Divergent role of heme oxygenase inhibition in the pathogenesis of sepsis

The reduction of neutrophil migration to an infectious focus is associated with a high mortality in severe sepsis. Previously, we showed that heme oxygenase (HO) products downregulate neutrophil recruitment in a noninfectious inflammatory model. The present study was designed to determine the role of HO in sepsis induced by cecal ligation and puncture (CLP) model. We demonstrated that pretreatment, but not the combination of pretreatment plus posttreatment with zinc protoporphyrin IX (ZnPP IX), an HO inhibitor, prevented the reduction of CXCR2 on circulating neutrophils and the failure of intraperitoneal neutrophil migration to the site of infection. Consequently, bacterial dissemination, systemic inflammatory response, and organ injury were prevented. In addition, pretreatment with the HO inhibitor avoided hypotension and consequently increased survival. Moreover, in mice subjected to severe CLP, the pretreatment, but not the combination of pretreatment plus posttreatment with ZnPP IX, prevented the increase of plasmatic free heme observed in nontreated severe CLP. The administration of exogenous hemin to mice subjected to moderate sepsis consistently increased the mortality rate. Furthermore, hemin resulted in a reduction of neutrophil migration both in vivo and in vitro. Altogether, our results demonstrated that pretreatment with the HO inhibitor prevents the pathological findings in severe CLP. However, the combination of pretreatment plus posttreatment with ZnPP IX enhances sepsis severity because of an increase in circulating levels of heme, which is deleterious to the host tissues and also inhibits neutrophil migration.     

Once-daily ceftriaxone therapy for serious bacterial infections in children.

Ceftriaxone administered as a single daily dose of 50 mg/kg was evaluated in the treatment of 35 children with a variety of nonmeningitic bacterial infections. In two of the patients, the drug was discontinued before the response to the drug could be evaluated. All of the remaining patients had a satisfactory response. In 22 of the patients, plasma was available for the determination of ceftriaxone levels 1 h after a dose and immediately before the next dose. All but one of these patients had trough ceftriaxone levels which exceeded the MIC of the infecting organism, although marginally so for Staphylococcus aureus. Ceftriaxone appears to be safe and effective in the treatment of a variety of bacterial pathogens in children when administered at a single daily dose of 50 mg/kg. This drug may be especially useful in those patients in whom outpatient antibiotic therapy is contemplated or in whom maintenance of intravenous access is difficult.     

Low-density lipoprotein subclass and its correlating factors in diabetics

OBJECTIVES: Small dense LDL, low density lipoprotein (LDL) particles with small size and high density, is regarded as a significant risk factor for cardiovascular diseases. Diabetes mellitus is one of the conditions accompanied by increased small dense LDL. We analyzed LDL subclass in type 2 diabetics and normal controls with LipoPrint LDL System to investigate the LDL heterogeneity in diabetics and factors affecting it. DESIGN AND METHODS: We selected 40 normal controls and 40 type 2 diabetics with fasting blood glucose level over 7.0 mmol/L and HbA1c level over 7%. LDL subclass was determined with LipoPrint LDL System. LipoPrint LDL System fractionates LDL into seven parts (LDL1-7) by size and LDL3 to LDL7 are defined as small-sized LDL. In addition we estimated 'the percent of small-sized LDL over whole LDL' and defined it as 'small-sized LDL proportion'. RESULTS: Mean small-sized LDL proportion was significantly higher in diabetics (23.4%) than in controls (11.8%) (p<0.001) and small-sized LDL proportion showed positive correlation with blood levels of glucose, HbA1c, total cholesterol, triglyceride, and oxidized LDL and negative correlation with HDL cholesterol level in univariate analysis (p<0.001). Of these parameters, triglyceride, HbA1c, oxidized LDL were statistically significant variables contributing to the small-sized LDL proportion in stepwise multiple regression analysis. CONCLUSIONS: We analyzed small-sized LDL proportion in type 2 diabetics and found that it was significantly increased in diabetics than control subjects and it was independently correlated with triglyceride, HbA1c, oxidized LDL in descending order, which are reflecting lipid metabolism, glycation, and oxidative stress, respectively.     

Pain assessment in nonverbal children with severe cognitive impairments: the Individualized Numeric Rating Scale (INRS)

Children's Hospital Boston began a major pain assessment and management initiative 3 years ago: Pain assessment and management are considered one of the institution's primary standards of care. The initiative included State of the Science meetings with internationally renowned nursing pain researchers and clinicians. These meetings generated nursing staff interest in specific applications of what is known about pain; how evidence-based knowledge can be used to ask population-specific clinical questions; and how an evidence-based approach can be applied to systematically develop, implement, and assess interventions that suit a population's clinical needs. This article is an example of an evidence-based pain assessment project at Children's Hospital Boston that focused on nonverbal children with cognitive impairments. After developing a clinical question, the authors did a literature review and a benchmarking analysis of best practice. The pilot of an adapted, existing pain assessment tool is described in this article.     

Transfer of allergic airway responses with antigen-primed CD4+ but not CD8+ T cells in brown Norway rats.

Activated CD4+ helper T cells have been demonstrated in asthmatic airways and postulated to play a central role in eliciting allergic inflammation; direct evidence of their involvement seems to be lacking. We hypothesized that CD4+ T cells have the potential to induce allergic responses to antigen challenge, and tested this hypothesis in a model of allergic bronchoconstriction, the Brown Norway rat, using the approach of adoptive transfer. Animals were actively sensitized to either ovalbumin (OVA) or BSA and were used as donors of T cells. W3/25(CD4)+ or OX8(CD8)+ T cells were isolated from the cervical lymph nodes of sensitized donors and transferred to naive BN rats. 2 d after adoptive transfer recipient rats were challenged by OVA inhalation, and changes in lung resistance (RL), bronchoalveolar lavage (BAL) cells, and serum levels of antigen-specific IgE were studied. After OVA challenge recipients of OVA-primed W3/25+ T cells exhibited sustained increases in RL throughout the entire 8-h observation period and had significant bronchoalveolar lavage eosinophilia, which was detected by immunocytochemistry using an antimajor basic protein mAb. Recipients of BSA-primed W3/25+ T cells or OVA-primed OX8+ T cells failed to respond to inhaled OVA. OVA-specific immunoglobulin E was undetectable by ELISA or skin testing in any of the recipient rats after adoptive transfer. In conclusion, antigen-induced airway bronchoconstriction and eosinophilia were successfully transferred by antigen-specific W3/25+ T cells in Brown Norway rats. These responses were dependent on antigen-primed W3/25+ T cells and appeared to be independent of IgE-mediated mast cell activation. This study provides clear evidence for T cell mediated immune mechanisms in allergic airway responses in this experimental model.     

Differential in situ cytokine gene expression in acute versus chronic atopic dermatitis.

We tested effects of long-term exposure of pancreatic islets to free fatty acids (FFA) in vitro on B cell function. Islets isolated from male Sprague-Dawley rats were exposed to palmitate (0.125 or 0.25 mM), oleate (0.125 mM), or octanoate (2.0 mM) during culture. Insulin responses were subsequently tested in the absence of FFA. After a 48-h exposure to FFA, insulin secretion during basal glucose (3.3 mM) was several-fold increased. However, during stimulation with 27 mM glucose, secretion was inhibited by 30-50% and proinsulin biosynthesis by 30-40%. Total protein synthesis was similarly affected. Conversely, previous palmitate did not impair alpha-ketoisocaproic acid (5 mM)-induced insulin release. Induction and reversibility of the inhibitory effect on glucose-induced insulin secretion required between 6 and 24 h. Addition of the carnitine palmitoyltransferase I inhibitor etomoxir (1 microM) partially reversed (by > 50%) FFA-associated decrease in secretory as well as proinsulin biosynthetic responses to 27 mM glucose. The inhibitory effect of previous palmitate was similar when co-culture was performed with 5.5, 11, or 27 mM glucose. Exposure to palmitate or oleate reduced the production of 14CO2 from D-[U-14C]glucose, and of 14CO2 from D-[3,4-14C]-glucose, both effects being reversed by etomoxir. Conclusions: long-term exposure to FFA inhibits glucose-induced insulin secretion and biosynthesis probably through a glucose fatty acid cycle.     

北方汉族人原发性高血压易感性与肿瘤坏死因子α和转化生长因子β基因型多态性的关联

目的：探讨中国北方地区汉族人肿瘤坏死因子α和转化生长因子β基因型的多态性与原发性高血压发病的相关性。 方法：①选择2004-06／2005—01哈尔滨市第一医院门诊和住院原发性高血压患者36例为高血压组，男20例，女16例。选择2004—04／2005-12哈尔滨市第一医院健康体检者40人为对照组，男23人，女17人。均为北方汉族，且均对检测项目知情同意。②采用顺序特异性引物聚合酶链反应方法检测肿瘤坏死因子α和转化生长因子β基因型别多态性变化。③计数资料差异性比较采用χ^2检验。 结果：原发性高血压患者36例和健康者40人均进入结果分析。①原发性高血压组肿瘤坏死因子α（308A）等位基因频率明显高于对照组（42％，10％，P〈0．01）。②两组转化生长因子β基因频率差异不明显（P〉0．05）。 结论：中国北方地区汉族人肿瘤坏死因子α（308h）等位基因位点的多态性可能与原发性高血压的易感性相关联。     

Anti-human immunodeficiency virus type 1 activity and in vitro toxicity of 2''-deoxy-3''-thiacytidine (BCH-189), a novel heterocyclic nucleoside analog.

We describe a novel nucleoside analog, 2'-deoxy-3'-thiacytidine (BCH-189), in which the 3' carbon of the ribose ring of 2'-deoxycytidine has been replaced by a sulfur atom. In MT-4 T cells, this compound had significant time- and dose-dependent antiviral activity against five different strains of human immunodeficiency virus type 1 (HIV-1) (mean 50% inhibitory dose, 0.73 microM); known 3'-azido-3'-deoxythymidine (AZT)-resistant HIV-1 variants did not exhibit cross-resistance to it. BCH-189 also suppressed HIV-1 replication in the U937 monocytoid cell line as well as in primary cultures of human peripheral blood mononuclear cells; in these latter systems, suppression was fuller and longer lasting than that induced by AZT. Moreover, BCH-189 was less toxic than AZT in cell culture. BCH-189 may be a promising drug for the treatment of HIV-1-associated disease.     

Diagnosis of solid breast lesions by elastography 5-point score and strain ratio method

Purpose

To compare the diagnostic performance of 5-point scoring system and strain ratio by sonoelastography in the assessment of solid breast lesions.

Material and methods

One hundred and eighty-seven solid masses in 155 patients were scanned by two-dimensional ultrasonography and sonoelastography. Elasticity scores were determined with a 5-point scoring method, and the strain ratio was based on the comparison of the average strain measured in the lesion with the adjacent breast tissue in the same depth. Pathological results were taken as gold standards to compare the diagnostic efficacy of two methods with clinical diagnostic test and receiver operating characteristic (ROC) curves.

Results

Among 187 lesions, 130 were benign and 57 were malignant. The mean scores (1.62 ± 0.69 vs 4.07 ± 0.26, P < 0.05) and strain ratios (2.06 ± 1.27 vs 6.66 ± 4.62, P < 0.05) were significantly higher of malignant than benign lesions. The area under the curve for the 5-point scoring system and for strain ratio-based elastographic analysis was 0.892 and 0.909, respectively (P > 0.05). For 5-point scoring, sonoelastography had 84.2% sensitivity, 84.6% specificity, 84.5% accuracy, 70.6% positive predictive value and 92.4% negative predictive value. When a cutoff point of 3.06 was used, sensitivity, specificity, accuracy, positive and negative predictive values were 87.7%, 88.5%, 88.2%, 76.9% and 94.3%, respectively for the strain ratio (P > 0.05).

Conclusions

The 5-point scoring system and strain ratio has similar diagnostic performance, and the strain ratio could be more objective to differentiate the masses when those masses were difficult to be judged by using 5-point scoring system in sonoelastographic images.