Nanomolar concentrations of neuropeptides induce histamine release from peritoneal mast cells of a substrain of Wistar rats.

Substance P causes histamine release from rat peritoneal mast cells probably through direct activation of a specific G protein at micromolar concentrations. We found that peritoneal mast cells of a substrain of Wistar rats (Std:Wistar) responds to nanomolar concentrations of substance P by releasing histamine in a concentration-dependent manner. In addition, potent histamine release from peritoneal mast cells of the substrain rats was also induced by neurokinin A in a concentration-dependent fashion. Histamine release induced by low concentrations of substance P was significantly blocked by a tachykinin NK1 receptor antagonist, CP-96345 [(2S,3S)-cis-2-(diphenylmethyl)-N-[(2-methoxyphenyl)-methyl]-1-aza bicyclo[2.2.2]octan-3-amine dihydrochloride], whereas that induced by concentrations as high as 10 microM appeared resistant to the antagonist. The concentration-histamine release curve for neurokinin A was parallel-shifted to the right by the drug. A tachykinin NK2 receptor antagonist, SR-48968 [(S)-N-methyl-N[4-(4-acetylamino-4-phenyl piperadino)-2-(3,4-dichlorophenyl)butyl]benzamide], did not influence release stimulated by substance P and neurokinin A. On the other hand, peritoneal mast cells of Sprague-Dawley and other Wistar rats did not respond to neurokinin A. At over 1 microM but not at nanomolar concentrations, substance P caused modest histamine release from peritoneal mast cells of these rats. The results suggest that neurokinin A and nanomolar, but not micromolar concentrations of substance P stimulate tachykinin NK receptors on the peritoneal mast cells of Std:Wistar rat to release histamine.     

Chronic hepatitis in interferon-gamma transgenic mice is associated with elevated CPP32-like activity and interleukin-1beta-converting enzyme activity suppression

Interferon-gamma (IFN-gamma) transgenic mice strongly express IFN-gamma in the liver and develop chronic hepatitis. Furthermore, hepatocyte apoptosis was shown by the TdT-mediated dUTP-biotin nick endlabeling method. In the present study, interleukin-1beta-converting enzyme (ICE) and CPP32-like protease activities in the liver of IFN-gamma transgenic mice were measured, using the synthetic substrates Ac-YVAD-MCA and Ac-DEVD-MCA. Plasma aspartate aminotransferase and alanine aminotransferase activities as well as CPP32-like activity were significantly elevated, while ICE activity was significantly reduced. The addition of the ICE inhibitor Ac-YVAD-CHO to IFN-gamma transgenic mouse liver cell cytosol had no effect on the CPP32 activity, in contrast to a CPP32 inhibitor. The present results indicate that chronic hepatitis in the IFN-gamma transgenic mouse is associated with a decrease in ICE and induction of CPP32-like activity.     

Effect of beraprost sodium on pulmonaryvascular resistance in candidates for a Fontan procedure: A preliminarystudy

OBJECTIVE: Although long-term prostacyclin(PGI2) therapy in patients with severe pulmonary hypertension (PH)reduces pulmonary vascular resistance (PVR), there have been no reports on its therapeutic effects in patients with mild PH. We investigated the chronic effect of beraprost sodium (BPS), an oral PGI2 analog, in children with mild PH. METHODS: We studied 20 patients who were destined for a Fontan procedure with a mean pulmonary arterial pressure(PAP) of>20 mmHg and/or PVR of>3.0 Wood units. Both the PAP and the PVR in these cases were too high for patients to undergo a successful Fontan procedure. Seven patients received BPS (PG group) and 13 did not (control group). All patients underwent repeat cardiac catheterization to examine pulmonary hemodynamics. RESULTS: In the PG group, the pulmonary-to-systemic flow ratio (Qp/Qs) did not change after BPS administration(1.1 +/- 0.6 vs 1.3 +/- 0.9);however, the mean PAP decreased significantly (25.3 +/- 8.2 vs 19.9 +/- 6.5 mmHg; P < 0.05),as did PVR (3.7 +/- 1.3 vs 2.3 +/- 0.9 Wood units; P < 0.05), whereas the pulmonary artery (PA) index increased significantly (312 +/- 136 vs 375 +/- 165; P < 0.05). In the control group, the mean PAP decreased significantly (24.9 +/- 4.7 vs 19.8 +/- 6.3 mmHg; P < 0.05)and the PA index increased significantly (295 +/- 72 vs 362 +/- 114; P < 0.05). No significant changes in Qp/Qs (1.5 +/- 0.8 vs 1.4 +/- 0.6)or PVR (2.9 +/- 1.3 vs 2.5 +/- 0.8 Wood units) were observed. CONCLUSION: We conclude that long-term BPS administration probably reduces PVR in potential candidates for a Fontan procedure with mild PH. This treatment would reduce the risks associated with the Fontan procedure and would also improve its outcome.     

精子异常症:治疗篇

众所周知，有47%的不育是由于精子异常引起的。尽管医学发展迅速，仍有40%的不育患者存在病因不明的精液异常使临床疗效受限。另一方面，有报道显示中医疗法治疗精索静脉曲张、前列腺炎和精子异常疗效满意。我们尝试通过盲法对照试验观察针灸对精子异常不育患者的精子浓度、形态和活力是否有改善作用。     

Modulation of platelet aggregation after percutaneous transluminal angioplasty of the iliac artery for atherosclerosis obliterans

BACKGROUND: Platelet aggregation is modulated by blood flow. We investigated whether platelet function is altered during percutaneous transluminal balloon angioplasty in patients with atherosclerosis obliterans. METHODS: Blood samples were obtained from the iliac artery in 9 lower limbs of 7 patients undergoing percutaneous balloon angioplasty of the iliac artery. An agonists-induced platelet aggregation test was performed with an aggregometer. Femoral blood flow was measured with a Doppler velocimeter before and after the procedure. RESULTS: Before dilatation, the maximum platelet aggregation rates (+/- SEM) induced by adenosine phosphate, epinephrine, and arachidonic acid were 54.7% +/- 5.8%, 64.8% +/- 4.3%, and 60.5% +/- 6.1%, respectively. After angioplasty, these values reduced to 36.7% +/- 4.1%, 36.1% +/- 8.6%, and 40.1% +/- 5.0%, respectively (P < .05). The pre-procedural ankle-brachial pressure index, mean flow rate, mean velocity, and shear stress variation were 0.63 +/- 0.1, 218.1 +/- 32.1 mL/min, 9.4 +/- 1.1 cm/sec, and 60.6 +/- 17.7 dyne/cm2, respectively. The mean velocity at the stenotic lesion was 215.1 +/- 83.9 cm/sec, which was significantly greater than those of the distal artery or after angioplasty (P < .01). Both ankle-brachial pressure index and shear stress variation increased after angioplasty to 0.99 +/- 0.07 (P < .05) and 139.8 +/- 17.0 (P < .05) dyne/cm2, but the mean flow rate and the mean velocity (198.3 +/- 24.5 mL/min and 8.8 +/- 1.2 cm/sec after angioplasty) did not change significantly. CONCLUSIONS: These results indicate that activated platelet function at a stenosed artery was decreased after angioplasty, possibly because of normalized blood flow with reduction of stenotic lesion.     

Fusobacterium nucleatum confers chemoresistance by modulating autophagy in oesophageal squamous cell carcinoma

Background Fusobacterium nucleatum (F. nucleatum) is a gut microbe implicated in gastrointestinal tumorigenesis. Predicting the chemotherapeutic response is critical to developing personalised therapeutic strategies for oesophageal cancer patients. The present study investigated the relationship between F. nucleatum and chemotherapeutic resistance in oesophageal squamous cell carcinoma (ESCC).Methods We examined the relationship between F. nucleatum and chemotherapy response in 120 ESCC resected specimens and 30 pre-treatment biopsy specimens. In vitro studies using ESCC cell lines and co-culture assays further uncovered the mechanism underlying chemotherapeutic resistance.Results ESCC patients with F. nucleatum infection displayed lesser chemotherapeutic response. The infiltration and subsistence of F. nucleatum in the ESCC cells were observed by transmission electron microscopy and laser scanning confocal microscopy. We also observed that F. nucleatum modulates the endogenous LC3 and ATG7 expression, as well as autophagosome formation to induce chemoresistance against 5-FU, CDDP, and Docetaxel. ATG7 knockdown resulted in reversal of F. nucleatum-induced chemoresistance. In addition, immunohistochemical studies confirmed the correlation between F. nucleatum infection and ATG7 expression in 284 ESCC specimens.Conclusions F. nucleatum confers chemoresistance to ESCC cells by modulating autophagy. These findings suggest that targeting F. nucleatum, during chemotherapy, could result in variable therapeutic outcomes for ESCC patients.Subject terms: Tumour biomarkers, Oesophageal cancer     

High calcium enhances the expression of double‐stranded RNA sensors and antiviral activity in epidermal keratinocytes

Double‐stranded RNA (dsRNA) sensors including TLR3, MDA5 and RIG‐I are expressed in epidermal keratinocytes and play an important immunological role by enhancing various innate and adaptive immune responses. Although the role of elevated extracellular calcium concentration in keratinocyte differentiation is well understood, the effect of high calcium on dsRNA sensors is not well studied. We investigated alterations in dsRNA sensor expression and antiviral activity induced by a high extracellular concentration of calcium in epidermal keratinocytes. Normal human epidermal keratinocytes (NHEKs) were stimulated with high calcium and/or synthetic dsRNA, poly (I:C). TLR3, IFIH1 (MDA5) and DDX58 (RIG‐I) expression were measured via qPCR, and IFN‐β and human beta‐defensin 2 (HBD2) levels were measured using ELISA. TLR3 localization was evaluated with immunocytofluorescence. Antiviral activity was quantified with virus plaque assays using herpes simplex virus type 1 (HSV‐1). High calcium significantly upregulated mRNA expression of TLR3, IFIH1 and DDX58 in NHEKs. In addition, high calcium significantly enhanced poly (I:C)‐induced anti‐HSV‐1 activity in NHEKs. The antiviral molecule HBD2 but not IFN‐β induction by poly (I:C) was enhanced by high calcium. Our findings indicate that high levels of extracellular calcium enhance the expression of dsRNA sensors and augment antiviral activity in epidermal keratinocytes.