雷公藤多甙与棉酚合用对雄大鼠生育力的影响

本研究探讨雷公藤多甙(GTW)与棉酚合用对雄大鼠生育力的影响。SD雄大鼠用棉酚及GTW各6 mg/kg/d,灌胃给药,每周6日,共11周。10只用药动物全部不育,附睾精子密度和活率也明显下降,而体重增长如常,性行为存在。睾丸光镜下结构绝大多数无明显异常,血清睾酮水平正常,副性腺重量无明显变化。停药6周后生育力恢复。在相同剂量下,单用GTW或棉酚均无抗生育效果。表明两药合用有相加作用,为减少棉酚和GTW副作用提供一条可能途径。     

Pregnancy-induced periodontal inflammation: Influence of salivary cytokines and antimicrobial proteins

The aim of this study was to evaluate the association between pregnancy-induced periodontal inflammation and levels of some salivary cytokines and antimicrobial proteins (AMPs). The study was a cohort longitudinal study that included pregnant women attending a secondary health facility. Consented participants had oral examination and saliva sampling during pregnancy and post-partum (three months after pregnancy). Saliva samples were used for the analysis of cytokines (TNF-α, IFN-gamma and IL-1β) and AMPs (Lactoferin, Lysozyme, and β defensin-1) using ELISA. Data are presented as median with interquartile range and compared using related sample Wilcoxon signed rank test. Correlations between levels of the salivary factors and indices of periodontal inflammation were determined using Spearman’s correlation test. Salivary flow rate, pH, levels of salivary IL-1β and IFN-gamma were significantly lower; while gingival index, periodontal index and level of salivary TNF-α were significantly higher during pregnancy compared with postpartum period. However, salivary lactoferin, lysozyme and β defensin-1 did not show significant difference comparing during pregnancy and postpartum period. Level of salivary IFN-gamma showed negative correlation with gingival index while level of salivary TNF-α showed positive correlation with gingival and periodontal indices. Lower levels of salivary IL-1β and IFN-gamma along with higher TNF-α concentration during pregnancy suggest their contributions to the pathophysiology of pregnancy-induced periodontal inflammation.     

Suicide risk among adults with epilepsy in Kaduna,Nigeria

Objective

There is paucity of information on epilepsy and suicide in Nigeria. The objective of this study therefore was to assess the prevalence and determinants of suicide risk among adults with epilepsy (AWE) in Kaduna, Nigeria.

Method

We administered the suicidality module of the Mini International Neuropsychiatric Interview, the three-item Oslo Social Support Scale and the Hospital Anxiety and Depression Scale to 170 consecutive AWE attending the outpatient clinic of Federal Neuropsychiatric Hospital, Kaduna, between January and June 2011 to determine the prevalence of suicide risk, the level of social support and the psychological symptoms, respectively. We also recorded the sociodemographic and clinical characteristics of the subjects.

Results

There are 99 males and 71 females. The subject’s mean age was 28.7±12.1 years. The prevalence of suicide risk was 20.0%. Short seizure-free periods (χ²= 4.658, P= .031), previous suicide attempts (χ²= 12.216, P< .001), anxiety symptoms (χ²= 5.075, P= .024) and depressive symptoms (χ²= 5.093, P= .016) were significantly associated with suicidal tendencies. However, after a logistic regression analysis, none of the above variables predicted suicide risk.

Conclusion

Suicide risk is common among AWE. Poor seizure control, previous suicidal attempts and emotional distress are associated factors.     

ADAM-10 and -17 regulate endometriotic cell migration via concerted ligand and receptor shedding feedback on kinase signaling

A Disintegrin and Metalloproteinases (ADAMs) are the principal enzymes for shedding receptor tyrosine kinase (RTK) ectodomains and ligands from the cell surface. Multiple layers of activity regulation, feedback, and catalytic promiscuity impede our understanding of context-dependent ADAM “sheddase” function and our ability to predictably target that function in disease. This study uses combined measurement and computational modeling to examine how various growth factor environments influence sheddase activity and cell migration in the invasive disease of endometriosis. We find that ADAM-10 and -17 dynamically integrate numerous signaling pathways to direct cell motility. Data-driven modeling reveals that induced cell migration is a quantitative function of positive feedback through EGF ligand release and negative feedback through RTK shedding. Although sheddase inhibition prevents autocrine ligand shedding and resultant EGF receptor transactivation, it also leads to an accumulation of phosphorylated receptors (HER2, HER4, and MET) on the cell surface, which subsequently enhances Jnk/p38 signaling. Jnk/p38 inhibition reduces cell migration by blocking sheddase activity while additionally preventing the compensatory signaling from accumulated RTKs. In contrast, Mek inhibition reduces ADAM-10 and -17 activities but fails to inhibit compensatory signaling from accumulated RTKs, which actually enhances cell motility in some contexts. Thus, here we present a sheddase-based mechanism of rapidly acquired resistance to Mek inhibition through reduced RTK shedding that can be overcome with rationally directed combination inhibitor treatment. We investigate the clinical relevance of these findings using targeted proteomics of peritoneal fluid from endometriosis patients and find growth-factor–driven ADAM-10 activity and MET shedding are jointly dysregulated with disease.A Disintegrin and Metalloproteinases (ADAMs), especially ADAM-10 and -17, are the principal mediators of proteolytic ectodomain shedding on the cell surface (1). ADAMs and the closely related matrix metalloproteinases (MMPs) work together as “sheddases” to cleave hundreds of diverse transmembrane substrates including growth factor ligands, receptor tyrosine kinases (RTKs), adhesion molecules, and even proteases themselves from the cell surface. Unfortunately, little is known regarding how such a broad palette of proteolytic activity integrates to modulate behaviors such as cellular motility. Furthermore, extensive cross-talk and complexity among signaling networks, proteases, and their substrates make understanding sheddase regulation on a component-by-component basis challenging (2). Therapeutics have targeted sheddases and their substrates for the treatment of invasive diseases such as cancer, yet many of these inhibitors have failed in clinical trials (3). Therefore, a need exists for understanding how the balance of sheddase-mediated degradation integrates multiple layers of signaling networks to coordinately influence cell behavior in various disease contexts.Here we study how sheddase activity contributes to cell migration in the invasive disease of endometriosis, defined by the presence of endometrial-like tissue residing outside the uterus. Up to 10% of adult females and 40% of infertile women have the disease, which also exhibits comorbidity with several cancers (4, 5). Endometriosis currently has no cure: hormonal therapies merely manage the disease with significant side effects, and surgery provides only temporary relief for many, with recurrence rates as great as 40% within 5 y postoperation (6). Like cancer, endometriosis is associated with aberrant cell invasion into ectopic organ sites, and endometriotic tissues often exhibit dysregulated molecular pathways commonly perturbed in other invasive diseases. Mitogenic and inflammatory phospho-signaling [for example, phosphorylated extracellular-signal-related kinase 1/2 (p-Erk1/2), phosphorylated protein kinase B (p-Akt), and phosphorylated p38 mitogen-activated protein kinase (p-p38)], RTKs (including epidermal growth factor receptor, EGFR), and metalloproteinases have all been clinically associated with endometriosis (7, 8), and consequently represent attractive therapeutic strategies (9–11).Many challenges in developing targeted therapeutics stem from network-level complexities such as compensatory feedback, and recent work has demonstrated how critical such mechanisms are to achieving therapeutic success, especially in cancer (12, 13). Computational models of systems-level biochemical networks have shown promise as tools to understand how multiple enzymatic reactions integrate to impact overall biological behavior, often with the goal of aiding the design of personalized or combination therapies (14, 15). Considering its complex role in disease, sheddase regulation represents an ideal application of such network-level approaches. In this work, we apply the “cue–signal–response” (CSR) paradigm (14, 15) (Fig. 1A) to examine how disease-implicated growth-factor cues interact with experimentally monitored phospho-protein and protease networks (collectively referred to as signals), ultimately to influence cellular migration response. Computational modeling elucidates quantitative and predictive relationships among multiple layers of experimental data and offers testable hypotheses of context-dependent behavior and signaling feedback. We find ADAM-10 and -17 to be critical regulators of motility that are dynamically controlled through several signaling pathways, thereby affecting cell behavior through both positive feedback from EGF ligand release and negative feedback from Hepatocyte Growth Factor Receptor (HGFR; MET), Human Epidermal Growth Factor Receptor 2 (HER2), and HER4 RTK shedding. We find kinase inhibition generally reduces ADAM-10 and -17 activities, reduces subsequent RTK shedding, and consequently allows the accumulated RTKs to enhance downstream c-Jun N-terminal kinase (Jnk) and p38 signaling. Thus, here we demonstrate an ADAM-10 and -17–based mechanism of rapidly acquired resistance to kinase inhibition through reduced RTK shedding that can be overcome with combination therapy. Targeted proteomic analysis of clinical samples from endometriosis patients indeed confirms growth-factor–driven ADAM-10 activity and consequent MET shedding are dysregulated with disease. Overall, our results have wide implications for designing combination therapies and identifying context-dependent personalized therapeutic strategies for both kinase and protease inhibitors.Open in a separate windowFig. 1.CSR study design. (A) CSR overview: we stimulate endometriotic cells with a panel of growth factor cues; record multiple downstream signals comprising measurements of phospho-signaling, sheddase regulation, and sheddase substrate regulation; and use computational modeling to map these observations onto cell migration responses. (B) Overview of signals and responses included in the CSR dataset. All receptors shown were directly measured and/or stimulated. (C) Experimental timeline of CSR study. Dark colored lines denote measurement time points. At lower left, cell migration is depicted as single-cell tracks, where initial cell positions were centered for visualization.     

Low-dose inhaled nitric oxide for neonates with pulmonary hypertension

Objective : Inhaled nitric oxide (iNO) has been shown to cause selective pulmonary vasodilatation and improve ventilation-perfusion matching and may be an important therapeutic option for the treatment of persistent pulmonary hypertension of the newborn (PPHN). We report our experience on the use of iNO in neonates with severe PPHN.
Methodology : Inhaled NO was administered to 10 infants with PPHN and persistent hypoxaemia (meconium aspiration syndrome, n = 9; pneumonia, n = 1) after failure of conventional therapy to improve oxygenation. With the exception of one infant, iNO was commenced at 10 ppm.
Results : After 30 min exposure to iNO, the arterial oxygen tension (PaO₂) rose from a median of 49 mmHg (6.5 kPa) [range 12-82 mmHg (1.6-10.9 kPa)] to 75 mmHg (10 kPa) [range 17-450 mmHg (2.3-60 kPa)] ( P = 0.005), while the median oxygenation index fell (pre-iNO of 37 vs post-iNO 20) ( P = 0.005) and median systemic arterial pressure rose (pre-iNO 46.5 mmHg (6.2 kPa) [range 32-63 mmHg (4.3 to 8.4 kPa vs post-iNO 54.5 mmHg (7.3 kPa) [range 36-74 kPa]) P = 0.005). All infants subsequently continued to receive iNO with the duration of exposure to iNO ranging from 12 to 168 h (median duration 100 h). Three infants died despite showing an initial beneficial response to iNO. The mean duration of intubation for survivors was 11.9 ± 2.6 days. Methaemoglobinaemia and toxic levels of nitrogen dioxide were not seen during iNO administration. Of the seven survivors, 12 month follow up in two infants and 4 month follow up in four infants showed age-appropriate neurodevelopmental skills, with one infant having very mild hearing loss.
Conclusions : Inhaled NO reduces the oxygenation index by improving the PaO₂ and decreasing ventilation pressures, and appears to be clinically useful in severely hypoxaemic infants with PPHN refractory to conventional treatment.     

Inhaled nitric oxide during emergency neonatal transportation

ABSTRACT Inhaled nitric oxide is currently being investigated as a selective pulmonary vasodilator for neonates with persistent pulmonary hypertension. The use of continuous inhaled nitric oxide during emergency transportation of three critically ill neonates with meconium aspiration and pulmonary hypertension is described. The successful application of this technique may allow safer transportation of neonates who require high level intensive care including ongoing nitric oxide, high frequency ventilation and/or extracorporeal life support. Regionally based nitric oxide-equipped retrieval teams may relieve the pressure on smaller neonatal intensive care units to provide inhaled nitric oxide therapy and allow centralization of nitric oxide resources, thus facilitating development of expertise and the completion of meaningful research programs with substantial recruitment.     

Age-related hearing loss, vitamin B12, and folate in the elderly

Objective

Determine the correlation between the hearing threshold and the serum levels of vitamin B12 (cobalamin) and folic acid among elderly subjects (> 60 years) with age-related hearing loss (ARHL).

Study Design

Cross-sectional.

Setting

Community.

Subjects and Methods

Subjects included elderly who were found apparently healthy following repeated examination by physicians. The pure tone average (PTA) for the speech and high frequencies, and the serum folate and cobalamin were determined and the correlation found.

Results

The mean ± SD values of serum folate among the subjects with normal PTA in the speech frequencies (0-30 dB) was 412.3 nmol/L ± 17.6 nmol/L, while among those with hearing loss (HL), it was 279.1 nmol/L ± 17.2 nmol/L (P = 0.01). In the high frequencies, the mean ± SD values among the subjects with normal PTA was 426.3 nmol/L ± 17.6 nmol/L, while among those with HL, it was 279.14 nmol/L ± 171.2 nmol/L. The serum cobalamin among the subjects with normal PTA within the speech frequencies was 49.7 pmol/L ± 9.4 pmol/L, while among those with speech-frequency HL, it was 42.6 pmol/L ± 10.2 pmol/L. However, for high frequencies, the mean ± SD values among the subjects with normal PTA was 47.4 pmol/L ± 7.3 pmol/L, while among those with HL, it was 41.3 pmol/L ± 9.2 pmol/L. Spearman's correlation revealed that low folate (correlation coefficient = −0.27, P = 0.01) and cyanocobalamin (correlation coefficient = −0.35, P = 0.02) were significantly associated with increasing hearing threshold in the high frequencies. After adjusting for age, serum folate (correlation coefficient = −0.01, P = 0.01) was significant, while vitamin B12 (correlation coefficient = −0.01, P = 0.74) was not.

Conclusion

Serum folate was significantly lower among elderly with ARHL. Trials on nutritional supplementation may substantiate the role of serum folate in ARHL.     

Nontransferrin-bound iron in plasma from hemochromatosis patients: effect of phlebotomy therapy

Plasma from patients with iron overload resulting from idiopathic hemochromatosis contains nontransferrin-bound iron, measurable by the bleomycin, assay. During venesection therapy, the concentration of bleomycin iron declines in a way highly correlated with plasma ferritin concentrations. Even when patients had been venesected to give very low total plasma iron concentrations and high transferrin iron-binding capacity, bleomycin-detectable iron was still present at low concentrations. Bleomycin-detectable iron can stimulate damaging free radical reactions, and its persistence in plasma even after prolonged venesection might contribute to the tissue damage that results from iron overload.