Association of common KIBRA variants with episodic memory and AD risk

KIBRA single nucleotide polymorphism (SNP) rs17070145 was identified in a genome-wide association study (GWAS) of memory performance, with some but not all follow-up studies confirming association of its T allele with enhanced memory. This allele was associated with reduced Alzheimer's disease (AD) risk in 1 study, which also found overexpression of KIBRA in memory-related brain regions of AD. We genotyped rs17070145 and 14 additional SNPs in 2571 late onset Alzheimer's disease (LOAD) patients vs. 2842 controls, including African-Americans. We found significantly reduced risk for rs17070145 T allele in the older African-American subjects (p = 0.007) and a suggestive effect in the older Caucasian series. Meta-analysis of this allele in > 8000 subjects from our and published series showed a suggestive protective effect (p = 0.07). Analysis of episodic memory in control subjects did not identify associations with rs17070145, though other SNPs showed significant associations in 1 series. KIBRA showed evidence of overexpression in the AD temporal cortex (p = 0.06) but not cerebellum. These results suggest a modest role for KIBRA as a cognition and AD risk gene, and also highlight the multifactorial complexity of its genetic associations.     

Humidification during high-frequency oscillation ventilation is affected by ventilator circuit and ventilatory setting

Background:  High-frequency oscillation ventilation (HFOV) is an accepted ventilatory mode for acute respiratory failure in neonates. As conventional mechanical ventilation, inspiratory gas humidification is essential. However, humidification during HFOV has not been clarified. In this bench study, we evaluated humidification during HFOV in the open circumstance of ICU. Our hypothesis is that humidification during HFOV is affected by circuit design and ventilatory settings.
Methods/Materials:  We connected a ventilator with HFOV mode to a neonatal lung model that was placed in an infant incubator set at 37°C. We set a heated humidifier (Fisher & Paykel) to obtain 37°C at the chamber outlet and 40°C at the distal temperature probe. We measured absolute humidity and temperature at the Y-piece using a rapid-response hygrometer. We evaluated two types of ventilator circuit: a circuit with inner heating wire and another with embedded heating element. In addition, we evaluated three lengths of the inspiratory limb, three stroke volumes, three frequencies, and three mean airway pressures.
Results:  The circuit with embedded heating element provided significantly higher absolute humidity and temperature than one with inner heating wire. As an extended tube lacking a heating wire was shorter, absolute humidity and temperature became higher. In the circuit with inner heating wire, absolute humidity and temperature increased as stroke volume increased.
Conclusion:  Humidification during HFOV is affected by circuit design and ventilatory settings.     

髋关节骨性关节炎的诊断和治疗进展

髋关节骨性关节炎是一种慢性进行性骨关节病,也是骨科常见疾患,多见于老年人,发病率随年龄增大而增高;是以慢性进行性软骨变性和软骨下及关节周围新骨形成为主要特点的退行性疾病。随着人口老龄化,越来越多的人患有髋关节骨性关节炎。     

Confounding and interaction effect of Treponema denticola salivary carriage in chronic periodontitis

Oral Diseases (2010) 16 , 278–285 Aim: To evaluate the salivary carriage of Treponema denticola and its association with demographic variables in the etiopathogenesis of chronic periodontitis. Subjects and methods: Ninety‐seven chronic periodontitis (CP) patients and a control group of 51 healthy subjects (HC) were selected. Periodontal status was assessed by criteria based on probing depth, attachment loss, extent, and severity of periodontal breakdown. A polymerase chain reaction method was used to determine the occurrence of T. denticola in saliva samples. Risk indicators for CP were assessed individually and adjusted for confounding and/or interaction using a logistic regression model. Results: Although univariate analysis revealed a positive association of age ≥30 years, smoking, and salivary carriage of T. denticola with CP, after logistic regression analysis, the association between age ≥30 years/smoking and CP persisted, whereas salivary carriage of T. denticola failed to achieve statistical significance. An interaction effect was significantly detected between these three variables. Conclusion: Although salivary carriage of T. denticola may be a risk indicator for CP, its pathogenicity should not be exclusively endorsed to its detection in saliva, but it might be associated with the synergistic biological interaction of the bacterium with some demographic characteristics of the susceptible host.     

Pharmacogenetic characterization of indacaterol,a novel β2-adrenoceptor agonist

Background and purpose:

Indacaterol is a novel β₂-adrenoceptor agonist in development for the treatment of chronic obstructive pulmonary disease. The aim of this study was to investigate the comparative pharmacology of indacaterol in recombinant cells expressing the common polymorphic variants of the human β₂-adrenoceptor and in human primary airway smooth muscle (ASM) cells.

Experimental approach:

Chinese hamster ovarian-K1 cell lines expressing high and low levels of the common human β₂-adrenoceptor variants were generated [Gly16-Glu27-Val34-Thr164(GEVT), RQVT, GQVT] and also the rare GQVI variant. Human primary ASM cells were isolated from explants of trachealis muscle. Adenosine-3′,5′-cyclic-monophosphate production was used as an outcome measure.

Key results:

In both the low- and high-expression recombinant GEVT ‘wild type’ cell lines indacaterol is a high-efficacy agonist. Salmeterol and formoterol were identified as low- and high-efficacy agonists, respectively, and showed similar potencies to indacaterol irrespective of the β₂-adrenoceptor genotype. The I164 variant cell line was associated with a reduced capacity to generate adenosine-3′,5′-cyclic-monophosphate in response to β₂-adrenoceptor agonist. In the human primary ASM cells indacaterol gave a maximal response intermediate between that of salmeterol and formoterol.

Conclusions and implications:

These data demonstrate that indacaterol is a high-efficacy agonist in recombinant cell systems but acts with lower efficacy in human primary ASM cells. No marked genotype-dependent effects were observed for common variants; however, changes in I164 receptor activity were identified, which were dependent on the level of expression of β₂-adrenoceptors.     

Therapeutic action and underlying mechanisms of a combination of two pentacyclic triterpenes, α- and β-amyrin,in a mouse model of colitis

Background and purpose:

α- and β-amyrin are pentacyclic triterpenes found in plants and are known to exhibit pronounced anti-inflammatory effects. Here, we evaluated the effects of a 1:1 mixture of α- and β-amyrin (α,β-amyrin) on an experimental model of colitis in mice.

Experimental approach:

Colitis was induced in Swiss male mice by trinitrobenzene sulphonic acid (TNBS) and followed up to 72 h; animals were treated systemically with α,β-amyrin, dexamethasone or vehicle. Macro- and microscopic damage, myeloperoxidase activity and cytokine levels were assessed in colons. Histological sections were immunostained for cyclooxygenase-2 (COX-2), vascular endothelial growth factor, phospho-p65 nuclear factor-κB (NF-κB) and phospho-cyclic AMP response element-binding protein (CREB)

Key results:

TNBS-induced colitis was associated with tissue damage, neutrophil infiltration and time-dependent increase of inflammatory mediators. Treatment with α,β-amyrin (3 mg·kg⁻¹, i.p.) or dexamethasone (1 mg·kg⁻¹, s.c.) consistently improved tissue damage scores and abolished polymorphonuclear cell infiltration. α,β-Amyrin, like dexamethasone, significantly diminished interleukin (IL)-1β levels and partially restored IL-10 levels in colon tissues 72 h after colitis induction, but only α,β-amyrin reduced vascular endothelial growth factor expression by immunohistochemistry. The colonic expression of COX-2 at 24 h and that of phospho-NF-κB and phospho-CREB (peaking at 6 h) after colitis induction were consistently inhibited by both α,β-amyrin and dexamethasone.

Conclusions and implications:

Systemic administration of α,β-amyrin exerted a marked and rapid inhibition of TNBS-induced colitis, related to the local suppression of inflammatory cytokines and COX-2 levels, possibly via inhibition of NF-κB and CREB-signalling pathways. Taken together, our data suggest a potential use of α,β-amyrin to control inflammatory responses in bowel disease.     

Evaluation of subclinical cerebral injury and neuropsychologic function in patients undergoing carotid endarterectomy

We examined subclinical alterations of cerebral function during carotid endarterectomy (CEA) and predictability of minor cerebral damage by perioperative levels of biochemical markers of brain damage (S100B and neuron-specific enolase [NSE]). Twenty consecutive patients with > or =70% asymptomatic carotid stenosis undergoing elective CEA were enrolled. Pre- and postoperative testing included magnetic resonance imaging (MRI) of the head, a standardized neurological exam, a battery of neuropsychological tests, and measurement of serum levels of S100B and NSE. There were no major ischemic strokes. In one patient, a mild weakness of the contralateral lower extremity was discovered on neurological examination; in another individual, postoperative MRI revealed two new small subcortical lesions without clinical correlate. While S100B increased significantly early after opening of the carotid clamp (p = 0.015), the NSE increase did not reach statistical significance. As a group, participants obtained a significantly higher mean overall neuropsychological score at follow-up testing (p < 0.05). In one patient, a significant decline of cognitive function was observed. This was the only individual to obtain a consistently high S100B and NSE increase. Neuropsychological testing combined with measurements of S100B and NSE may improve sensitivity when assessing subtle cerebral damage following CEA.