Substance P potentiates 5-HT3 receptor-mediated current in rat trigeminal ganglion neurons

The present study aimed to investigate the interaction between the coexistent SP receptor and 5-HT3 receptor in trigeminal ganglion (TG) neurons using whole-cell patch clamp technique. The majority of the neurons examined responded to 5-HT with an inward current (I5-HT) (78.2%, 79/101) that could be blocked by 5-HT3 receptor antagonist, ICS-205,930. The I5-HT was potentiated by preapplication of SP (10(-10) to 10(-8) M) in most 5-HT-sensitive cells(78.5%, 62/79). Coapplication of SP and GR-82334, antagonist of NK1 receptor, had no enhancing effect on I5-HT. The concentration-response curves for 5-HT with and without SP preapplication show that: (1) the threshold 5-HT concentrations with and without SP preapplication are basically the same, while SP preapplication increased the maximal value of I5-HT by 38.0% of its control; (2) the EC50 values of the curves with and without SP pretreatment are very close, i.e. 1.89 x 10(-5) M and 2.08 x 10(-5) M (P > 0.1; n = 9), respectively. Intracellular dialysis of GDP-beta-S, a non-hydrolyzable GDP analog, and GF-109203X, a selective protein kinase C inhibitor, removed the SP potentiation of I5-HT. These results may offer a clue to understanding the mechanism underlying the generation and/or regulation of peripheral pain caused by tissue damage inflammation, etc.     

Effect of intracellular dialysis of ATP on the hyperpolarization-activated cation current in rat dorsal root ganglion neurons

The mechanism of the effect of intracellular ATP on the hyperpolarization-activated non-selective cation current (Ih) in rat dorsal root ganglion neurons was investigated using a whole cell voltage-clamp technique. Under voltage-clamp conditions, Ih was activated by hyperpolarizing pulses raised to a voltage of between -70 and -130 mV. The activation curve of Ih in rat dorsal root ganglion (DRG) neurons shifted by about 15 mV in the positive direction with an intracellular solution containing 1 mM cAMP. When ATP (2 mM) was applied intracellularly, the half-maximal activation voltage (Vhalf) of Ih shifted from -97.4 +/- 1.9 to -86.8 +/- 1.6 mV, resulting in an increase in the current amplitude of Ih by the pulse to between -80 and -90 mV. In the presence of an adenylate cyclase inhibitor, SQ-22536 (100 microM), the intracellular dialysis of ATP also produced a shift in the voltage-dependence of Ih in rat DRG neurons, indicating that the effect of ATP was not caused by cAMP converted by adenylate cyclase. Intracellular dialysis of a nonhydrolysable ATP analog, AMP-PNP or ATP-gamma-S, also produced a positive shift in the voltage-dependence of Ih activation, suggesting that the effect of ATP results from its direct action on the channel protein. These results indicate that cytosolic ATP directly regulates the voltage dependence of Ih activation as an intracellular modulating factor.     

Effects of thyroxine on hyperkalemia and renal cortical Na+, K+ - ATPase activity induced by cyclosporin A

Cyclosporin A (CsA)-induced hyperkalemia is caused by alterations in transepithelial K+ secretion resulting from the inhibition of renal tubular Na+, K+ -ATPase activity. Thyroxine enhances renal cortical Na+, K+ -ATPase activity. This study investigated the effect of thyroxine on CsA-induced hyperkalemia. Sprague-Dawley rats were treated with either CsA, thyroxine, CsA and thyroxine, or olive-oil vehicle. CsA resulted in an increase in BUN and serum K+, along with a decrease in creatinine clearance, fractional excretion of potassium, and renal cortical Na+, K+ -ATPase activity, as compared with oil vehicle administration. Histochemical study showed reduced Na+, K+ -ATPase activity in the proximal tubular epithelial cells of the CsA-treated compared with the oil-treated rats. Histologically, isometric intracytoplasmic vacuolation, disruption of the arrangement and swelling of the mitochondria, and a large number of lysosomes in the tubular epithelium were characteristic of the CsA-treated rats. Co-administration of thyroxine prevented CsA-induced hyperkalemia and reduced creatinine clearance, Na+, K+ -ATPase activity, and severity of the histologic changes in the renal tubular cells when compared with the CsA-treated rats. Thyroxine increased the fractional excretion of potassium via the preservation of Na+, K+ -ATPase activity in the renal tubular cells. Thus, the beneficial effects of thyroxine may be suited to treatment modalities for CsA-induced hyperkalemia.     

Photodynamic therapy induced Fas-mediated apoptosis in human carcinoma cells

Photodynamic therapy (PDT) is a clinical approach that utilizes light-activated drugs for the treatment of a variety of pathologic conditions. Human poorly (CNE2) and moderately differentiated (TW0-1) human nasopharyngeal carcinoma (NPC) cells undergo rapid apoptosis when treated with PDT sensitized with Hypocrellin A (HA) and Hypocrellin B (HB). It has been shown that these compounds have a strong photodynamic effect on tumors and viruses. The initiating events of PDT sensitized HA and HB-induced apoptosis are poorly defined. In the current study, we sought to determine whether Fas/FasL upregulation and involvement of mitochondrial events are an early event in HA and HB-treated PDT induced apoptosis. Loss of mitochondrial transmembrane potential, release of cytochrome c, involvement of caspases-8 and -3 and the status caspase-3 specific substrate PARP, were evaluated in PDT treated tumor cells. Photoactivation of HA and HB enhanced both CD95/CD95L expression and induced CD95-signaling dependent cell death in all tumor cell lines studied. CD95/ CD95L expression appeared within 2 h following light activation and appeared to be a primary event in PDT induced apoptosis. Furthermore, these results indicate that release of mitochondrial cytochrome c into the cytoplasm is a secondary event following the activation of initiator caspase-8 preceding caspase-3 activation, cleavage of PARP and DNA fragmentation. Cytochrome c appeared in the cytosol within 2-3 h post PDT. Cleavage of PARP was observed at 3-4 h following PDT and caspase-3 specific inhibitor DEVD-CHO and broad-spectrum caspases inhibitor z-VAD-fmk blocked caspase-3 activation and PARP cleavage suggesting that caspase-3 plays an important role in HA and HB-induced apoptosis.     

结节病患者肺功能变化研究

目的：肺结节病患者肺功能测试的研究。方法：40例肺结节病患者不同时期肺功能测试结果和应用激素的回顾分析。结果：显示此类患者有限性通气功能障碍并伴有弥散功能下降和小气道功能受限,PaO2明显下降,pH升高,PaCO2也有下降的趋势。激素治疗结果显示,患者的MMF有明显的提高。其它肺功能指标如VC,RV,RV/TLC,MVV,FEV1,DLCO等都有升高的趋势。结论：VC,RV,MMF,DLCO,DLCO/VA等对诊断结节病的病情发展有直接参考价值,而MMF在糖皮质激素治疗后有显著的变化,提高MMF对结节病的治疗和预后具有动态参考价值。     

Incidence and risk factors of suicide among patients diagnosed with bladder cancer: A systematic review and meta-analysis

Background: Patients with bladder cancer have a high risk of suicide. This study aimed to assess how bladder cancer increases suicide risk and to identify the demographic and clinical factors associated with suicidal death among patients with bladder cancer. Methods: Literature search of MEDLINE, PsycINFO, Embase, Web of Sciences and Cochrane Library databases was conducted up to April 2020 to identify eligible studies related to the incidence and risk factors of suicide after bladder cancer diagnosis. Summary multivariate-adjusted risk estimates and their associated 95% confidence intervals (CIs) were calculated using inverse variance method with random or fixed-effect modeling. Results: Five retrospective cohorts comprising 563,680 patients with bladder cancer were included. Higher risk of suicide by 1.90-fold was observed among patients with bladder cancer (hazard ratio, HR = 1.90, 95% CI: 1.29–2.81; P = 0.001; I² = 81.2%), especially in those aged 70 years or older (HR = 1.36, 95% CI: 1.29–1.43; P < 0.001; I² = 0%), unmarried (HR = 1.72, 95% CI: 1.61–1.83; P < 0.001; I² = 0%), and those with regional bladder cancer (HR = 1.88, 95% CI: 1.10–3.21; P = 0.021; I² = 96.3%), compared with those without bladder cancer. Furthermore, gender and race were not associated with increased suicide risk among patients with bladder cancer. Conclusions: Suicide risk is increased among patients with bladder cancer, particularly those aged 70 years or older, unmarried and those with regional bladder cancer. Hence, early psychological support must be provided during the follow-up period of these special populations with a high suicide risk.     

Differential contribution of the factors determining long-term renal function after partial nephrectomy over time

PurposeTo define how much of renal function was determined by the preserved renal parenchymal volume and the ischemic insult during partial nephrectomy (PN) long after surgery.MethodsWe analyzed the data of 530 consecutive patients who had undergone PN. For all patients, renal function was measured preoperatively and again at 3 postoperative months, then annually using ^99mTc-diethylenetriaminepentaacetic acid renal scan. Perioperative variables potentially affecting the long-term ipsilateral glomerular filtration rate (GFR) and their time-varying contribution were assessed using a linear mixed model.ResultsThe mean preoperative ipsilateral GFR was 42.9 ml/min, which decreased by 27.3% at 3 months but began to recover thereafter continuing until 4 years (Δ% GFR at 1, 2, 3, 4, and 5 years: 22.3%, 18.5%, 14.7%, 10.0%, and 9.6%, respectively). Parenchymal volume reduction and ischemic time were significantly associated with postoperative ipsilateral GFR throughout observation period unvarying with time. Diabetes and proteinuria were not significant determinants of ipsilateral function at 3 months but became significant at 5 years. In multivariate analysis regarding recovery slope, volume reduction (β = ?0.026, SE 0.006, P < 0.0001), preoperative ipsilateral GFR (β = ?0.021, SE 0.007, P = 0.0012), proteinuria (β = ?0.942, SE 0.372, P = 0.0116), and diabetes (β = ?0.396, SE 0.197, P = 0.0447) were independently significant.ConclusionIpsilateral renal function continued to improve until 5 years after PN. Parenchymal volume loss was the major determinant and its impact on long-term ipsilateral renal function remained constant while ischemic time affected early GFR reduction with its impact diminishing over time. Patient-related factors including diabetes and proteinuria gained significance over time and became independent determinants of recovery slope.     

“They Assume That You’re Not Having Sex”: A Qualitative Exploration of How Paediatric Healthcare Providers Can Have Positive Sexuality-Related Conversations with Youth with Disabilities

Sexuality and Disability - Every individual should have equal access to sexuality-related information and services. Regrettably, societal stigma revolves around the sexuality of youth with...