儿童输注少白细胞血制品前使用扑热息痛或苯海拉明的研究

儿科血液病或癌症病人常因血小板减少及贫血而需要输血。输血可能导致不良反应的发生,包括那些少见但却潜在威胁病人生命的一些输血反应,如ABO血型不合的溶血反应、输血相关性脓毒血症、循环超负荷和输血相关急性肺损伤等。非溶血性发热反应和过敏反应是较常见的两种输血反应,它们通常不会造成严重的临床后果,或降低输血疗效。过去非溶血性发热反应发生率高达30%。而使用少白细胞血液制品(包括单采血小板)后,其发生率仅有0.03%~2.18%,过敏反应的发生率则小于1%。发热反应发生率高的原因可能是病人输注手工混合血小板及未经去白细胞处理的…     

In vitro and in vivo characterization of A-940894: a potent histamine H4 receptor antagonist with anti-inflammatory properties

Background and purpose:

The histamine H₄ receptor is widely expressed in cells of immune origin and has been shown to play a role in a variety of inflammatory processes mediated by histamine. In this report, we describe the in vitro and in vivo anti-inflammatory properties of a potent histamine H₄ receptor antagonist, A-940894 (4-piperazin-1-yl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine).

Experimental approach:

We have analysed the pharmacological profile of A-940894 at mouse native, rat recombinant and human recombinant and native, histamine H₄ receptors by radioligand binding, calcium mobilization, mast cell shape change, eosinophil chemotaxis assays and in the mouse model of zymosan-induced peritonitis.

Key results:

A-940894 potently binds to both human and rat histamine H₄ receptors and exhibits considerably lower affinity for the human histamine H₁, H₂ or H₃ receptors. It potently blocked histamine-evoked calcium mobilization in the fluorometric imaging plate reader assays and inhibited histamine-induced shape change of mouse bone marrow-derived mast cells and chemotaxis of human eosinophils in vitro. In a mouse mast cell-dependent model of zymosan-induced peritonitis, A-940894 significantly blocked neutrophil influx and reduced intraperitoneal prostaglandin D₂ levels. Finally, A-940894 has good pharmacokinetic properties, including half-life and oral bioavailability in rats and mice.

Conclusions and Implications:

These data suggest that A-940894 is a potent and selective histamine H₄ receptor antagonist with pharmacokinetic properties suitable for long-term in vivo testing and could serve as a useful tool for the further characterization of histamine H₄ receptor pharmacology.     

41Temporary gastric electrical stimulation and the EGG: the SENSA phenomenon.

Introduction: We previously reported that temporary gastric electrical stimulation (GES) is associated with an increase in EGG frequency (IEGGS 2005). We now report further on this phenomenon, which we have labeled Submucosal Enteric Nervous System Activation or SENSA. Patients: We studied 121 patients (18 m, 103 f, mean age 39 years with dx: 71 Idiopathic, 37 diabetes mellitus and 13 post‐surgical disorders) who underwent temporary endoscopic GES. All patients had complete data for baseline cutaneous EGG (Base) and a repeat cutaneous EGG (Temp) after 3 day of temporary GES. Methods: Patients had cutaneous EGGs at baseline and again after temporary GES, performed with high‐frequency, low‐energy stimulation parameters, as previously described (GIE, 2005). Temporary GES mucosal electrode placement was near the submucosal plexus, confirmed by endoscopy. EGGs, performed at a standard time in relation to a low‐fat meal, were reported as average frequency (F, in cpm), were compared by t‐tests with baseline, reported as mean ± SE. Results: For the whole group EGG done with Temporary GES revealed a slight increase in frequency over baseline, but the results were not statistically significant. However, when stratified at baseline as Low (average F < 3.3) or High (≥3.3) a number of differences were present: the patients with Low EEG increased significantly (2.7 (0.1) at Base to 4.5 (0.2) with Temp , p = 0.001) but not for high EGG (4.7 (0.1) to 4.4 (0.1), p = 0.67). See the results detailed in the table below. Conclusion: The occurrence of the phenomena of Submucosal Enteric Nervous System Activation (SENSA) appears dependent on the characteristics of the baseline EGG. As with gastric emptying, careful characterization of baseline values is important when reporting the effects of GES on the EGG. The SENSA phenomena, when occurring, may give important clues to the mechanisms involved in the beneficial effects of temporary gastric electrical stimulation.

Contribution of SNRNP200 sequence variations to retinitis pigmentosa

Purpose

Mutations in the SNRNP200 gene have been reported to cause autosomal dominant retinitis pigmentosa (adRP). In this study, we evaluate the mutation profile of SNRNP200 in a cohort of southern Chinese RP patients.

Methods

Twenty adRP patients from 11 families and 165 index patients with non-syndromic RP with mixed inheritance patterns were screened for mutations in the mutation hotspots of SNRNP200. These included exons 12–16, 22–32, and 38–45, which covered the two helicase ATP-binding domains in DEAD-box and two sec-63 domains. The targeted regions were amplified by polymerase chain reaction and analyzed by direct DNA sequencing, followed by in silico analyses.

Results

Totally 26 variants were identified, 18 of which were novel. Three non-synonymous variants (p.C502R, p.R1779H and p.I698V) were found exclusively in patients. Two of them, p.C502R and p.R1779H, were each identified in one simplex RP patient, whereas p.I698V occurred in one patient with unknown inheritance pattern. All three residues are highly conserved in SNRNP200 orthologs. Nevertheless, only p.C502R and p.R1779H were predicted to affect protein function by in silico analyses, suggesting these two variants are likely to be disease-causing mutations. Notably, all mutations previously identified in other study populations were not detected in this study.

Conclusions

Our results reveal a distinct mutation profile of the SNRNP200 gene in a southern Chinese cohort of RP patients. The identification of two novel candidate mutations in two respective patients affirmed that SNRNP200 contributes to a proportion of overall RP.     

Spinal glial TLR4-mediated nociception and production of prostaglandin E2 and TNF

Background and purpose:

Toll-like receptor 4 (TLR4) expressed on spinal microglia and astrocytes has been suggested to play an important role in the regulation of pain signalling. The purpose of the present work was to examine the links between TLR4, glial activation and spinal release of prostaglandin E₂ (PGE₂) and tumour necrosis factor (TNF), and the role these factors play in TLR4-induced tactile allodynia.

Experimental approach:

Toll-like receptor 4 was activated by intrathecal (i.t.) injection of lipopolysaccharide (LPS) and KDO₂-Lipid A (KDO₂) to rats. Tactile allodynia was assessed using von Frey filaments and cerebrospinal fluid collected through spinal dialysis and lumbar puncture. PGE₂ and TNF levels were measured by mass spectometry and elisa. Minocycline and pentoxifylline (glia inhibitors), etanercept (TNF-blocker) and ketorolac (COX-inhibitor) were given i.t. prior to injection of the TLR4-agonists, in order to determine if these agents alter TLR4-mediated nociception and the spinal release of PGE₂ and TNF.

Key results:

Spinal administration of LPS and KDO₂ produced a dose-dependent tactile allodynia, which was attenuated by pentoxifylline, minocycline and etanercept but not ketorolac. Both TLR4 agonists induced the spinal release of PGE₂ and TNF. Intrathecal pentoxifylline blunted PGE₂ and TNF release, while i.t. minocycline only prevented the spinal release of TNF. The release of PGE₂ induced by LPS and KDO₂ was attenuated by i.t. administration of ketorolac.

Conclusions and implications:

Activation of TLR4 induces tactile allodynia, which is probably mediated by TNF released by activated spinal glia.     

Dendritic cell generation and CD4+CD25HIGHFOXP3+ regulatory T cells in human head and neck carcinoma during Radio-chemotherapy

Background

Regulatory T cells (Treg) and dendritic cells (DC) play an important role in tumor immunity and immune escape. However, their interplay and the effects of anti-cancer therapy on the human immune system are largely unknown.

Methods

For DC generation, CD14⁺ monocytes were enriched by immunomagnetic selection from peripheral blood of advanced head and neck squamous cell carcinoma (HNSCC) patients and differentiated into immature DC using GM-SCF and IL-4. DC maturation was induced by addition of TNFα. The frequency of CD4⁺CD25^highF0XP3⁺ Treg in HNSCC patients was analyzed before and after radio-chemotherapy (RCT) by four-color flow cytometry.

Results

In HNSCC patients, the frequency of Treg (0.33 ± 0.06%) was significantly (p = 0.001) increased compared to healthy controls (0.11 ± 0.02%), whereas RCT had variable effects on the Treg frequency inducing its increase in some patients and decrease in others. After six days in culture, monocytes of all patients had differentiated into immature DC. However, DC maturation indicated by CD83 up-regulation (70.7 ± 5.5%) was successful only in a subgroup of patients and correlated well with lower frequencies of peripheral blood Treg in those patients.

Conclusion

The frequency of regulatory T cells is elevated in HNSCC patients and may be modulated by RCT. Monocyte-derived DC in HNSCC patients show a maturation deficiency ex vivo. Those preliminary data may have an impact on multimodality clinical trials integrating cellular immune modulation in patients with advanced HNSCC.     

Surgical repair of pulmonary vein injury from blunt trauma

Pulmonary vein deceleration injury is rare and patients can be deceptively stable for a period after injury. Quick diagnosis and transfer to the operating theatre is the only way to treat this potentially lethal injury successfully. Techniques of repair are a useful addition to the cardiovascular surgeon’s repertoire.