Activation of the Calcium Receptor by Calcimimetic Agents Is Preserved Despite Modest Attenuating Effects of Hyperphosphatemia.

BACKGROUND: Phosphorus levels in the range seen clinically among patients undergoing dialysis have been reported to attenuate calcium receptor activation and modify parathyroid hormone (PTH) release from isolated parathyroid glands in vitro. Some clinicians and providers of dialysis thus have suggested that calcimimetic agents are ineffective and should not be used to manage secondary hyperparathyroidism among those undergoing dialysis when serum phosphorus concentrations exceed certain threshold levels. METHODS: To determine whether hyperphosphatemia diminishes the therapeutic response to calcimimetic agents, we used data from large clinical trials to analyze the effects of etelcalcetide and cinacalcet to lower plasma PTH levels in individuals on hemodialysis who had secondary hyperparathyroidism and varying degrees of hyperphosphatemia. RESULTS: Plasma PTH levels declined progressively during 26 weeks of treatment with either etelcalcetide or cinacalcet without regard to the degree of hyperphosphatemia at baseline. However, with each calcimimetic agent, the decreases in PTH from baseline were less at each interval of follow-up during the trials among participants with serum phosphorus levels above one of three prespecified threshold values compared with those with serum phosphorus levels below these thresholds. CONCLUSIONS: These in vivo findings are the first in humans to support the idea that hyperphosphatemia attenuates calcium receptor activation by calcium ions and by calcimimetic agents. The effect of hyperphosphatemia on the responsiveness to calcimimetic agents appears relatively modest, however, and unlikely to be significant therapeutically. The efficacy of treatment with calcimimetic agents for lowering plasma PTH levels among those with secondary hyperparathyroidism remains robust despite substantial elevations in serum phosphorus.

Infectious Morbidity, Mortality and Nutrition in HIV-exposed, Uninfected, Formula-fed Infants: Results From the HPTN 040/PACTG 1043 Trial.

BACKGROUND: HIV-exposed uninfected (HEU) infants are a growing population with potentially poor health outcomes. We evaluated morbidity and mortality in HEU formula-fed infants enrolled in the NICHD HPTN 040/PACTG 1043 trial. METHODS: Infectious morbidity, mortality and undernutrition were evaluated within a cohort of 1000 HEU infants enrolled between April 2004 and April 2010 in Brazil (n = 766) and South Africa (n = 234) as part of the NICHD/HPTN 040 trial of 3 different antiretroviral regimens to decrease intrapartum HIV vertical transmission. RESULTS: Twenty-three percent of infants had at least 1 infectious serious adverse effect. Infants born to mothers with <12 years of education [adjusted odds ratio (AOR), 2.6; 95% confidence interval [CI], 1.2-5.9), with maternal viral load of >1,000,000 copies/mL at delivery (AOR, 9.9; 95% CI, 1.6-63.1) were more likely to have infectious serious adverse effects. At 6 months, the infant mortality rate per 1000 live births overall was 22 ± 2.6, 9.1 ± 1.8 in Brazil and 64.1 ± 3 in South Africa. Undernutrition and stunting peaked at 1 month of age with 18% having a weight-for-age Z score ≤-2, and 22% with height for Z score ≤-2. The likelihood of infant mortality was greater among infants born in South Africa compared with Brazil (AOR, 6.2; 95% CI, 2.5-15.8), high maternal viral load (AOR, 1.7; 95% CI, 1.01-2.9) and birth weight-for-age Z score ≤-2 (AOR, 5.2; 95% CI, 1.8-14.8). CONCLUSIONS: There were high rates of undernutrition, stunting and infectious serious adverse effect in this study's formula-fed HEU population. Suppressing maternal HIV viral load during the peripartum period may be a modifiable risk factor to decrease infant mortality.

A metabolomics study on the immunosuppressive effect of Tripterygium hypoglaucum (Levl.) Hutch in mice: The discovery of pathway differences in serum metabolites.

Tripterygium hypoglaucum (Levl.) Hutch (THH), a typical traditional Chinese medicine, is widely used in clinical practice for the treatment of rheumatoid arthritis, systemic lupus erythematous, and other connective tissue and autoimmune diseases. However, most related researches focused on the pharmacological effects of THH, while less attention has been paid to the immunosuppressive mechanism. The present study aims to determine the metabolic profiles, based on UPLC-Q-TOF-MS, identify differential metabolites, and find related metabolic pathways among the sensitization red blood cell (SRBC) model mice, THH treated mice, and cyclophosphamide treated group. Totally, 24 and 19 changed metabolites were found in the THH and cyclophosphamide treated groups respectively. Among them, we found that urocanate metabolic pathway change could be considered as the most relevant pathway associated with immunosuppression. This is the first study that comprehensively assessed the differences in metabolome between the model and THH treated groups. The results provide insights into the difference between the immunosuppressive mechanisms of THH and cyclophosphamide and also demonstrated that metabolomics is a valuable tool for investigating the efficacy of drugs in the treatment of diseases and the associated mechanism involved.

Traditional Chinese Medication Qiliqiangxin Protects Against Cardiac Remodeling and Dysfunction in Spontaneously Hypertensive Rats.

Qiliqiangxin (QLQX), a traditional Chinese herbs medication, exerted protective effect in chronic heart failure patients in a multicenter randomized double-blind study. QLQX has also been found to improve cardiac function and reduce cardiac fibrosis in spontaneously hypertension animal model. However, the effect of longterm treatment with QLQX in such a condition and the related molecular mechanisms remain largely unknown. In the present study, thirteen-week-old spontaneously hypertensive rats (SHRs) were treated by daily intragastric administration of QLQX or saline for one year. Echocardiography, electron microscopy, and Masson's trichrome staining were used to determine cardiac function, mitochondria ultrastructure, and cardiac fibrosis, respectively. Quantitative reverse transcription polymerase chain reactions (qRT-PCRs) and Western blotting were used to determine gene expressions. We found that QLQX significantly improved cardiac function and reduced gene markers of pathological hypertrophy including ANP, BNP, and Myh7. QLQX also attenuated cardiac fibrosis and apoptosis in SHRs as evidenced by downregulation of α-SMA, collagen I, collagen III, and TGF-ß expressions and reduction of Bax to Bcl-2 ratio. Moreover, the damage of mitochondrial ultrastructure was greatly improved and the reduction of PPAR-α, PPAR-γ, and PGC-1α expression levels was significantly restored in SHRs by treatment with QLQX. In conclusion, longterm treatment with QLQX protects against cardiac remodeling and dysfunction in hypertension by increasing PPARs and PGC-1α.

Ginsenoside Rg3 attenuates myocardial ischemia/reperfusion injury via Akt/endothelial nitric oxide synthase signaling and the B­cell lymphoma/B­cell lymphoma­associated X protein pathway.

Previous studies have suggested that ginsenoside Rg3 (GSRg3) extract from the medicinal plant Panax ginseng, may increase nitric oxide production via increases in the phosphorylation and expression of endothelial nitric oxide synthase (eNOS). The present study used an in vitro neonatal rat cardiomyocyte (NRC) model of anoxia­reoxygenation injury and an in vivo rat model of myocardial ischemia/reperfusion (MI/R) injury. Hemodynamic, histopathological and biochemical assessment of the myocardial injury was performed and the expression levels of lactate dehydrogenase (LDH), superoxide dismutase and creatine kinase (CK) were measured in serum from the animal model, which may reflect myocardial injury. NRC injury was determined using a Cell Counting kit­8. The GSRg3 anti­apoptotic effects were assessed using flow cytometry to investigate the number of early­late apoptotic cells and western blot analysis was performed to analyze the protein expression levels of caspase­3, caspase­9, B­cell lymphoma­2 (Bcl­2), phosphorylated (p­)Akt and eNOS. The results suggested that pretreatment with GSRg3 (60 mg/kg) significantly improved rat cardiac function, as demonstrated by increased left ventricular systolic pressure, heart rate and first derivative of left ventricular pressure. GSRg3 also reduced the size of the myocardial infarct and LDH/CK levels in the blood following MI/R. In vitro investigations revealed that GSRg3 (10 mM) decreased NRC apoptosis through inhibiting the activation of caspase­3 and caspase­9, and increasing the expression levels of p­Akt, eNOS and the ratio of Bcl­2/Bcl­2­associated X protein (Bax). Overall, the present study revealed that GSRg3 mediated a cardioprotective effect against MI/R­induced apoptosis via Akt/eNOS signaling and the Bcl­2/Bax pathway.

Substance abuse treatment for HIV infected young people: an open pilot trial.

The purpose of this study was to test an integrated cognitive behavioral and contingency management (CBT/CM) intervention for young people living with HIV (YPLH) with an alcohol and/or cannabis use disorder in an open pilot trial. Seventeen participants (ages 18-24) were recruited from three HIV community clinics. Assessments were completed at pre-and post-treatment as well as 3 month follow-up. Eighty percent of participants were retained in the study. Results suggest that the CBT/CM intervention was acceptable, feasible, and could be delivered with fidelity. Further, participants reported significant reductions in alcohol use, withdrawal symptoms, dependence symptoms and related problems, as well as co-occurring depressive symptoms and delinquent behavior across assessment periods. A trend was evident for reductions in marijuana use and related problems. Overall, these preliminary results suggest that a substance abuse CBT/CM intervention tailored to YPLH is acceptable, feasible, and holds promise for symptomatic improvement. Further testing of this type of protocol is warranted.

Effect of Danggui Buxue Tang on immune-mediated aplastic anemia bone marrow proliferation mice.

To investigate the pharmacological effects of Danggui Buxue Tang (DBT) on immune-mediated aplasia anemia mice. The model of immune-mediated aplasia anemia mice was induced by means of (60)Co γ-ray irradiation and mixed cells of thymus and lymphnode of DBA/2 mice infusion through tail vein, the parameters tested indices were as following: blood picture, bone marrow nucleated cell count (BMNC), murine colony-forming unit-megakaryocytes (CFU-GM) of bone marrow cells, murine colony-forming unit-erthroid (CFU-E) and burst forming unit-erythroid (BFU-E). The results showed that DBT could not only withstand significantly decreation of blood cells by immune-mediated, but also stimulate on the growth of bone marrow colony cell and increase the weight of hemopoietic progenitor of bone marrow. Therefore, DBT had an obvious treat effect on immune-mediated aplasia anemia models mice.

The effects of Polygonum cuspidatum extract on wound healing in rats.

AIM OF THE STUDY: Polygonum cuspidatum has long been used as a traditional medicine inducing wound healing. In this study, the extract from the Chinese medicinal herb Polygonum cuspidatum was investigated on its wound healing activity, in order to obtain an accurate elucidation of its traditional use value. MATERIALS AND METHODS: After creating wound healing model on the back of rats, the extract from the Chinese medicinal herb Polygonum cuspidatum was applied. Wound healing rates were calculated at 3, 7, 14, and 21 days after the wounding, and tissues were harvested at 1, 3, 7, 14 and 21 days for histological and immunohistochemistry analysis. The stages of wound granulation tissues were evaluated histopathologically. The expression of TGF-ß1 was determined by immunohistochemically. RESULTS: Wound healing rates were significantly higher at 3, 7, 14 and 21 days in the extract group than in the control (p<0.05). Histological results showed more well-organized bands of collagen, more fibroblasts and hair follicle and less inflammatory cells in the extract group. The immunohistochemical results revealed that TGF-ß1 increased in the extract group on day 1, 3 and 7 post-wounding (p<0.05). CONCLUSION: The present study has shown that the extract from the Chinese medicinal herb Polygonum cuspidatum possesses wound healing activity, and thus provided the evidence for its traditional use value.

[Experiment study of total anthraquinone in cassiae semen on lipid peroxidation and PPAR-gamma expression in liver tissues of rats with alcoholic fatty liver].

OBJECTIVE: To investigate the effect of total anthraquinone in Cassiae Semen on lipid peroxidation and peroxisome proliferator activated receptors gamma (PPAR-gamma) expression in liver tissues of rats with alcoholic fatty liver. METHOD: Referring to literature, it was established animal models of fatty liver feeding with alcohol. Rats were randomized into 6 groups, except the normal group, the other 5 groups of rats had been administered alcohol two times a day for 3 months. Rats were killed at the end of this experiment. It were respectively measured that the contents of ALT, AST, AKP, TG, TC, HDL-C, LDL-C, MDA, SOD, FFA in the serum and TG, TC, MDA, SOD, HL, LPL, FFA in the liver. The left leaf of liver was observed by histopathological staining, the immunohistochemical staining and RT-PCR were used to observe the effects on the expressions of PPAR-gamma mRNA. RESULT: Compared with the model group, total anthraquinone in Cassiae Semen could remarkably decrease the content of ALT, AST, TC, TG, MDA and increase the content of SOD in the serum of the experimental fatty liver induced by alcohol; remarkably decrease the content of TC, TG, FFA and increase the content of HL, LPL, SOD in the liver of the experimental fatty liver with induced by alcohol. Total anthraquinone in Cassiae Semen group was the similar the model group, but remarkably lighten inflammatory cell intiltration and fibrosis increasing. The RT-PCR and immunohistochemical staining results showed that: compared with the normal group,the model group could remarkably decrease the expression of PPAR-gamma mRNA in the liver (P < 0.01). Compared with the model group, total anthraquinone in Cassiae Semen could remarkably increase the expression of PPAR-gamma mRNA in the liver of the experimental fatty liver (P < 0.01). CONCLUSION: The results showed that total anthraquinone in Cassiae Semen has good effects on the treatment of hepatic fat induced by alcohol diet in rats. the possible action mechanism of total anthraquinone in Cassiae Semen possess obvious effect of regulating the disorder of lipid metabolism, ameliorating hepatic function, as well as anti-lipidperoxidation, increasing the expression of PPAR-gamma in hepatic cells of rats.

[Effect of traditional Chinese medicine injections on type I allergy].

OBJECTIVE: To investigate allergic reactions of traditional Chinese medicine (TCM) injections, and to determine the contents of serum IgE and histamine in sensitized animal. The correlation between the preceding contents in serum and allergic reactions may be found, thus offering experimental evidences for advancing the accuracy of anticipation by type I allergy. METHOD: We carried out passive cutaneous anaphylaxis (PCA) tests,active systemic anaphylaxis (ASA) tests and anaphylactoid reactions using three TCM injections, and determined the contents of serum OVA-sIgE, total serum IgE and histamine in sensitized animals by ELISA method. RESULT: The results of PCA test were negative, and there was no significant difference for total serum IgE level between experimental group and normal saline group. In the study of adjuvant effect in TCM injections + OVA (at the dose level that doesn't cause allergic reactions), the PCA results of SHL and YXC were positive and there was a increase in content of serum OVA-sIgE, while the PCA result of QKL was negative with a unobvious increase in the content of serum OVA-sIgE. The content of total serum IgE wasn't remarkably increased in each group and the results of ASA test were all positive. Three injections all caused anaphylactoid symptoms in guinea pigs in different doses or injection speed and the response intensity was found to be dosage and injection speed dependant. Furthermore, there was no significant difference for the content of total serum IgE in each group, whereas serum histamine concentration in every experimental group was markedly higher than normal saline group. CONCLUSION: SHL and YXC increase the sensitivity of guinea pigs on OVA, and three TCM injections can cause allergic reactions in guinea pig. Allergic reactions of three TCM injections are correlated with specific IgE antibodies and histamine contents.

[Effects of Tripterygium hypoglaucum on serum IL-1, IL-6, and TNF-alpha in chronic nephritis rats].

OBJECTIVE: To investigate the effects and mechanism of Tripterygium hypoglaucum (THH) on serum IL-1, IL-6, and TNF-alpha in chronic, nephritis rats. METHOD: The rabbit serum of anti-rat kidney was initially prepared, and then injected into normal rats to induce the formation of chronic glomerulonephritis. In this model, THH was administrated for 4 weeks, while saline and prednisone were respectively used as negative and positive controls. Some of laboratory parameters were observed from the rats above. RESULT: THH not only significantly decreased urine protein, reduced serum urea nitrogen, but also decreased the releases of inflammatory mediators (such as IL-1, IL-6 and TNF-alpha). CONCLUSION: THH is effective in treating rat nephrotoxic serum glormerulonephritis, its mechanism probably related to decreasing inflammatory mediator levels.

Refractoriness of the sheep superior vena cava myocardial sleeve.

The cardiomyocytes in the superior vena cava (SVC) myocardial sleeve have distinct action potentials and ionic current profiles, but the refractoriness of these cells has not been reported. Using standard intracellular microelectrode techniques, we demonstrated in sheep that the effective refractory period (ERP) of the cardiomyocytes in the SVC (114.7 +/- 6.5 ms) is shorter than that in the inferior vena cava (IVC) (166.7 +/- 6.2 ms), right atrial free wall (RAFW) (201.0 +/- 6.0 ms) and right atrial appendage (RAA) (203.1 +/- 5.8 ms) (P < 0.05). The right atrial cardiomyocyte ERP was heterogeneously shortened by acetylcholine, a muscarinic type 2 receptor (M(2)R) agonist. After perfusion with 15 microM acetylcholine, the shortest ERP occurred in the SVC (the ERP in the SVC, IVC, RAFW and RAA was 53.6 +/- 2.7, 98.9 +/- 2.2, 121.8 +/- 6.0 and 109.7 +/- 5.1 ms, respectively; P < 0.05). Carbachol (1 microM), another M(2)R agonist, produced a similar effect as acetylcholine. Furthermore, we used methoctramine, a M(2)R blocker, 4-DAMP, a muscarinic type 3 receptor (M(3)R) blocker, and tropicamide, a muscarinic type 4 receptor (M(4)R) blocker to inhibit the acetylcholine-induced ERP shortening of SVC cardiomyocytes, and found that the 50% inhibitory concentration for methoctramine, 4-DAMP and tropicamide was 5.91, 45.72 and 80.34 nM, respectively. Therefore, we conclude that the sheep SVC myocardial sleeve is a unique electrophysiological region of the right atrium with the shortest ERP both under physiological condition and under cholinergic agonist stimulation. M(2)R might play a major role in the response of the SVC myocardial sleeve to parasympathetic nerve tone. The association between the distinct refractoriness in SVC and atrial fibrillation originating from the region deserves further investigation.