (SC), but little is known about the morphology of GABA-ergic spinal cord neuron (SCN) in culture. Moreover, whether GA-BA-ergic neuron existed in dorsal root ganglion (DRG) or not is still under discussion. Considering together with the fact that the same neuron can synthesize different. kinds of neurotransmitter in different periods of development, we find that it is attractive to study the GABA immunoreactivity of cultured SCNs and DRG cells. The SC and DRG were dissected from 12-14 day old mouse (C57BL/6J) embryo and plated at a density of 1 x 10(6)-2 x 10(6) cells per dish. At 5 day in vitro (DIV), the cells reaggregate and form complicated neurite network. While SCNs varies in the morphology of cell body and neurite, DRG cells of different sizes can be easily discriminated by their round cell bodies and sharply defined nuclei and nucleoli, and their sizes do not undergo major change during the culture period. Immunoreaction was performed by using a polyclonal anti-GABA serum (rabbit) and PAP procedure. Two types of immunoreactive SCNs were observed: 1. SCNs with intensely positive reacted somata, nucleoli, and neurites. 2. SCNs with reactivity shown only on part or whole of neurites and cell membrane while the cell body is negative (to be considered as the result of GABA uptake).(ABSTRACT TRUNCATED AT 250 WORDS)