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Objective: Perioperative anxiety and depression syndrome (PADS) is a common clinical concern among women with systemic tumors. Esketamine has been considered for its potential to alleviate anxiety and depressive symptoms. However, its specific application and effectiveness in PADS among women with systemic tumors remain unclear. This study aimed to analyze the utility of Machine Learning (ML) algorithms based on electroencephalogram (EEG) signals in evaluating perioperative anxiety and depression in women with systemic tumors treated with Esketamine, utilizing a large-scale medical data background., Patients and Methods: A single-center, randomized, placebo-controlled (SC-RPC) trial design was adopted. A total of 112 female patients with systemic tumors and PADS who received Esketamine treatment were included as study participants. A moderate dose (0.7 mg/kg) of Esketamine was administered through intravenous infusion over a duration of 60 minutes. EEG signals were collected from all patients, and the EEG signal features of individuals with depression were compared to those without depression. In this study, a Support Vector Machine (SVM)-K-Nearest Neighbour (KNN) hybrid classifier was constructed based on SVM and KNN algorithms. Using the EEG signals, the classifier was utilized to assess the anxiety and depression status of the patients. The predictive performance of the classifier was evaluated using accuracy, sensitivity, and specificity measures., Results: The C2 correntropy feature of the delta rhythm in the left-brain EEG signal was significantly higher in individuals with depression compared to those without depression (p<0.05). Moreover, the C2 correntropy feature of the Alpha, Beta, and Gamma rhythms in the left-brain EEG signal was significantly lower in individuals with depression compared to those without depression (p<0.05). In the right brain EEG signal, the C2 correntropy feature of the delta rhythm was significantly higher in individuals with depression (p<0.05), while the C2 correntropy feature of the alpha and gamma rhythms was significantly lower in individuals with depression compared to those without depression (p<0.05). Additionally, the C1 correntropy feature of the Gamma rhythm in the right brain EEG signal was significantly higher in individuals with depression compared to those without depression (p<0.05). The SVM classifier achieved accuracy, sensitivity, and specificity of 98.23%, 98.10%, and 98.56%, respectively, in recognizing the left-brain EEG signals, with a correlation coefficient of 0.95. In recognizing the right brain EEG signals, the SVM classifier achieved accuracy, sensitivity, and specificity of 98.74%, 98.43%, and 99.03%, respectively, with a correlation coefficient of 0.96. The improved SVM-KNN approach yielded an accuracy, recall, precision, F-score, area over the curve (AOC), and Receiver Operation Characteristics (ROC) of 0.829, 0.811, 0.791, 0.853, 0.787, and 0.877, respectively, in predicting anxiety. For predicting depression, the accuracy, recall, precision, F-score, AOC, and ROC were 0.869, 0.842, 0.831, 0.893, 0.827, and 0.917, respectively., Conclusions: Significant differences were observed in the brain EEG signals between individuals with depression and those without depression. The improved SVM-KNN algorithm developed in this study demonstrates good predictive capability for anxiety and depression.

Objective: To investigate the effectiveness of percutaneous pedicle screw fixation combined expandable tubular retractor in the treatment of patients with spinal metastases., Methods: In the study, 12 patients of spinal metastases treated with percutaneous pedicle screw fixation combined expandable tubular retractor in our hospital were retrospectively reviewed between June 2017 and October 2019. Among the 12 patients, 9 were males and 3 were females; the median age was 62.5 years [(65.1±2.9) years]. The decompression segment of 7 patients was located at the lower thoracic spine (including 1 patient with incomplete paraplegia) and the decompression segment of 5 patients was located at the lumbar spine; Tomita score was 6.0±0.6. Perioperative data of the patients were reviewed. Visual analog scale (VAS score), Karnofsky score, and Eastern Cooperative Oncology Group (ECOG) score were compared before and after surgery. The patient's survival, adjuvant treatment, and internal fixation failure were observed in the follow-up period., Results: All the 12 patients had a successful operation with percuta-neous pedicle screw fixation combined expandable tubular retractor. The average operative time, blood loss, and blood transfused of the patients were (247.0±14.6) min, (804.2±222.3) mL and (500.0±100.0) mL, respectively. The average amount of drainage was (240.8±79.3) mL. Drainage tubes were pulled out early postoperative [(3.2±0.3) d], allowing early mobilization. The patients discharged (7.8±0.8) d postoperative. All the patients were followed up for 6-30 months, and the average overall survival time was (13.6±2.4) months. During the follow-up period, 2 patients experienced screw displacement, the internal fixation was stable after conservative treatment and no revision surgery was performed. The VAS of the patients was 7.1±0.2 before surgery, which decreased to 2.3±0.1 and 2.8±0.4 at 3 and 6 months after surgery ( P < 0.05). The Karnofsky score of the patients was 59.2±1.9 before surgery, which increased to 75.0±1.9 and 74.2±3.1 at 3 and 6 months after surgery ( P < 0.05). The ECOG of the patients was 2.3±0.2 before surgery, which decreased to 1.7±0.1 and 1.7±0.2 at 3 and 6 months after surgery ( P < 0.05)., Conclusion: For selected patients with spinal metastases, minimally invasive surgical treatment of spinal metastases (percutaneous pedicle screw internal fixation combined with expandable tubular retractor) can effectively relieve the clinical symptoms and improve the quality of life, with satisfactory clinical outcome.

Objective: To summarize the genetic and clinical phenotypic characteristics of patients with early-onset myopathy, areflexia, respiratory distress and dysphagia (EMARDD) caused by multiple epidermal growth factor 10 (MEGF10) gene defect. Methods: The clinical data of 3 infants in 1 family with EMARDD caused by MEGF10 gene defect diagnosed in the Department of Neonatology, Xiamen Children's Hospital in April 2022 were analyzed retrospectively. Using "multiple epidermal growth factor 10" "myopathy" or "MEGF10" "myopathy" as the key words, and searching the relevant literature reports of CNKI, Wanfang Database and PubMed Database from the establishment of the database to September 2022. Combined with this family, the main clinical information and genotype characteristics of EMARDD patients caused by MEGF10 gene defect were summarized. Results: The proband, male, first infant of monozygotic twins, was admitted to hospital 7 days after birth "due to intermittent cyanosis with weak sucking". The infant had dysphagia accompanied with cyanosis of lips during feeding and crying after birth. Physical examination on admission revealed reduced muscle tone of the extremities, flexion of the second to fifth fingers of both hands with limited passive extension of proximal interphalangeal joints, and limited abduction of both hips. He was diagnosed as dysphagia of newborn, congenital dactyly. After admission, he was given limb and oral rehabilitation training, breathing gradually became stable and oral feeding fully allowed, and discharged along with improvement. The younger brother of the proband was admitted to the hospital at the same time, and his clinical manifestations, diagnosis and treatment process were the same as those of the proband. The elder brother of the proband died at the age of 8 months due to the delayed growth and development, severe malnutrition, hypotonia, single palmoclal crease and weak crying. A whole exon sequencing of the family was done, and found that the 3 children were all compound heterozygous variations at the same site of MEGF10 gene, with 2 splicing variants (c.218+1G>A, c.2362+1G>A), which came from the father and mother respectively, and the new variation was consistent with the autosomal recessive inheritance model. Three children were finally diagnosed as EMARDD caused by MEGF10 gene defect. There are 0 Chinese literature and 18 English literature that met the search conditions. Totally 17 families including 28 patients were reported. There were 31 EMARDD patients including 3 infants from this family. Among them, there were 13 males and 18 females. The reported age of onset ranged from 0 to 61 years. Except for 5 patients with incomplete clinical data, 26 patients were included in the analysis of phenotypic and genotypic characteristics. The clinical features were mainly dyspnea (25 cases), scoliosis (22 cases), feeding difficulties (21 cases), myasthenia (20 cases), and other features including areflexia (16 cases) and cleft palate or high palatal arch(15 cases). Muscle biopsy showed non-specific changes, with histological characteristics ranging from slight muscle fiber size variation to minicores change which was seen in all 5 patients with at least 1 missense mutation of allele. In addition, the adult onset was found in patients with at least 1 missense variant of MEGF10 gene. Conclusions: MEGF10 gene defect related EMARDD can occur in the neonatal period, and the main clinical features are muscle weakness, breathing and feeding difficulties. Patients with myopathy who have at least 1 missense mutation and muscle biopsy indicating minicores change may be relatively mild.

Objective: To investigate the effect of clinical factors on the pathogen culture results in the patients with pyogenic spondylitis, and to find out clinical controllable factors which could increase the positive rate of the pathogen culture., Methods: A retrospective study reviewed 40 patients who were diagnosed with pyogenic spondylitis in Peking University First Hospital from January 2011 to July 2017. The patients were divided into two groups depending on the culture results, culture negative or culture positive. The influence of clinical uncontrollable factors [the patient's age, gender, predisposing factors, infection site except spine, visual analogue score (VAS), course of disease, spinal segment, white blood cell (WBC), (neutrophilic granulocyte)% (NE%), the incidence of systemic inflammatory response syndrome (SIRS), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), the incidence of paravertebral abscess] and controllable factors (prior antibiotics exposure within 2 weeks, tissue homogenate, surgical approach) on pathogen culture results were analyzed., Results: Of the 40 patients, 18 patients were female and 22 patients were male. Causative germ was identified in 24/40 patients (60.00%) and dominant by gram positive cocci (68.00%). For clinical uncontrollable factors, there was no significant difference between the two groups in the patient's age, gender, predisposing factors, infection site except spine, VAS, course of disease, spinal segment, WBC, NE% and the incidence of SIRS. ESR [(94.38±6.91) mm/h, P=0.023)], CRP [(64.74±13.51) mg/L, P=0.040], and the incidence of paravertebral abscess (75%, P=0.018) in culture negative group were lower in contrast to culture positive group. For clinical controllable factors, prior antibiotics exposure within 2 weeks (P=0.058, OR=4.030, 95%CI: 0.956-16.993) and tissue homogenate (P=0.014, OR=0.171, 95%CI: 0.042-0.695) were significantly associated with the pathogen culture result. Surgical approach was not significantly associated with pathogen culture result., Conclusion: Patients with high level of ESR, CRP, and paravertebral abscess, would have high positive rate of pathogenic culture. Prior antibiotics exposure was associated with lower positive pathogen culture rate. Culture with tissue homogenate was more likely to find the causative germ, especially for patients without paravertebral abscess who had low level of ESR, CRP and prior antibiotics exposure.

Objective: To investigate the perioperative clinical characteristics of patients with pathological fracture of proximal femur., Methods: A retrospective study reviewed 28 patients who received proximal resection and tumor hemiarthroplasty for malignant proximal femoral tumor in Peking University First Hospital from January 2011 to February 2017. According to the fracture, the patients were divided into two groups: pathological fracture group and non-pathological fracture group. We investigated the clinical characteristics during perioperative period between the two groups., Results: Of the 28 patients, 14 (50.0%) patients suffered pathological fracture, and there was no significant difference between the two groups in the patient's age, gender, limb involvement, and tumor source (P>0.05). There was no significant difference between the two groups in hemoglobin (HGB), hematocrit (Hct), and lower extremity thrombosis. The albumin (ALB) of pathological fracture group were lower in contrast to non-pathological fracture group (P=0.031). There was no significant difference between the two groups in decline of HGB and Hct on postoperation day 1, operative time, bleeding during operation, time for walking with help of ambulation aid postoperative, and postoperative hospital stay (P>0.05). On post-operation day 7, HGB (P=0.025) and Hct (P=0.039) of pathological fracture group were significant lower in contrast to non-pathological fracture group. Whereas, the total blood loss calculated by Gross equation of pathological fracture group was significant higher in contrast to non-pathological fracture group [(2 066.3±419.8) mL vs. (786.0±152.6) mL, P=0.039]. The patient needed blood transfusion during operation (7/14 vs. 1/14, P=0.033) and postoperative (8/14 vs. 1/14, P=0.013) in pathological fracture group were more than in non-pathological fracture group. At last, Barthel daily life ability score (P=0.009) of pathological fracture group was lower in contrast to non-pathological fracture group, and visual analogue scale (VAS) score was higher (P<0.001). They were almost equal when the patients were discharged (P>0.05)., Conclusion: Patients with pathological fracture had lower ALB during perioperative period. Pathological fracture had no effect on operative time, bleeding during operation and function outcomes. However, the patients with pathological fracture had more total blood loss and lower HGB, Hct in contrast to the patients without pathological fracture. Blood transfusion was more needed in pathological fracture patients.

Objective: To investigate the clinical characteristics of the evoked nystagmus in the non-affected side during Dix-Hallpike test(D-H test)in unilateral posterior semicircular canal benign paroxysmal positional vertigo(PC-BPPV). Method: Two hundred and thirty-six patients were diagnosed with unilateral PC-BPPV in the Tinnitus and Dizziness clinic.Among them,14 patients exhibited positive nystagmus when the non-affected side was stimulated by D-H test. The clinical data from this subgroup of patients were retrospectively analyzed. Result: The upbeat and torsional nystagmus of 14 patients were all evoked by D-H test in the affected side. 11 cases were right PC-BPPV and 3 cases were left PC-BPPV. Among these 14 patients, 5 patients exhibited the upbeat and torsional nystagmus during D-H test in the non-affected side, which was in the same direction as that evoked in the affected side. Among them, 4 cases were right PC-BPPV and 1 case was left PC-BPPV. However, the downbeat nystagmus of the remaining 9 patients were evoked by D-H test in the non-affected side, in which 7 cases were right PC-BPPV and 2 cases were left PC-BPPV.The nystagmus and vertigo of all patients completely disappeared after performing the Epley or Semont repositioning maneuvers on the affected side. Conclusion: The bilateral positive nystagmus of unilateral PC-BPPV can be evoked by D-H test. The form of nystagmus on the non-affected side is related with the initial position of otoconia in affected semicircular canal and the moving direction of otoconia during the positional test. It is effective to perform Epley or Semont repositioning maneuvers on the affected side. Meanwhile, both the effect of maneuvers and the type of nystagmus evoked by D-H test can verify which side is affected., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Editorial Department of Journal of Clinical Otorhinolaryngology Head and Neck Surgery.)

Objectives: To determine bone morphogenetic proteins (BMPs) and Dickkopf homologue-1 (Dkk-1) levels in ankylosing spondylitis (AS)., Method: Serum BMPs and Dkk-1 were measured in 72 AS patients and 30 healthy controls. For AS patients, we recorded the demographic data, disease activity, functional index, and global assessment with questionnaires, and image changes with roentgenography. We also measured human leucocyte antigen-B27 and systemic inflammatory reactants., Results: BMPs were higher but Dkk-1 was significantly lower in AS patients than in controls. Dkk-1 was higher in AS patients who received non-steroidal anti-inflammatory drugs (NSAIDs) regularly in the past year (p = 0.001). Serum BMP-7 level and the BMP-7/Dkk-1 ratio correlated significantly with sacroiliitis severity, Bath Ankylosing Spondylitis Radiology Index (BASRI)-total, modified Stoke Ankylosing Spondylitis Spinal Score, and disease duration. There were also significant positive correlations among serum levels of BMP-2, -4, and -6, BASRI-total, and disease duration (p < 0.05). However, BMP-2/Dkk-1 was only significantly correlated with disease duration. The calculated area under the standard receiver operating characteristics curve suggested that BMP-2/Dkk-1 and serum BMP-2 are good indicators to predict disease activity, functional index, and patient global assessment in AS patients., Conclusion: BMPs and BMPs/Dkk-1 were significantly correlated with disease activity, and radiological and functional indices in AS patients. Dkk-1 was lower in AS patients than in controls. Among AS patients, Dkk-1 was higher in those taking NSAIDs regularly. BMP or Dkk-1 may be taken as a biomarker for disease severity or a treatment outcome predictor in AS, but this needs further study.

Two novel red phosphors KBaEu(XO 4 ) 3 (X = Mo, W) have been synthesized by high-temperature solid-state reactions and the crystal structures were determined for the first time. Single-crystal X-ray diffraction data reveal that their space groups are C2/c. The crystalline structure is constituted of K/BaO 8 distorted square antiprisms and distorted EuO 8 polyhedra which form chains lying along the c-axis and two kinds of distorted XO 4 tetrahedra. This high disorder of K/Ba which might lower the crystal field symmetry around Eu 3+ results in the high purity of red emission around 615 nm originating from 5 D 0 → 7 F 2 transition under near-ultraviolet (NUV) excitation. With increasing temperature, the luminescence of KBaEu(XO 4 ) 3 (X = Mo, W) phosphors decreases almost linearly with subtle alteration for the CIE coordinate. As the temperature reaches 550 K, the red emission intensity decreases to 37.3% and 50.7% of that at 300 K for KBaEu(MoO 4 ) 3 and KBaEu(WO 4 ) 3 , respectively. The analysis of the decay curves of the 5 D 0 → 7 F 2 emission at variable temperatures indicates the weak cross relaxation and non-radiative energy transfer between Eu 3+ ions. These results demonstrate that the investigated phosphors are attractive for application in high power NUV excited white LEDs.

Objective: There are limited data describing the clinical characteristics and prognosis of culture negative pyogenic spondylitis. The aim of this study was to investigate the treatment, prognosis and clinical characteristics of culture negative pyogenic spondylitis., Methods: A retrospective study reviewed 74 patients who were diagnosed with spondylitis in Peking University First Hospital from January 2010 to December 2015. A total of 27 patients suffered from pyogenic spondylitis. According to the pathogenic culture results, the patients were divided into two groups: culture negative group and culture positive group. The clinical characteristics and treatment outcomes between the two groups were compared., Results: The elder were more vulnerable to pyogenic spondylitis, and of the 27 patients, 12 patients were female and 15 male. All patients had no history of administration of antibiotics prior to obtaining culture samples. A causative germ was identified in 14/27 patients (51.9%) with Staphylococcus aureus being the most common pathogen. There was no significant difference between the two groups in the patient's age, gender, visual analogue score (VAS), predisposing factor, clinical symptom, sign and spinal segment (P>0.05). Erythrocyte sedimentation rate (ESR) (P=0.056) and C-reactive protein (CRP) (P=0.040) of culture negative group were lower in contrast to culture positive group. The incidence of vertebral abscess in culture negative group was higher than in culture positive group (P=0.046). After treatment, ESR dropped almost equally in both groups, and CRP dropped faster in the culture positive group (P=0.192). At last, there was no significant difference between the two groups in hospital stay, pain relief, open debridement operation rate, and recurrence rate of infection., Conclusion: ESR and CRP of the culture negative patient were lower than those of the culture positive patient, and the incidence rate of paravertebral abscess was higher than that of the culture positive patient. After administration of antibiotics, there was no significant difference between the two groups in duration of antibiotics, open debridement operation rate and recurrence rate of infection. So, culture negative may not necessarily be a negative prognostic factor for pyogenic spondylitis. However, we should watch out for the drug resistant bacteria or double infection, due to the long term use of wide-spectrum antibiotic in culture negative patients.

Phosphorylation of the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) at the Thr2609 cluster is essential for its complete function in DNA repair and tissue stem cell homeostasis. This phenomenon is demonstrated by congenital bone marrow failure occurring in DNA-PKcs(3A/3A) mutant mice, which require bone marrow transplantation (BMT) to prevent early mortality. Surprisingly, an increased incidence of spontaneous tumors, especially skin cancer, was observed in adult BMT-rescued DNA-PKcs(3A/3A) mice. Upon further investigation, we found that spontaneous γH2AX foci occurred in DNA-PKcs(3A/3A) skin biopsies and primary keratinocytes and that these foci overlapped with telomeres during mitosis, indicating impairment of telomere replication and maturation. Consistently, we observed significantly elevated frequencies of telomere fusion events in DNA-PKcs(3A/3A) cells as compared with wild-type and DNA-PKcs-knockout cells. In addition, a previously identified DNA-PKcs Thr2609Pro mutation, found in breast cancer, also induces a similar impairment of telomere leading-end maturation. Taken together, our current analyses indicate that the functional DNA-PKcs T2609 cluster is required to facilitate telomere leading strand maturation and prevention of genomic instability and cancer development.

End-pumped by a continuous-wave 976 nm diode laser, efficient 1522 nm laser operation was demonstrated in an Er:Yb:GdAl(3)(BO(3))(4) crystal when a sapphire crystal was used as a heat diffuser. A continuous-wave 1522 nm laser with a maximum output power of 750 mW and slope efficiency of 36% was realized at an absorbed pump power of 4.1 W. The pulse performances of an acousto-optic Q-switched laser with various repetition frequencies were investigated in detail. In a repetition frequency range of 1-10 kHz, 1522 nm pulse lasers with a slope efficiency of about 10%, peak output power at the kilowatt level, and width of about 50 ns were first obtained in an Er:Yb:GdAl(3)(BO(3))(4) crystal pumped by a continuous-wave diode laser. The results indicate that the crystal is a promising gain medium for an actively Q-switched 1.5 μm laser.

We investigated the effects of smoking and aging on proteins involved in the forkhead box O3 (FOXO3) signaling pathways in the lungs. Sixteen senescence-accelerated mouse-resistant 1 (SAMR1) and senescence-accelerated mouse-prone 8 (SAMP8) mice at 3 months of age were divided into a normally aged, smoke-exposed group (4 SAMR1 mice), a normally aged, air-exposed group (4 SAMR1 mice), an aging-accelerated, smoke-exposed group (4 SAMP8 mice), and an aging-accelerated, air-exposed group (4 SAMP8 mice). Expression of genes and proteins related to the FOXO3 signaling pathways in each group was examined by western blot analysis and immunohistochemistry. FOXO3a expression was significantly increased in the normally aged, air-exposed group compared with the aging-accelerated, air-exposed group. FOXO3a expression was significantly reduced in the aging-accelerated, smoke-exposed group compared with the aging-accelerated, air-exposed group. Sirtuin 1, manganese superoxide dis-mutase, and phosphatidylinositol 3-kinase (PI3K)/Akt expression decreased significantly in the smoke-exposed groups compared with the air-exposed groups and in the aging-accelerated groups compared with the normally aged groups. Signal transduction pathways mediated by the transcription factor FOXO3a (such as the PI3K/Akt pathway) may be involved in the accelerated aging of lung tissues in chronic obstructive pulmonary disease. Smoking inactivates the transcription factor FOXO3, thus accelerating lung tissue aging during chronic obstructive pulmonary disease.

The blocking of advanced glycation end-products (AGE) has been shown to reduce diabetic complications and control periodontitis. This study investigated the pattern of palatal wound-healing after graft harvesting under the administration of aminoguanidine (AG), an AGE inhibitor, or N-phenacylthiazolium bromide (PTB), a glycated cross-link breaker. Full-thickness palatal excisional wounds (5.0 x 1.5 mm(2)) were created in 72 Sprague-Dawley rats. The rats received daily intraperitoneal injections of normal saline (control), AG, or PTB and were euthanized after 4 to 28 days. The wound-healing pattern was assessed by histology, histochemistry for collagen matrix deposition, immunohistochemistry for AGE and the AGE receptor (RAGE), and the expression of RAGE, as well as inflammation- and recovery-associated genes. In the first 14 days following AG or PTB treatments, wound closure, re-epithelialization, and collagen matrix deposition were accelerated, whereas AGE deposition, RAGE-positive cells, and inflammation were reduced. RAGE and tumor necrosis factor-alpha were significantly down-regulated at day 7, and heme oxygenase-1 was persistently down-regulated until day 14. The levels of vascular endothelial growth factor, periostin, type I collagen, and fibronectin were all increased at day 14. In conclusion, anti-AGE agents appeared to facilitate palatal wound-healing by reducing AGE-associated inflammation and promoting the recovery process.

The catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) is known to have a critical role in DNA double-strand break repair. We have previously reported that DNA-PKcs is activated when cells enter mitosis and functions in mitotic spindle assembly and chromosome segregation. Here we report that DNA-PKcs is the upstream regulator of the Chk2-Brca1 pathway, which impacts microtubule dynamics, kinetochore attachment and chromosomal segregation in mitosis. Downstream from Chk2, Brca1 promotes monoubiquitination of γ-tubulin to inhibit microtubule nucleation and growth. We found that DNA-PKcs is essential for mitotic Chk2 phosphorylation at Thr68. As in Chk2- and Brca1-deficient cells, loss of DNA-PKcs resulted in chromosome misalignment and lagging during anaphase owing to elevation in microtubule dynamics. Importantly, these mitotic aberrations in DNA-PKcs-defective cells were alleviated by the overexpression of phosphomimetic Chk2 or Brca1 mutant proteins but not their wild-type counterparts. Taken together, these results demonstrate that DNA-PKcs regulates mitotic spindle organization and chromosomal instability via the Chk2-Brca1 signaling pathway.

We have previously demonstrated that interrupting the protein-protein interaction (PPI) of β-tubulin:chaperonin-containing TCP-1β (CCT-β) induces the selective killing of multidrug-resistant cancer cells due to CCT-β overexpression. However, the molecular mechanism has not yet been identified. In this study, we found that CCT-β interacts with a myriad of intracellular proteins involved in the cellular functions of the endoplasmic reticulum (ER), mitochondria, cytoskeleton, proteasome and apoptosome. Our data show that the targeted cells activate both the heat-shock protein 90 (Hsp90)-associated protein ubiquitination/degradation pathway to eliminate misfolded proteins in the cytoplasm and the valosin-containing protein (VCP)-centered ER-associated protein degradation pathway to reduce the excessive levels of unfolded polypeptides from the ER, thereby mitigating ER stress, at the onset of β-tubulin:CCT-β complex disruption. Once ER stress is expanded, ER stress-associated apoptotic signaling is enforced, as exhibited by cellular vacuolization and intracellular Ca2+ release. Furthermore, the elevated intracellular Ca2+ levels resulting from capacitative Ca2+ entry augments apoptotic signaling by provoking mitochondrial perturbation and caspase overactivation in the targeted cells. These findings not only provide a detailed picture of the apoptotic signaling cascades evoked by targeting the β-tubulin:CCT-β complex but also demonstrate a strategy to combat malignancies with chemoresistance to Hsp90- and VCP-related anticancer agents.

This study examines whether a higher rate of physician adherence to quality-of-care indicators for colorectal cancer patients is associated with improved survival and using a bubble chart to help interpret physician performance. A set of 13 core measures was used to evaluate the quality of care in 708 colorectal cancer patients treated from 2004 to 2007 at a hospital in Taiwan. A 100% adherence standard was used to measure the relationship of adherence to patient survival. Each indicator assigned by each cancer stage was dichotomously coded. The associations between the adherence and survival rates and demographic characteristics were assessed using Cox's proportional hazard regression. Physician adherence to core indicators was plotted using a bubble chart to motivate physicians' performance adhering to quality-of-care guidelines for colorectal cancer patients. The 100% adherence rate criterion contributed to a relatively low hazard ratio of 0.36 (95% confidence interval, 0.14-0.85; P= 0.02). The association between the adherence rate and survival indicated significant improvements for stage III patients compared with stage I patients. A graphical representation of bubble charts helped to monitor physician performance, which improved the adherence rate to quality-of-care guidelines for colorectal cancer patients., (© 2012 Blackwell Publishing Ltd.)

Background: Febuxostat is a novel non-purine selective inhibitor of xanthine oxidase developed for the management of hyperuricemia in patients with gout., Objective: To investigate the pharmacokinetics and also evaluate the effects of gender and food on the pharmacokinetics of febuxostat in healthy Chinese volunteers., Methods: A phase I, 3-period study was performed in healthy Chinese male and female subjects. Subjects either received single 40 mg, multiple 40 mg and single 80 mg doses of febuxostat under fasted conditions, or received single 80 mg doses under fed condition. Plasma concentrations of febuxostat were collected and determined at 14 time points over 48 h., Results: After 40 mg and 80 mg single dose administration of febuxostat, the C max were 2.308±0.812 and 4.559±1.246 μg/mL, the T max were 1.6±0.6 and 2.1±1.0 h, the t 1/2 were 6.8±1.7 and 6.7±1.9 h, and the AUC0-∞ were 7.704±1.723 and 16.34±3.87 μg∙h/mL, respectively. In the multiple-dose study at 40 mg dose for 6 consecutive days, the mean (SD) steady-state pharmacokinetic parameters on day 8 were similar to those following a single dose of febuxostat on day 1. In addition, food caused a decrease of 33% for C max and a delay of 0.3 h for T max. Gender had no significant effect on the pharmacokinetics of febuxostat. Febuxostat was well tolerated over the investigated dose range., Conclusion: Compared with the previous study, the pharmacokinetics of febuxostat appeared to be different between Chinese and other races., (© Georg Thieme Verlag KG Stuttgart · New York.)

The objective of this study was to evaluate the efficacy of cognitive behavioral therapy intervention for patients who experienced pain during orthodontic treatment. The baseline characteristics were assessed via questionnaires and oral examinations. Four hundred and fifty eligible individuals were recruited and randomized by computer-generated block randomization into three groups: cognitive behavioral therapy intervention (n = 150), ibuprofen intervention (n = 150), and no intervention (control; n = 150). Primary outcomes were the change from baseline in pain intensity measured with 100-mm Visual Analog Scale (VAS) scores at 1, 2, 3, 7, 14, and 30 days after initial archwire placement. Outcomes assessment was blinded and followed the intention-to-treat principle. One hundred forty-three (95.30%), 145 (96.70%), and 141 (94.00%) individuals in the cognitive behavioral therapy, the ibuprofen, and the control groups, respectively, completed the one-month follow-up evaluations. Those in the cognitive behavioral therapy group showed a greater decrease in mean VAS scores than did those in the control group over the previous five time-points (p < 0.001). Cognitive behavioral therapy was shown to be effective in pain control during the initial stage of orthodontic treatment. The study registration number was ChiCTR-TRC-00000556.

Background: Overcrowding in emergency departments (ED) around the world is an increasingly serious problem with an adverse impact on both patient flow and patient outcomes. A significant contributing factor to ED overcrowding is possibly due to readmission. Risk factors for readmission in patients admitted from ED are rarely studied, particularly in Asian countries where the length of stay is reportedly longer., Methods: A retrospective study of patients admitted to general medical wards from the ED of a referral centre in northern Taiwan from November 2009 to April 2010 was conducted. The primary outcome was 30-day hospital readmission and clinical characteristics were analysed for predictors of readmission., Results: Of the recruited 2698 patients, 451 (16.7%) were readmitted within 30 days after discharge. Age, gender, marital status and the activities of daily living (Barthel's score) were not associated with 30-day readmission. Higher Charlson score ((score 2-4) hazard ratio (HR): 1.42, 95% confidence interval (CI): 1.07-1.89; (score >4) HR: 1.93, 95% CI: 1.37-2.73), longer hospital stay ((8-14 days) HR: 1.51, 95% CI: 1.17-1.95; (15-28 days) HR: 1.64, 95% CI: 1.22-2.19; (>28 days) HR: 1.97, 95% CI: 1.43-2.71), and presence of underlying active malignancy (HR: 1.66, 95% CI: 1.27-2.16) and anaemia (HR: 1.26, 95% CI: 1.02-1.55) were independently associated with readmission., Conclusion: Medical patients admitted from the ED of a referral centre have a 30-day readmission rate of 16.7%. Post-discharge care should focus on patients with higher Charlson score, longer hospitalisation, anaemia and underlying active malignancy, which are independent predictive factors for 30-day readmission., (© 2011 The Authors. Internal Medicine Journal © 2011 Royal Australasian College of Physicians.)

Several systems of metallic metal-oxide nanowires (NWs), including pure RuO2 and as-implanted and annealed Ru(0.98)Cu(0.02)O2 and Ru(0.93)Cu(0.07)O2 NWs, have been employed in two-probe electrical characterizations by using a transmission electron microscope-scanning tunneling microscope technique with a gold tip. Thermal, mechanical, and electron beam exposing treatments are consecutively applied to reduce the electrical contact resistance, generated from the interface between the NW and the gold tip, so as to evaluate the intrinsic NW resistance. It is found that the residual contact resistance cannot be entirely removed. For each system of metallic metal-oxide NWs, several tens of NWs are applied to electrical characterizations and the total resistances unveil a linear dependence on the ratio of the length to the area of the NWs. As a result, the average resistivity and the contact resistance of the metallic metal-oxide NWs could be evaluated at room temperatures. The average resistivities of pure RuO2 NWs agree well with the results obtained from standard two- and four-probe electrical-transport measurements. In addition, the as-implanted Cu-RuO2 NWs reveal disordered crystalline structures in high-resolution TEM images and give higher resistivities in comparison with that of pure RuO2 NWs. The residual contact resistances of all kinds of metallic metal-oxide NWs unveil, more surprisingly, an approximation value of several kilohms, even though the average resistivities of these NWs change by more than one order of magnitude. It is argued that the ductile gold tip makes one or more soft contacts on the stiff metal-oxide NWs with nanometer roughness and the nanocontacts on the NWs contribute to the electrical contact resistance.

Aims: Protamine, when administered to neutralize heparin in cardiovascular surgery, is associated with occasionally severe antigen-antibody reactions associated with substantial morbidity and mortality. The objective of this study is to investigate whether patients on hemodialysis are more susceptible to the protamine adverse effects., Method: First, a retrospective analysis of a protamine-associated hypotension episode (PAHE) in 239 patients undergoing coronary artery bypass grafting surgery was performed for the incidence study in the period of 1999 to 2005. Second, an ELISA determination of serum anti-protamine IgG antibody in 255 serum samples from individuals without previous surgical histories was conducted for prevalence survey. In both studies, patients on HD were matched for age with non HD patients., Results: The highest incidence (57%) of PAHE occurred in patients on hemodialysis using of M-insulin (a mixed type of insulin aspart 30%, insulin aspart protamine 70%) formulation, and this group also exhibited a high anti-protamine IgG antibody titer in serum (odds ratio: 18.31)., Conclusions: A substantial proportion of patients on hemodialysis are at high risk of acquiring protamine adverse effects, but definite conclusion about the association between uremia and PAHE, however, still needs to be made with caution.

Aims: Acute interstitial nephritis (AIN) is common, but prominent eosinophil infiltration in patients with acute interstitial nephritis is rare. The possible etiologies, predisposing factors and treatment of such patients are the subjects of this study., Methods: one patient was reported from our medical center; nine more patients with similar findings were reviewed from the literature. Suspected offending drugs, clinical presentations, predisposing factors and patient outcomes after therapy were recorded., Results: A case of clam extract-associated acute interstitial nephritis with prominent eosinophil infiltration was reported. Ten cases including ours were analyzed. A variety of drugs was thought to be causative. In all, 7 of the 10 patients had a preexisting nephrotic syndrome, and eosinophilia was found in 6. Bone marrow biopsy was not performed in most cases and only available for 2 patients including ours. 9 patients treated with steroids had good responses but 1 patient died despite treatment., Conclusions: Acute interstitial nephritis with prominent eosinophil infiltration can be caused by a great diversity of drugs, which can include clam extract tablets. A preexisting nephrotic syndrome seemed to be a predisposing factor for this condition. This disease rarely led to fatality and most patients responded well to steroid therapy.

Objectives: In this study, a group of cells that expressed both osteogenic and adipogenic characters was identified from murine adipose stromal cells., Materials and Methods: These cells could be enriched in the Sca-1-1 population and express both osteogenic and adipogenic genes. Osteogenic induction enhanced expression of osteogenic genes and inhibited expression of adipogenic genes, while adipogenic induction enhanced expression of adipogenic genes and inhibited expression of osteogenic genes. These cells have been called osteo-adipo progenitors (OAPs)., Results: OAPs expressed transcription factor runt-related transcription factor 2 (RUNX2) and peroxisome proliferator-activated receptor-gamma (PPAR-gamma) proteins in cytoplasm. When OAPs were cultured in adipogenic medium, PPAR-gamma moved to the nucleus and the cells differentiated into adipocytes, while the RUNX2 remained in the cytoplasm. In contrast, when OAPs were cultured in osteogenic medium, RUNX2 moved to the nucleus and the cells differentiated to osteocytes, while the PPAR-gamma remained in the cytoplasm., Conclusions: These experiments suggest that osteoblasts and adipocytes share a common predecessor, the OAP, in murine adipose stromal cells.

ATP-sensitive potassium (K(ATP)) channels play an important role in controlling insulin secretion and vascular tone as well as protecting neurons under metabolic stress. We have previously demonstrated that stimulation of the K(ATP) channel by nitric oxide (NO) requires activation of Ras- and extracellular signal-regulated kinase (ERK) of the mitogen-activated protein kinase (MAPK) family. However, the mechanistic link between ERK and the K(atp) channel remained unknown. To investigate how ERK modulates the function of K(ATP) channels, we performed single-channel recordings in combination with site-directed mutagenesis. The Kir6.2/SUR1 channel, a neuronal K(ATP) channel isoform, was expressed in human embryonic kidney (HEK) 293 cells by transient transfection. Direct application of the activated ERK2 to the cytoplasmic surface of excised, inside-out patches markedly enhanced the single-channel activity of Kir6.2/SUR1 channels. The normalized open probability (NPo) and opening frequency were significantly increased, whereas the mean closed duration was reduced. The single-channel conductance level was not affected. The ERK2-induced stimulation of Kir6.2/SUR1 channels was prevented by heat-inactivation of the enzyme. Furthermore, alanine substitutions of T341 and S385 to disrupt the potential ERK phosphorylation sites present in the Kir6.2 subunit significantly abrogated the stimulatory effects of ERK2, while aspartate substitutions of T341 and S385 to mimic the (negative) charge effect of phosphorylation rendered a small yet significant reduction in the ATP sensitivity of the channel. Taken together, here we report for the first time that ERK2/MAPK activates neuronal-type K(ATP) channels, and this stimulation requires ERK phosphorylation of the Kir6.2 subunit at T341 and S385 residues. The ERK2-induced K(ATP) channel stimulation can be accounted for by changes in channel gating that destabilize the closed states and by reduction in the ATP sensitivity. As Kir6.2 is the pore-forming subunit of K(ATP) channels, ERK2-mediated phosphorylation may represent a common mechanism for K(ATP) channel regulation in different tissues.

Background and Purpose: It has been found that 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) exert various vascular protective effects, beyond their cholesterol-lowering property, including inhibition of platelet-dependent thrombus formation. The objective of the present study was to determine whether the nitric oxide (NO)/cyclic GMP-mediated processes in platelets contribute to the anti-aggregatory activity of simvastatin., Experimental Approach: After rabbit platelets were incubated with simvastatin for 5 min, aggregation was induced and the platelet aggregation, nitric oxide synthase activity, guanylyl cyclase activity, NO and cyclic GMP formation were measured appropriately., Key Results: Treatment with simvastatin concentration-dependently inhibited platelet aggregation induced by collagen or arachidonic acid with an IC(50) range of 52-158 microM. We also demonstrated that simvastatin (20-80 microM) concentration-dependently further enhanced collagen-induced NO and cyclic GMP formation through increasing NOS activity (from 2.64+/-0.12 to 3.52+/-0.21-5.10+/-0.14 micromol min(-1) mg protein(-1)) and guanylyl cyclase activity (from 142.9+/-7.2 to 163.5+/-17.5-283.8+/-19.5 pmol min(-1) mg protein(-1)) in the platelets. On the contrary, inhibition of platelet aggregation by simvastatin was markedly attenuated (by about 50%) by addition of a nitric oxide synthase inhibitor, a NO scavenger or a NO-sensitive guanylyl cyclase inhibitor. The anti-aggregatory effects of simvastatin were significantly increased by addition of a selective inhibitor of cyclic GMP phosphodiesterase., Conclusions and Implications: Our findings indicate that enhancement of a NO/cyclic GMP-mediated process plays an important role in the anti-aggregatory activity of simvastatin.

Membranous nephropathy is an autoimmune-mediated glomerulonephritis and a major cause of nephrotic syndrome. We studied the kinetics of adaptive immunity in the pathogenesis of membranous nephropathy in T1/T2 double transgenic mice (T1/T2 TG mice) that express human Thy1 protein under the control of interferon-gamma (INF-gamma) and mouse Thy1.1 protein under the control of interleukin (IL)-4. Nephropathy was induced by cationic bovine serum albumin. We found that splenocytes expressed a progressive Th2 response and a subsequent compensatory T-helper 1 (Th1) response, with a gradual augmentation of IL-4-producing Th2 cells and INF-gamma-producing Th1 cells. Increased Th2 marker expression was seen in peripheral blood and kidney cells, with the immunoglobulin G1 (IgG1) antibody isotype predominant in the serum and kidneys. We found that CD8+ T cells contribute more to the augmented INF-gamma production than CD4+ T cells. Moreover, CD19+ B cells demonstrated a greater production of IL-4 than the CD4+ T cells. Cytokine-related gene expression in kidneys and splenocytes showed an upregulation of proinflammatory Th1 and Th2 cytokines. Th2 cells but not Th1 cells were significantly correlated with serum cholesterol and proteinuria. Our study shows that both peripheral and renal immune reactions are strongly polarized toward Th2-type immune responses during the course of membranous nephropathy. The T1/T2 mouse model may help decipher the kinetic changes of adaptive immunity in glomerulonephritis.

Objectives: Systemic lupus erythematosus is occasionally accompanied with bacterial infection. Lipopolysaccharide (LPS) from bacteria can accelerate and exacerbate lupus nephritis (LN) in animal models, but some mechanisms underlying the LPS-induced acceleration are still unclear. First, it is not known whether LPS can stimulate mesangial cells (MCs) to secrete the pro-inflammatory cytokine, interleukin (IL)-18. Second, it is also unclear whether LPS and/or IL-18 can induce MC apoptosis. Here, we attempted to clarify the cause-and-effect relationships between LPS stimulation, IL-18 production and MC apoptosis to address the above questions., Methods: LPS was used to induce accelerated LN in LN-prone mice. LPS and IL-18 were also used to treat cultured MCs isolated from the mice. IL-18 expression and MC apoptosis were investigated by in situ hybridization, the TUNEL method, reverse transcription- polymerase chain reaction (RT-PCR), western blotting, DNA electrophoresis and flow cytometry. NFkappaB was detected by immunofluorescent staining., Results: In the LPS-accelerated LN mice, we observed co-existence of IL-18 expression, hyperplasia, apoptosis, and activated apoptotic signal transduction in MCs, as well as marked neutrophil infiltration in the glomerulus, especially around the mesangial region. In cultured MCs, LPS greatly enhanced IL-18 expression, but did not induce apoptosis, while mouse IL-18 did not induce apoptosis or activate apoptotic signal transduction in MCs., Conclusions: We conclude that LPS can evoke IL-18 production in MCs, but neither LPS nor IL-18 directly induces apoptosis or activates apoptotic signal transduction in the cells. We infer that LPS-induced IL-18 production by MCs could be a mediator by which LPS accelerates and exacerbates LN.

Aim: To determine whether higher expression of fascin, an actin-bundling protein associated with motility, in conventional renal cell carcinoma (RCC) is associated with more advanced stages of the disease., Methods: Immunohistochemical analysis of fascin expression was performed in tissue microarrays of 108 RCCs including 55 clear cell RCCs (CRCCs), 39 CRCCs with granular cell differentiation (GRCCs), 8 CRCCs with sarcomatoid differentiation (SRCCs) and 6 metastatic RCCs., Results: The expression of fascin was undetectable in normal renal tubules of all control cases. However, among the 108 RCC cases, fascin immunoreactivity was seen on the cell membrane and cytoplasm. The average immunostaining score for fascin was 128/400 in grade I, 170/400 in grade II, 207/400 in grade III, and 323/400 in grade IV RCC. The average immunostaining score of fascin was 187/400 for stage T1, 205/400 for stage T2, 288/400 for stage T3, and 355/400 for stage T4 cases of RCCs. Higher fascin scores in RCC were significantly correlated with higher T and N stages and nuclear grade. In addition, the fascin scores in GRCC (368+/-19) and SRCC (263+/-21) were significantly higher than in CRCC (95+/-18)., Conclusions: Our findings demonstrate for the first time that increased expression of fascin is associated with clinicopathological parameters of aggressiveness in patients with RCC. Fascin may be a novel biomarker for diagnosis and treatment of RCC.

Artificial neural network (ANN) is increasingly applied in clinical medicine. We therefore constructed an ANN to predict intracellular water (ICW) volume in 44 healthy Taiwaners. Demographic and anthropometric data were recorded as predictors, and ICW volume measured by bioelectrical impedance analysis (ICW-BIA) was the reference. ICW volume predicted by ANN (ICW-ANN) was compared with ICW-BIA. ICW-BIA (21.26 +/- 0.58 l) and ICW-ANN (21.25 +/- 0.57 l) was insignificantly different (p = 0.76). ICW-BIA and ICW-ANN were strongly correlated (r = 0.94, p < 0.0001) with a significant agreement (mean difference, 0.01; lower and upper limits of agreement, -2.31 and 2.33) in Bland-Altman plot. Passing-Bablok regression was described as ICW-BIA = 1.04 x ICW-ANN - 0.49, with 95% confidence interval for slope 0.94-1.14 and for intercept -2.76-1.49, indicating that both methods were interchangeable. ANN provided an excellent alternative of BIA to predict ICW volume in healthy subjects.

In animal models of IgA nephropathy, the inevitable endogenous immune response to passively administered antigens alone or in complex with specific IgA mask the exact role each might play in pathogenesis. To delineate the role the immune response might play, we have developed a passive model with exclusive IgA-immune complex-mediated nephropathy in B-cell-deficient (BCD) mice. Glomerular IgA immune deposits were induced by administration of purified IgA antiphosphorylcholine and the specific pneumococcal C-polysaccharide (PnC) antigen daily for 2 weeks into BCD and wild-type (WT) mice. In BCD mice IgA+PnC deposits induced severe glomerular injury and renal dysfunction. In contrast, WT mice developed intense glomerular IgG and IgM and C3 co-deposits of the IgA+PnC with significantly less renal injury. Cytofluorometric analysis revealed that PnC induced in BCD, but not in WT, a rapid and dramatic increase in number of activated CD3(+)/CD69(+) T-cell population. The nuclear factor-kappa B (NF-kappaB) transcription factor was activated early and progressively increased in response to glomerular IgA+PnC deposits. These results suggest that nephritogenic IgA+PnC immune deposits induce glomerular and renal dysfunction through activation of the NF-kappaB. This inflammatory pathway is modulated by the endogenous cellular and antibody response to the antigen affecting the course of IgA nephropathy progression.

Background: Acute renal failure (ARF) is a life-threatening entity that frequently complicates advanced liver disease. This study documents a number of factors that may predispose to or precipitate ARF and influence outcomes in patients with advanced liver disease. Comparisons are also made between subgroups of patients with viral and alcohol-induced liver cirrhosis in those with ARF., Patients and Methods: We conducted a retrospective chart review over one year of 127 consecutive hospital admissions in 82 patients who were diagnosed with advanced liver cirrhosis (Child-Pugh Class C) in a tertiary care center. A diagnosis of ARF was made in 29 admissions and another 98 admissions not complicated by ARF served as controls. This study evaluated different etiologies of ARF and developed a database which included clinical features, biochemical parameters, the etiology of cirrhosis, possible predisposing factors, and precipitating events. Version II of the Acute Physiology and Chronic Health Physiology Scoring system (APACHE II) was applied to predict short-term hospital mortality rates., Results: ARF occurred in 29 admissions over the one-year study period (23%). The mean age of these patients was 56.8 +/- 12.0 years, and 73% were men. The patients with ARF had significant hyponatremia and higher levels of serum bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and white cell counts on admission than the controls. Patients who developed ARF were more likely to have had infection, especially septicemia, and gastrointestinal (GI) bleeding. Mortality rate in the patients with ARF was much higher than in those patients without ARF (72% vs. 13%, p < 0.001). The patients with viral cirrhosis and ARF were found to have higher leukocyte counts, serum bilirubin levels, and more frequent incidence of infection, septicemia and GI bleeding compared to the patients with alcoholic liver cirrhosis and ARF. Those with viral hepatitis were also significantly older and had more frequent incidence of ascites, but had lower levels of gamma-glutamyl transpeptidase and less frequent incidence of encephalopathy., Conclusions: The risk of ARF is significantly increased in patients with advanced liver cirrhosis presenting with marked hyperbilirubinemia, hyponatremia, elevated liver enzymes, infection, and GI bleeding. The presence of ARF leads to higher mortality rates in both viral and alcohol-induced liver cirrhosis.

Background: There is an increased rate of apoptosis of peripheral blood mononuclear cells (PBMCs) in patients undergoing hemodialysis (HD), but little is known about how different dialysis membranes may contribute to the process. We, therefore, studied the influence of two different dialysis membranes on apoptotic markers during HD., Methods: 8 healthy controls and 8 patients on regular HD 3 times per week were enrolled in this cross-controlled study. Patients received HD using polysulfone and then regenerated cellulose dialysis membranes for one week each, sequentially. Serum was collected for C-reactive protein (CRP) detection; flow cytometry with dual antibody staining was used to measure the apoptotic markers Fas (CD95), FasL (CD 178) and TNF-R2 (CD120b) in T cells (CD3+), B cells (CD19+), and monocytes (CD14+) at 0, 15, 120 and 240 min after starting HD. We also measured total leukocyte numbers and differential white cell counts., Results: Hemodialysis patients revealed lymphocytopenia, monocytopenia, higher CRP levels and higher Fas and TNF-R2 expression on lymphocytes and monocytes at baseline when compared with normal controls. Leukocyte numbers, including neutrophils, lymphocytes and monocytes, dropped significantly after 15 min of dialysis. There were no significant differences in Fas levels during hemodialysis on T and B lymphocytes or on monocytes. T lymphocyte FasL (CD 178) levels remained unchanged throughout the process. There was a significantly lower overall level of CD120b at 15 min of HD, whereas this marker was higher on monocytes after dialysis. There were no significant differences in the levels of apoptotic markers between the two membranes., Conclusion: Our results suggest that uremia itself contributes to PBMC apoptosis. The two different dialysis membranes used in this study did not influence apoptotic markers on PBMCs significantly, but increased TNF-R2 expression on monocytes during a single dialysis session.

One-day-old Taiwan native male chicks were fed with maize-soybean rearing diets without supplemental vitamin E to 23 weeks of age. From 23 to 52 weeks of age, the cockerels (n = 90) were assigned at random to 5 dietary treatments and fed with maize-soybean diets supplemented with 0, 20, 40, 80 and 160 mg/kg of vitamin E (dl-alpha-tocopherol acetate). Pullets (225) of the same age were fed with standard diets throughout. They were artificially inseminated with one dose of 0.04 ml/bird intact and 5-fold diluted pooled semen at 31 to 43 weeks of age and at 49 weeks of age, respectively. The criteria evaluated included: semen quality, fertility and maximum and effective duration of fertility, blood characteristics, body and testes weight. Supplemental vitamin E did not affect cockerels' effective duration of fertility and percentage of fertility. However, when pullets were inseminated with diluted semen, supplementing 160 mg/kg vitamin E increased the maximum duration of fertility at 49 weeks of age. Cockerels receiving 40 to 160mg/kg supplements had higher sperm viability and motility after 39 weeks of age and those fed 80 mg/kg had higher sperm concentration at 39 weeks of age. Cockerels receiving supplements of more than 40 mg/kg vitamin E had higher body weight gain. Plasma cholesterol and testosterone were not affected by supplemental vitamin E. However, plasma luteinising hormone (LH) concentration was lower in cockerels fed 160 mg/kg. Lack of supplemental vitamin E over 39 weeks was associated with lower semen quality but did not reduce the proportion of fertile eggs laid by inseminated hens, perhaps because the insemination dose compensated for low sperm quality. We found that the maximum duration of fertility might be improved by supplementing 160 mg/kg vitamin E at 49 weeks of age.

1. One-day-old Taiwan Native Breeder female chicks were fed on maize/soybean growing diets without supplemental vitamin E from hatch to 17 weeks of age. After 17 weeks the birds (n = 300) were randomly assigned to 5 dietary treatments and fed on maize/soybean laying diets supplemented with 0, 40, 80, 120 and 160 mg/kg of vitamin E (dl-alpha-tocopherol acetate), respectively, until 46 weeks of age. The variates measured included: age at first egg, feed consumption (FC), feed efficiency (FE), egg production (EP), egg weight (EW), egg specific gravity (ESG), eggshell strength (ESS), fertility and hatchability. 2. The addition of 120mg/kg of vitamin E lowered the first EW (P<0.05); however, there was no significant difference in the age or body weight (BW) of pullets at first egg or mortality rate to 46 weeks of age among the treatments. FE and egg mass were improved (P<0.05) in pullets fed 80 mg/kg of supplemental vitamin E. A significant increase in EP was observed after peak EP in pullets given 80 mg/kg of supplemental vitamin E. However, this favourable effect decreased as supplemental vitamin E exceeded 80 mg/kg. 3. From 17 to 46 weeks of age, egg quality (ESG and ESS) decreased with age. However, there was no correlation between age and fertility or hatchability during the experimental period, suggesting that egg quality is more age-sensitive than reproductive performance for breeder pullets. 4. Compared with the control, fertility and hatchability of all eggs set for the treatment with 80 mg/kg supplemental vitamin E increased by 7.7 and 13.4%, respectively. There was no difference in the hatchability of fertile eggs. 5. These results suggest that using supplemental vitamin E during the laying period can improve the reproductive performance of breeder pullets. The addition of 80 mg/kg of vitamin E obtained the best performance in EP, egg mass, FE (feed/egg), hatchability and fertility.

Background: Although psoriasis vulgaris (PV) is strongly associated with HLA-Cw*0602, it has been proposed that the association of Cw*0602 is due to linkage disequilibrium and that other nearby genes are involved in PV susceptibility. The alpha-helix coiled-coil rod homologue (HCR) gene, located 110 kb telomeric to the HLA-C locus, is presumed to be one of the PV candidate genes. Recently, a 10-kb genomic segment, centromeric to HLA-C, defined by two new single nucleotide polymorphisms (SNPs) n.7*A and n.9*C, was found to have a stronger association with psoriasis than the HCR gene. Until now, no study of the association of the HCR gene, SNPs n.7, and n.9 has been conducted on Chinese patients with psoriasis., Objectives: We aimed to determine whether the genetic polymorphisms of the HCR gene, SNPs n.7*A, and n.9*C were associated with an increased risk of psoriasis in Chinese patients., Methods: Using direct sequencing of the HCR gene and the genomic region containing SNPs n.7 and n.9, we investigated the HCR gene, SNPs n.7, and n.9 for disease association in 115 Chinese patients with psoriasis and 103 control subjects. The HCR SNPs were confirmed by denaturing high performance liquid chromatography. Genotyping for HLA-Cw*0602 was also carried out using sequence-based typing., Results: We observed a different allelic distribution between patient and control groups at nucleotide positions 386, 404, 1802 and 2406 of the HCR gene, and SNPs n.7, and n.9. The associations were much stronger in early onset PV patients (for HCR-386*T and HCR-404*T, odds ratio = 5.63, Pc < 0.0001). The HLA-Cw*0602 also displayed a similar association with PV (odds ratio = 5.4, Pc < 0.0001). Moreover, SNP n.7*A, SNP n.9*C, Cw*0602, HCR-386*T, HCR-404*T and HCR-1802*T were in linkage disequilibrium with each other. Haplotype-based association analysis showed SNP n.7*A-SNP n.9*C-Cw*0602-HCR-386*T-HCR-404*T-HCR-1802*T-HCR-2406*G as a major susceptibility haplotype in this Chinese population (for early onset patients, odds ratio = 5.15, Pc < 0.0001)., Conclusions: Our results indicate that the HCR gene, SNP n.7*A, and SNP n.9*C as well as Cw*0602 are major susceptibility markers for psoriasis in Chinese patients.

A young adult was diagnosed with steroid-resistant minimal change disease (MCD) without evidence of focal segmental glomerulosclerosis (FSGS) despite serial and detailed sectioning and screening of the renal biopsy. He received initial treatment with steroids and then cyclosporine plus low-dose steroids for 2 years. Renal function progressively deteriorated due to resistance to steroid and cyclosporine. Two months after initiation of hemodialysis, the patient received a living-related allogenic kidney transplant. However, recurrent nephrotic syndrome and renal insufficiency occurred after transplantation. In spite of aggressive treatment, renal function showed no significant improvement. The kidney graft was removed 2 weeks after transplantation. Serial sectioning and thorough sampling and screening revealed no evidence of FSGS, but light microscopy and electron microscopy showed the typical morphologic pattern of MCD, corresponding to the pretransplant diagnosis. We believe that this is the first reported case of recurrent MCD after renal transplant.

Background: Although vasoactive substances may be important in the pathogenesis of some types of acute renal failure (ARF), their potential role in exertional heat stroke (ExHS) with ARF has not been explored., Aim: To evaluate whether changes in concentration of individual vasoactive mediators correlated with alterations in renal function and haemodynamics in patients with ExHS and ARF., Design: Prospective case-control study., Methods: Systemic and renal haemodynamics, circulating vasoactive hormones and urinary vasodilator metabolites were determined in 12 military recruits who developed ExHS with ARF but without other organ failure during a three-year period. The control group consisted of 12 recruits who performed similar exercise under the same conditions without developing ExHS., Results: There were significant elevations in circulating pressor hormones (catecholamines, renin, aldosterone and endothelin-1 (ET-1)) and significant decreases in the vasodilatory hormone prostaglandin E(2) (PGE(2)) in the acute phase of ExHS with ARF when compared to ExC. There was also a significant rise in nitric oxide metabolites (NOx) in the acute phase of ExHS. All of these abnormalities in circulating hormones returned to normal range during the recovery phase of ExHS. The ERPF correlated positively with GFR and urinary PGE(2) and negatively with plasma catecholamines, renin, ET-1 and NOx., Discussion: The changes in the plasma levels of these hormones, together with enhanced NO production, may both contribute to the pathophysiology of ARF in ExHS.

A 34-year-old Chinese man developed acute, severe, generalized muscle weakness while mountain climbing. In the Emergency Department that morning, the most striking abnormalities were flaccid paralysis of both upper and lower limbs and a plasma potassium (K+) concentration (P(K)) of 1.7 mmol/l. To explain the basis for this constellation of findings, an imaginary consultation was sought with Professor McCance, the legendary integrative physiologist. Using both a deductive and a quantitative analysis, he illustrated that a simple story of an acute shift of K+ into cells was not sufficient to explain the patient's hypokalaemia. The clue he used to suspect a large total body deficit of K+ was a higher than expected rate of K(+) excretion on the initial spot urine (higher than expected ratio of K+: creatinine in the urine). This interpretation was supported by the fact that the patient needed a large supplement of K(+) to raise his P(K) to just under 3 mmol/l. It was only after more detailed studies based on urine chemistry that an accurate diagnosis and effective treatment could be instituted. The final question was why one of the hallmarks of the diagnosis of hyperaldosteronism (hypertension) was absent, yet hypokalaemia was so severe.

Aim: Chronic hypotension is not uncommon in uremic patients on regular hemodialysis. This subset of patients often requires multiple operations to maintain their vascular access due to frequent thrombosis and occlusion of the arteriovenous fistula. Our aims was to assess whether surgical intervention with the brachial artery-transposed basilic vein fistula is effective in chronic hypotensive hemodialysis patients., Materials and Methods: Fifty-four hemodialysis patients with chronic hypotension were enrolled in this study. Most ofthem were referred from local hospitals. They were 23 men and 31 women. The brachial artery-transposed basilic vein arteriovenous fistula was performed in a period of 46 months at the teaching hospital. Primary patency was defined as the length of time from the fistula creation until the development of thrombosis or a complication that required operative revision ofthe fistula. Secondary patency was defined by whether the fistula could be salvaged by revision such that blood flow was maintained., Results: There was no technical failure and none of these patients died due to the surgical operation. The primary patency rate was 89.80% at 1 year, 73.08% at 2 years, and 64.710% at 3 years. The secondary patency rate was 95.92% at 1 year, 84.62% at 2 years, and 76.47% at 3 years., Conclusions: Brachial artery-transposed basilic vein arteriovenous fistula may present good primary alternative vascular access in chronic hypotensive hemodialysis patients.

Hyponatremia can result from a wide range of causes. While hyponatremia is known to occur in patients with hypopituitarism, severe hyponatremia occurring as the presenting feature of hypopituitarism is very rare. We present two cases in which severe hyponatremia developed with weakness, light-headedness and seizure. The hyponatremia in these 2 cases mimicked the laboratory diagnostic criteria of a syndrome of inappropriate secretion of antidiuretic hormone (SIADH). However, the hormone studies displayed hypopituitarism. Hyponatremia was completely corrected after administering a supplement of prednisolone and L-thyroxine. Computerized tomography of the brain revealed an adenoma of the pituitary gland. These two cases illustrate that severe hyponatremia may be the presenting feature of clinically non-functional pituitary adenoma with hypopituitarism, which should be kept in mind in the differential diagnosis of hyponatremia mimicking SIADH.

Background and Purpose: Previous in vitro study has shown that an acidic medium increases osteoclastic and inhibits osteoblastic activity. The present study sought to determine the role of alkali therapy in osteoblast function in patients with chronic renal failure by assessing the serum concentration of procollagen type I carboxyterminal propeptide (PICP), a marker of bone formation, before and after bicarbonate infusion., Patients and Methods: Eighteen patients with chronic renal failure (creatinine clearance 12 +/- 6.6 mL/min) associated with mild to moderate metabolic acidosis were enrolled in this study. None had undergone dialysis. Metabolic acidosis was corrected by continuous bicarbonate infusion while plasma ionized calcium was clamped at the preinfusion level by calcium gluconate infusion throughout the procedure., Results: After bicarbonate infusion, there were significant increases in plasma pH (7.31 +/- 0.04 to 7.40 +/- 0.03, p < 0.001), bicarbonate concentration (18.46 +/- 2.49 to 23.66 +/- 2.72, p < 0.001), serum total calcium concentration (2.01 +/- 0.24 to 2.12 +/- 0.24 mmol/L, p < 0.001), and PICP concentration (137.3 +/- 56.25 to 159.6 +/- 57.30 micrograms/L, p < 0.05), whereas serum parathyroid hormone concentrations assessed by radioimmunoassay decreased significantly (153.7 +/- 88.6 to 111.5 +/- 78.7, p < 0.001). Serum ionized calcium concentrations showed no significant difference before and after bicarbonate infusion., Conclusion: These results suggest that acute correction of metabolic acidosis improves osteoblast function and appear to underline the importance of maintaining normal acid-base homeostasis in chronic renal failure.

The mitogen-activated protein kinase (MAPK) pathway is believed to function as an important mediator of inducible nitric oxide synthase (iNOS) expression. In the present study, we investigated the role of the p38 MAPK signaling pathway in advanced glycosylation end products (AGEs)-induced iNOS expression in C6 glioma cells. AGEs caused a dose-dependent increase of nitrite accumulation in C6 glioma cells. The AGEs-stimulated nitrite production from C6 glioma cells was inhibited by actinomycin D, cyclohexamide, and the NO synthase inhibitor, Nomega-nitro-L-arginine methyl ester (L-NAME), suggesting that the increase of AGEs-induced nitrite release is due to iNOS up-regulation. Consistently, treatment of C6 glioma cells with AGEs induced iNOS protein expression. AGEs-stimulated nitrite production was inhibited by pretreatment of C6 glioma cells with anti-AGEs antibodies (1:100 or 1:50). The tyrosine kinase inhibitor (genistein and tyrphostin), the Ras-farnesyl transferase inhibitor (FPT inhibitor-II), or the p38 MAPK inhibitor (SB203580) suppressed AGEs-induced iNOS expression and nitrite release from C6 glioma cells. AGEs activated p38 MAPK in C6 glioma cells, and this effect was blocked by genistein (20 microM), tyrphostin (30 microM), FPT inhibitor-II (20 microM), and SB203580 (10 microM). Taken together, our data suggest that AGEs may activate the pathways of tyrosine kinase and Ras to induce p38 MAPK activation, which in turn induces iNOS expression and NO production in C6 glioma cells.

Neural signaling is based on the regulated timing and extent of channel opening; therefore, it is important to understand how ion channels open and close in response to neurotransmitters and intracellular messengers. Here, we examine this question for potassium channels, an extraordinarily diverse group of ion channels. Voltage-gated potassium (Kv) channels control action-potential waveforms and neuronal firing patterns by opening and closing in response to membrane-potential changes. These effects can be strongly modulated by cytoplasmic factors such as kinases, phosphatases, and small GTPases. A Kv alpha subunit contains six transmembrane segments, including an intrinsic voltage sensor. In contrast, inwardly rectifying potassium (Kir) channels have just two transmembrane segments in each of its four pore-lining alpha subunits. A variety of intracellular second messengers mediate transmitter and metabolic regulation of Kir channels. For example, Kir3 (GIRK) channels open on binding to the G protein betagamma subunits, thereby mediating slow inhibitory postsynaptic potentials in the brain. Our structure-based functional analysis on the cytoplasmic N-terminal tetramerization domain T1 of the voltage-gated channel, Kv1.2, uncovered a new function for this domain, modulation of voltage gating, and suggested a possible means of communication between second messenger pathways and Kv channels. A yeast screen for active Kir3.2 channels subjected to random mutagenesis has identified residues in the transmembrane segments that are crucial for controlling the opening of Kir3.2 channels. The identification of structural elements involved in potassium channel gating in these systems highlights principles that may be important in the regulation of other types of channels.

This study was conducted to characterize the denitrification and nitrification in a bench-scale sequencing batch reactor operating with a three-stage, alternating anoxic-oxic sequence and step feed (SAOSBR) for treating synthetic wastewater. The results of long-term operation and dynamic studies showed that the SAOSBR increased the availability of organic matter in wastewater for exogenous denitrification in anoxic periods, and subsequently allowed nitrification to occur under a lower organic loading in oxic periods. Comparatively high kinetic rates of 1.2 to 6.6 mg nitrate/g mixed liquor suspended solids (MLSS) x h for denitrification and 1.0 to 2.8 mg nitrogen/g MLSS x h for nitrification were found in dynamic studies. With sufficient influent organics and alkalinity, complete denitrification and full nitrification could be achieved sequentially in the alternating anoxic and oxic periods, resulting in an average total nitrogen removal efficiency up to approximately 90%. Alkalinity recovery because of exogenous denitrification was experienced, and a minimum influent alkalinity to total Kjeldahl nitrogen (TKN) ratio of 2.4 was required to reach complete TKN removal. The pH value would be a better parameter other than oxidation-reduction potential or dissolved oxgyen to determine the completeness of nitrification and denitrification in the SAOSBR.

Hypokalemia and hypophosphatemia are commonly encountered during paralysis in patients with thyrotoxic periodic paralysis (TPP) and may contribute to neuromuscular manifestations. Potassium and phosphate supplements have been recommended to hasten recovery and prevent cardiopulmonary complications. However, this recommendation has not yet proven efficacious. Hyperadrenergic activity has been implicated in the pathogenesis of TPP. We tested whether nonselective beta-blockers could terminate neuromuscular symptoms rapidly while reducing an intracellular shift of potassium and phosphate. We describe two patients who had an acute attack of TPP with characteristic hypokalemia and hypophosphatemia associated with low urinary potassium and phosphate excretion. After oral propranolol, 3 mg/kg, serum potassium and phosphate concentrations increased promptly in 2 hours in both patients, and there was complete amelioration of paralysis. No rebound hyperkalemia or hyperphosphatemia was detected. Given their efficacy in this pilot study, they should be considered as a first-line therapy for TPP.