Neutrophil activation and arteritis induced by C. albicans water-soluble mannoprotein-beta-glucan complex (CAWS)

We have established a mouse model which shows the symptoms of coronary arteritis after consecutive injections of CAWS, which is released from Candida albicans. In this study, we examined neutrophil activation in the initial period after CAWS injection intraperitoneally. During 10 min to 16 h after the injection, blood profiles and neutrophil functions were determined. At the same time, levels of inflammatory cytokines and chemokines in plasma were measured. Furthermore, level of ICAM-1 as a marker of lesion in arterial endothelial cells was measured. Counts of the peripheral leukocytes increased immediately after CAWS injection, especially involving neutrophil. In vitro sensitivity of neutrophils to stimuli was enhanced. Moreover, proinflammatory cytokines (IL-1beta, IL-12 and IL-6) increased in plasma initially followed by an increase in IL-10, G-CSF, MIP-2 and soluble ICAM-1. Locally, ICAM-1 message in arterial walls was significantly increased 16 h after CAWS injection. A decrease in C3 levels was observed in plasma, suggesting complement activation and consumption. In summary, neutrophil activation occurred after CAWS injection, followed by complement activation, and production of proinflammatory cytokines chemokines and G-CSF which may be involved in development of coronary arteritis.     

Distribution and frequencies of CDH23 mutations in Japanese patients with non-syndromic hearing loss

Mutations in the CDH23 gene are known to be responsible for both Usher syndrome type ID (USH1D) and non-syndromic hearing loss (DFNB12), and the molecular confirmation of the CDH23 gene has become important in the diagnosis of these conditions. The present study was performed to find whether the CDH23 mutations are also responsible for non-syndromic hearing loss in patients in the Japanese population. A total of 51 sequence variants were found in 64 Japanese probands with non-syndromic sensorineural hearing impairment from autosomal recessive families. Among them, at least four missense mutations in six patients from five families were confirmed to be responsible for deafness by segregation study. All mutations detected were missense mutations, corroborating the previous reports regarding DFNB12. The present data confirmed that CDH23 mutations are frequently found and significantly responsible in Japanese. Interestingly, the CDH23 mutation spectrum in Japanese is very different from that found in Caucasians. This Japanese spectrum may be representative of those in Eastern Asian populations and its elucidation is expected to facilitate the molecular diagnosis of DFNB12 and USH1D.     

Characterization of de novo microdeletions involving 17q11.2q12 identified through chromosomal comparative genomic hybridization

High-resolution array-comparative genome hybridization (CGH) is a powerful tool for detection of submicroscopic chromosome deletions and duplications. We describe two patients with mild mental retardation (MR) and de novo microdeletions of 17q11.2q12. Although the deletions did not involve the neurofibromatosis type 1 (NF1) gene, they overlap with long-range deletions of the NF1 region which have been encountered in a small group of NF1 patients with more severe MR. Given the overlap of the deletions in our two patients with the large-sized NF1 microdeletions but not with the more frequent and smaller NF1 deletions, we hypothesize that more than one gene in the 17q11.2q12 region may be involved in MR. We discuss candidate genes for MR within this interval that was precisely defined through array-CGH analysis.     

The influence of physicochemical properties on the reactivity and stability of acyl glucuronides†

1.?Formation of 1-O-acyl-β-d-glucuronide conjugates is a significant pathway in the metabolism of drugs containing a carboxylic acid group. The formation of acyl glucuronides results in an increase in both the aqueous solubility and molecular mass of the conjugate in comparison to the parent drug and thus facilitates excretion in both urine and bile.

2.?Acyl glucuronides are effectively esters, which undergo first order decomposition by both hydrolysis and the intra-migration of the acyl group around the glucuronide ring to yield 2-, 3- and 4-O-glucuronic acid esters which, unlike the metabolically formed 1-O-acyl-β-d-glucuronides, are not substrates for β-glucuronidase. The first order degradation half-life is therefore a composite value of these two reactions and a useful indicator of chemical reactivity and potential toxicity.

3.?Intra-molecular migration is expected to be the predominant pathway due to entropic considerations.

4.?Such conjugates, together with their isomeric ester derivatives, react with nucleophilic sites on proteins and small endogenous molecules, such as glutathione, which potentially contributes to the observed toxicity and adverse drug reactions associated with some drugs.

5.?Examination of the stability of the 1-O-acyl-β-d-glucuronides of aryl acetic acid, α-carbon substituted aryl acetic acid, aliphatic and aromatic acids, as determined by their first order degradation half-lives, indicates the significance of electronic and steric features that contribute to conjugate stability under physiological conditions.

6.?Examination of the of the electronic properties of the carbonyl carbon atom in acyl glucuronides, as measured by the pKa of the parent acid, together with the steric substituents about the acyl carbonyl provides insight into the reactivity of these conjugates.

7.?The investigations reported herein on a large number of 1-O-acyl-β-d-glucuronides has allowed rationalisation of their physicochemical properties in relation to the structure of the parent drug and has the potential to contribute to the design of carboxylic acid containing drug molecules with increased stability of a major metabolite with potential reduction in toxicity and adverse drug reactions.     

某三甲医院围手术期预防性使用抗菌药物的干预及效果

目的探讨科学有效的合理使用抗菌药物的干预方法,为提高抗菌药物预防性使用的合理率提供参考依据。方法选取2011年1—12月及2016年1—12月出院的Ⅰ类切口手术患者为研究对象,2011年为干预前组,2016年为干预后组。制定干预方案,并监测和比较干预前后两组Ⅰ类切口手术患者抗菌药物预防性使用率及合理率。结果干预前后两组分别监测Ⅰ类切口手术患者1 027、3 820例。2012年1月起对围手术期抗菌药物预防性合理使用采取综合干预措施,干预后抗菌药物预防性使用率Ⅰ类切口手术患者由97.18%(998/1 027)下降至21.23%(811/3 820),"7类"手术患者由96.33%(210/218)下降至1.88%(25/1 330);抗菌药物品种选择合理率由21.14%上升至99.38%;用药时机合理率由76.05%上升至99.01%;疗程合理率由23.95%上升至99.06%;联合用药率由12.73%降低至0;术中追加药物合理率由11.72%上升至95.18%;干预前后两组比较,差异均有统计学意义(均P0.01)。Ⅰ类切口手术患者SSI发病率干预前为0.32%,干预后为0.61%,差异无统计学意义(χ2=0.75,P=0.54)。结论有效的干预使围手术期预防性抗菌药物的使用逐步规范,符合国家相关要求。     

OPRM1 A118G and serum β-endorphin interact with sex and digit ratio (2D:4D) to influence risk and course of alcohol dependence

Activation of mesolimbic mu-opioid receptors by their endogenous ligand, β-endorphin, can mediate the rewarding effects of alcohol. However, there is conflicting evidence on the relationship between the mu-opioid receptor (OPRM1) A118G single nucleotide polymorphism (SNP) and alcohol dependence risk. Preclinical evidence suggests that sex and sex hormone-dependent prenatal brain organization may interact with the opioid system to influence alcohol drinking behavior. We genotyped 200 alcohol-dependent patients and 240 healthy individuals for the OPRM1 A118G SNP and measured serum β-endorphin level at recruitment and after acute withdrawal. We then determined the association between these factors and alcohol dependence risk and 24-month outcome in the context of both sex and second-to-fourth digit lengths ratio (2D:4D) – a biomarker of prenatal sex hormone levels. The OPRM1 A118G AA genotype associated with elevated risk of alcohol-related hospital readmission, more readmissions, and fewer days until first readmission in male patients only. After normalizing patient 2D:4D against control 2D:4D, we found that normalized 2D:4D ratios were lower in male 118G patients than male AA patients, suggesting prenatal androgens interact with OPRM1 to influence alcohol dependence risk. In addition, β-endorphin levels after acute withdrawal correlated negatively with withdrawal severity in females but not in males, which may indicate β-endorphin protects against withdrawal-induced stress in a sex-specific manner.     

头孢哌酮与β-内酰胺酶抑制剂复方研究进展

头孢哌酮是第三代头孢菌素类抗生素,抗菌谱广,对敏感菌引起的多种感染有良好疗效。随着头孢哌酮在临床上的广泛应用乃至滥用,耐药率逐渐升高。国内外研究表明β-内酰胺抗生素与β-内酰胺酶抑制剂联用是解决临床细菌耐药的有效方法之一。本文阐述国内头孢哌酮复方制剂的情况,对比了不同头孢哌酮复方制剂中联用β-内酰胺酶的配伍比例和用法用量的情况,为临床合理选择使用头孢哌酮复方制剂提供参考。     

Prevalence of vitamin B12 deficiency in healthy Indian school‐going adolescents from rural and urban localities and its relationship with various anthropometric indices: a cross‐sectional study

Background

Micronutrient deficiency is a global health burden, especially among developing countries. The present cross‐sectional study aimed to determine the prevalence of vitamin B₁₂ deficiency in healthy Indian school‐going adolescents, based on area of residence, sex and body mass index (BMI) . Furthermore, the relationship of serum B₁₂ concentration with dietary vitamin B₁₂ intake and anthropometric indices was assessed among adolescents from rural and urban India.

Methods

A total of 2403 school‐going adolescents (11–17 years) from National Capital Region and rural areas of Haryana, India were selected. Serum B₁₂ concentrations were estimated using an electrochemiluminescence immunoassay. Dietary assessments were conducted on 65% of total participants (n  = 1556) by two 24‐h diet recalls.

Results

The prevalence of vitamin B₁₂ deficiency in the total study population was 32.4% (rural: 43.9% versus urban: 30.1%, P  < 0.001; male: 34.4% versus female: 31.0%, P  < 0.05; normal weight: 28.1%, versus overweight: 39.8%, versus obese: 51.2%, P  < 0.001). More than half (51.2%) of obese adolescents were vitamin B₁₂ deficient. On multiple linear regression analysis, serum B₁₂ in rural adolescents was associated with age (β = ?0.12, P  < 0.05). Among urban adolescents, serum B₁₂ was associated with BMI (β = ?0.08, P  < 0.05) and adjusted dietary vitamin B₁₂ intake (β = 0.14, P  < 0.001). Serum vitamin B₁₂ levels were found to be lower in rural females (β = ?0.12, P  = 0.030) and urban males (β: 0.11, P  < 0.001) compared to their respective contemporaries.

Conclusions

Vitamin B₁₂ deficiency was higher among rural school‐going adolescents. Boys had a higher B₁₂ deficiency than girls. Inverse associations of serum B₁₂ with adiposity indices were observed. Serum B₁₂ levels were positively associated with dietary vitamin B₁₂ intake.

     

Two new p-coumaroylated sesquiterpenoids from Pilea cavaleriei

A new p-coumaroylated santalane-type sesquiterpenoid, 8-p-coumaroyl-α-santalene (1), a new p-coumaroylated oplopanane-type sesquiterpenoid, 8-β-p-coumaroyl-oplopanone (2), and three known p-coumaroylated humulene-type sesquiterpenoids (3–5) were isolated from the ethanol extract of the whole herbs of Pilea cavaleriei. Their structures were elucidated based on the combination of 1D and 2D NMR and HRMS methods. Compound 2 was found to show anti-tuberculosis activity with MIC of 16 μg/ml.