Effect of the changes of NMDA receptor in hypothalamic paraventricular nucleus on cardiac function and sympathetic nervous activity in rats with heart failure.

OBJECTIVE: To observe the effect of the changes of n-methyl-d-aspartate receptor 1 (NMDAR1), tyrosine hydroxylase (TH), and glutamic acid decarboxylase 67 (GAD67) in the hypothalamic paraventricular nucleus (PVN) on cardiac function and sympathetic nervous activity in rats with heart failure (HF). METHODS: Thirty-six adult male SD rats were randomly divided into the heart failure group (HF), the heart failure + NMDA receptors agonist AP5 intervention group (HF-AP5), and the Sham-operation group (SO) (n = 12). HF model in SD rats was induced by ligation of left coronary artery. AP5 (0.02 µg/h) was administrated by the paraventricular nucleus subsequently for 4 weeks. The cardiac function, renal sympathetic nerve activity (RSNA), lung/body weight ratio (L/BW), and right ventricle/body weight ratio (RV/BW), as well as the plasma noradrenaline (NE) and Angiotensin II (Ang II) level and the expressions of NMDAR1, GAD67, and TH in PVN, in different groups were recorded 4 weeks after the establishment of HF model. RESULTS: After the coronary artery was ligated, LVEDP was increased, ±dp/dt max and LVEF were decreased, lung/BW and RV/BW were raised. RSNA, Ang II and NE were raised. Expression of NMDAR1 and TH were increased, but GAD67 was decreased. The levels of LVEDP, lung/BW, and RV/BW in group HF-AP5 were reduced while ± dp/dtmax was increased after the treatment. The blood Ang II and NE content was decreased, RSNA was reduced, expression of NMDAR1 and TH were downregulated, but GAD67 was upregulated. CONCLUSIONS: NMDAR1 is significantly activated in PVN of HF rats, the activity of TH is increased, GAD67 is downregulated, RSNA is increased, and the heart function is decreased. NMDA receptor blockers can alleviate HF.

Opening of the inward rectifier potassium channel alleviates maladaptive tissue repair following myocardial infarction.

Activation of the inward rectifier potassium current (IK1) channel has been reported to be associated with suppression of ventricular arrhythmias. In this study, we tested the hypothesis that opening of the IK1 channel with zacopride (ZAC) was involved in the modulation of tissue repair after myocardial infarction. Sprague-Dawley rats were subject to coronary artery ligation and ZAC was administered intraperitoneally (15 µg/kg/day) for 28 days. Compared with the ischemia group, treatment with ZAC significantly reduced the ratio of heart/body weight and the cross-sectional area of cardiomyocytes, suggesting less cardiac hypertrophy. ZAC reduced the accumulation of collagen types I and III, accompanied with decrease of collagen area, which were associated with a reduction of collagen deposition in the fibrotic myocardium. Echocardiography showed improved cardiac function, evidenced by the reduced left ventricular end-diastolic dimension and left ventricular end-systolic dimension, and the increased ejection fraction and fractional shortening in ZAC-treated animals (all P < 0.05 vs. ischemia group). In coincidence with these changes, ZAC up-regulated the protein level of the IK1 channel and down-regulated the phosphorylation of mammalian target of rapamycin (mTOR) and 70-kDa ribosomal protein S6 (p70S6) kinase. Administration of chloroquine alone, an IK1 channel antagonist, had no effect on all the parameters measured, but significantly blocked the beneficial effects of ZAC on cardiac repair. In conclusion, opening of the IK1 channel with ZAC inhibits maladaptive tissue repair and improves cardiac function, potentially mediated by the inhibition of ischemia-activated mTOR-p70S6 signaling pathway via the IK1 channel. So the development of pharmacological agents specifically targeting the activation of the IK1 channel may protect the heart against myocardial ischemia-induced cardiac dysfunction.

Case Report: Upper Thoracic Esophageal Paralysis Accompanying a Type 1 Leprosy Reaction.

Type 1 leprosy reactions (T1LRs) occur mainly in patients with borderline leprosy and an unstable immune status. The main symptoms of T1LRs include aggravated skin lesions and nerve damage. Nerve damage involving the glossopharyngeal and vagus nerves causes dysfunction of the nose, pharynx, larynx, and even the esophagus, which are innervated by these nerves. Here, we report a case of upper thoracic esophageal paralysis caused by vagus nerve involvement in a patient with T1LRs. Although infrequent, this serious emergency merits attention.

A prediction model for prognosis of gastric adenocarcinoma based on six metabolism-related genes.

Background: The study of tumor metabolism is of great value to elucidate the mechanism of tumorigenesis and predict the prognosis of patients. However, the prognostic role of metabolism-related genes (MRGs) in gastric adenocarcinoma (GAD) remains poorly understood. Methods: We downloaded the gene chip dataset GSE79973 (n = 20) of GAD from the Gene Expression Omnibus (GEO) database to compare differentially expressed genes (DEGs) between normal and tumor tissues. We then extracted MRGs from these DEGs and systematically investigated the prognostic value of these differential MRGs for predicting patients' overall survival by univariable and multivariable Cox regression analysis. Six metabolic genes (ACOX3, APOE, DIO2, HSD17B4, NUAK1, and WHSC1L1) were identified as prognosis-associated hub genes, which were used to build a prognostic model in the training dataset GSE15459 (n = 200), and then validated in the dataset GSE62254 (n = 300). Results: Patients were divided into high-risk and low-risk subgroups based on the model's risk score, and it was found that patients in the high-risk subgroup had shorter overall survival than those in the low-risk subgroup, both in the training and testing datasets. In addition, for the training and testing cohorts, the area under the ROC curve of the prognostic model for one-year survival prediction was 0.723 and 0.667, respectively, indicating that the model has good predictive performance. Furthermore, we established a nomogram based on tumor stage and risk score to effectively predict the overall survival (OS) of GAD patients. The expression of 6 MRGs at the protein level was confirmed by immunohistochemistry (IHC). Kaplan-Meier survival analysis further confirmed that their expression influenced OS in GAD patients. Conclusion: Collectively, the 6 MRGs signature might be a reliable tool for assessing OS in GAD patients, with potential application value in clinical decision-making and individualized therapy.

[Bone remodeling after total hip arthroplasty with anatomic medullary locking prosthesis and its long-term effectiveness].

OBJECTIVE: To investigate the femoral bone remodeling and long-term effectiveness of total hip arthroplasty (THA) with anatomic medullary locking (AML) prosthesis. METHODS: The clinical data of 24 cases (26 hips) who were treated with THA with AML prosthesis between November 1997 and January 2003 were retrospectively analyzed. There were 12 males and 12 females with an age of 32-69 years (mean, 53.7 years). There were 5 cases (5 hips) of avascular necrosis of the femoral head, 6 cases (7 hips) of secondary osteoarthritis of the hip dysplasia, 6 cases (6 hips) of femoral neck fracture, 2 cases (2 hips) of primary osteoarthritis, 3 cases (3 hips) of revision surgery, 1 case (2 hips) of ankylosing spondylitis, 1 case (1 hip) of femoral head fracture. The patients were followed up at immediate, 6 weeks, 3 months, 6 months, 1 year, and then every year after operation for imaging evaluation (X-ray film was taken immediately after operation to evaluate the femoral isthmus compression, Engh standard was used to evaluate the biological fixation of the femoral shaft prosthesis, and Brooker method was used to evaluate the occurrence of heterotopic ossification); bone reconstruction evaluation [reconstruction of prosthesis and bone interface (type of bone reaction, Gruen zone, incidence, and occurrence time were recorded), reconstruction of bone around prosthesis (proximal femur stress shielding bone absorption was evaluated according to Engh and Bobyn methods, and bone mineral density change rate was measured)]; clinical efficacy evaluation [Harris score for efficacy, visual analogue scale (VAS) score for thigh pain]. RESULTS: All patients were followed up 15 years and 2 months to 20 years and 4 months, with a median of 16 years and 6 months. At immediate after operation, 24 hips (92.3%) had good femoral isthums compression, 24 hips (92.3%) had good bone ingrowth. Heterotopic ossification occurred in 2 patients with degree 1, 2 patients with degree 2, and 1 patient with degree 3 at 3-6 months after operation. Hyperplastic bone reactions were more common in Gruen 2, 3, 4, 5, 6, 10, 11, and 12 zones, mainly occurring at 6-20 months after operation, with the incidence of 3.8%-69.2%, with the highest incidence of spot welding. All absorptive bone reactions were osteolysis, which was common in Gruen 1 and 7 zones, and mainly occurred at 8 years after operation, with an incidence of 42.3%. No clear line (area) or enlarged sign of medullary cavity was observed. Twenty-one hips (80.8%) had 1 degree stress shieding, and 5 hips (19.2%) had 2 degree stress shieding. It mainly occurred at 10-24 months after operation in Gruen 1 and 7 zones. Dual energy X-ray absorptiometry showed that bone mineral density mainly decreased in Gruen 1, 2, 6, and 7 zones, mainly increased in Gruen 3, 4, and 5 zones. Bone mineral density loss progressed slowly after 2 years of operation, and it was stable in 5-8 years, but decreased rapidly in 8-9 years, and stabilized after 10 years. The Harris score increased from 51.1±6.2 before operation to 88.3±5.1 at last follow-up ( t=-21.774, P=0.000). Mild thigh pain occurred in only 2 cases (7.7%) with the VAS score of 2. No aseptic loosening or revision of femoral prosthesis occurred during the follow-up. CONCLUSION: The application of AML prosthesis in THA has a good bone remodeling and a good long-term effectiveness.

[Changes of nucleus pulposus after culture of whole intervertebral discs].

OBJECTIVE: To explore a practical method of culturing discs organ system by observing the changes of the nucleus pulposus after the whole intervertebral discs (including cartilage end-plate, nucleus pulposus, and annulus fibrous) were cultivated. METHODS: A total of 335 intervertebral discs were taken out completely from 60 healthy SD rats (about 150 g) aged 5-6 weeks of clear grade and rinsed by high osmotic saline solution containing heparin, then put to the culture plate after being divided into 5 groups randomly. The whole intervertebral discs were cultured with high osmotic (410 mOsmol/kg) culture medium and changed the medium once every day, then the cell viability (n=15), HE staining (n=15), Safranin O staining (n=15), and immunohistochemistry staining (n=2) were observed at 0, 3, 7, 14, and 21 days; RT-PCR result (n=5) was observed at 0, 3, 7, and 14 days. RESULTS: The cell viability was not changed significantly within 14 days (P > 0.05) and was significantly lower at 21 days than at other time points (P < 0.01). The immunohistochemistry staining results for collagen type II were positive in nucleus pulposus cells at every time point. HE staining showed that the tissue integrity and morphology of the whole intervertebral discs were not changed within 14 days. Safranin O staining showed no significant difference in the matrix grey scale within 14 days (P > 0.05) and significant differences between 21 days and 0-14 days (P < 0.05). RT-PCR results showed that the mRNA expression of collagen type I increased with time, but the expressions of collagen type II, aggrecan, and decorin decreased, showing significant differences in the mRNA expressions of the matrix protein at each time point (P < 0.05). CONCLUSION: High osmotic saline solution containing heparin could be used to cultivate the whole intervertebral discs, it is an ideal model for further studies on physiology and pathology of intervertebral discs.

Brain tumour necrosis factor-alpha modulates neurotransmitters in hypothalamic paraventricular nucleus in heart failure.

AIMS: Increased proinflammatory cytokines after myocardial infarction augment the progression of heart failure (HF) and are of prognostic significance. Recently, we demonstrated that increased proinflammatory cytokines in the brains of HF rats increased paraventricular nucleus (PVN) superoxide and down-regulated neuronal nitric oxide synthase (nNOS), contributing to sympathoexcitation. In this study, we explored the possible roles of brain proinflammatory cytokines and their effects on modulating PVN neurotransmitters in the exaggerated sympathetic activity in HF. METHODS AND RESULTS: Sprague-Dawley rats with HF or sham-operated control (SHAM) rats were treated for 4 weeks with a continuous intracerebroventricular (ICV) infusion of the cytokine blockers-pentoxifylline (PTX, 10 microg/h and 40 microg/h), etanercept (ETN, 5 microg/h and 10 microg/h), or vehicle. Another set of HF and SHAM rats were treated with intraperitoneal (ip) infusion of a similar dose of PTX or ETN. HF rats had increased neuronal excitation accompanied by higher levels of glutamate, norepinephrine (NE), and tyrosine hydroxylase (TH), and lower levels of gamma-aminobutyric acid (GABA), nNOS, and 67-kDa isoform of glutamate decarboxylase (GAD67) in the PVN when compared with SHAM rats. Plasma cytokines, NE, epinephrine, angiotensin II, and renal sympathetic nerve activity (RSNA) were also increased in HF rats. ICV treatment with low doses of PTX or ETN attenuated, and high doses prevented, increases in levels of glutamate, NE, and TH, and decreases in levels of GABA, nNOS, and GAD67 in the PVN in HF rats. The same ICV treatments also attenuated the increased RSNA seen in HF rats. IP treatment with similar doses of PTX or ETN did not affect glutamate, NE, TH, GABA, nNOS, and GAD67 in the PVN and had no effect on RSNA of HF rats. CONCLUSION: This study, for the first time, demonstrates that proinflammatory cytokines modulate neurotransmitters in the PVN and contribute to sympathoexcitation in HF.