Role of nuclear hormone receptors in butyrate-mediated up-regulation of the antimicrobial peptide cathelicidin in epithelial colorectal cells

BACKGROUND AND AIMS: The human cathelicidin (LL-37) is one of the major antimicrobial peptides of the non-specific innate immune system in the intestinal tract. Altered expression has been associated with gastrointestinal disease. Recent studies demonstrated that butyrate induces LL-37 mRNA in colonic epithelial cells, however the underlying molecular mechanisms have not been elucidated. The objective of this study was to investigate the regulatory pathways involved in butyrate-induced up-regulation of LL-37. METHODS AND RESULTS: Treatment of Caco-2 and HT-29 cells with butyrate led to a time-dependent up-regulation of LL-37 mRNA expression as determined by semi-quantitative RT-PCR. Up-regulation of LL-37 mRNA by butyrate was subsequently followed by an increase in LL-37 protein expression as observed by immunofluorescence. Co-incubation of butyrate with a VDR, p38 MAPK, ERK 1/2 and TGF-beta1 receptor kinase inhibitor all reduced butyrate-mediated LL-37 mRNA up-regulation. In contrast, transfection of Caco-2 cells with a dominant-negative PPARgamma mutant vector did not affect butyrate-mediated up-regulation of LL-37 mRNA. CONCLUSION: Our results clearly demonstrate that butyrate-mediated up-regulation of LL-37 is influenced by several signalling pathways and receptors including MAPKs as well as VDR and TGF-beta1, but not by PPARgamma. These data may provide new opportunities in the treatment of gastrointestinal diseases.     

Enhanced terminal room disinfection and acquisition and infection caused by multidrug-resistant organisms and Clostridium diffcile(the Benefits of Enhanced Terminal Room Disinfection study):a cluster-randomised,multicentre,crossover study

中文:背景患者入院后可从不当消毒的环境表面获得多药耐药菌和艰难梭菌。本文确定了3种强化的终末消毒(入住同一病房的两名患者之间的消毒)策略,对感染耐甲氧西林金黄色葡萄球菌(MRSA)、耐万古霉素肠球菌(VRE)、艰难梭菌(CD)和多重耐药不动杆菌的影响。方法本文在美国东南部的9家医院开展了一项务实的、集群-随机、交叉研究。凡曾有感染或定植目标细菌感染患者居住过的病房,患者出院后随机采取4种消毒策略中的一种方法进行终末消毒:对照(季胺盐类消毒剂消毒,但凡遇到CD采用含氯消毒剂);UV(季胺盐类+UV-C消毒,但凡遇到CD采用含氯消毒剂+UV-C);含氯消毒剂;含氯消毒剂+UV-C。凡入住目标病房的患者被列为暴露人群。这4种终末消毒方法分别在每家医院连续实施7个月的周期。本文随机设计这几种消毒策略在每家医院内的实施顺序(1:1:1:1)。主要产出的结果是,观察暴露患者中目标细菌的感染的发生或定植情况,以及ITT人群中暴露患者CD感染发生率。本研究ClinicalTrials.gov注册编号:NCT01579370。结果共有31 226名患者暴露,其中21 395(69%)符合标准,包括4 916名对照组,5 178名UV组,5 438名含氯消毒剂组,以及5 863名含氯消毒剂+UV组。在对照组中,22 426个暴露日中有115名患者发生目标细菌的感染(51.3/10000暴露日)。在标准清洁策略的基础上增加UV消毒的暴露患者,其目标细菌感染的发生率明显较低(n=76;33.9/10 000暴露日;RR:0.70,95%CI:0.50～0.988;P=0.036)。含氯消毒剂组(n=101;41.6/10 000暴露日;RR:0.85,95%CI:0.69～1.04;P=0.116),或含氯消毒剂+UV组患者(n=131;45.6/10 000暴露日;RR:0.91,95%CI:0.76～1.09;P=0.303)的目标细菌的感染率,其差异无统计学意义。同样,在含氯消毒剂的基础上增加UV消毒,暴露患者中CD感染率也没有发生改变((n=38 vs 36;30.4 vs 31.6/10 000暴露日;RR:1.0,95%CI:0.57-1.75;P=0.997)。解释污染的医疗机构环境是获得病原微生物的重要来源;强化终末消毒可以降低这一风险。     

Dairy-Based and Energy-Enriched Berry-Based Snacks Improve or Maintain Nutritional and Functional Status in Older People in Home Care

Objective

Consumption of energy- and nutrient-dense snacks are recommended for older people to maintain adequate nutrition. We evaluated the effects of dairy-based and energy-enriched berry products consumed as snacks on nutritional and functional status among vulnerable older people receiving home care services.

Design

Randomised controlled study.

Setting and participants

The study sample consisted of 85 home care clients, with mean age of 81.9 (SD 7.1) years in the intervention group (n=50) and 83.7 (SD 8.1) years in the control group (n=35), and 72% women in both groups.

Intervention

In the intervention group, the participants consumed both high-protein dairy-based products and energy-enriched berry purées for three months. The snack products provided nearly 300 kcal and 14 g protein per day.

Measurements

The Mini Nutritional Assessment (MNA), body mass index (BMI), mid-arm muscular area (MAMA) and concentrations of plasma albumin and prealbumin and blood haemoglobin were used to determine nutritional status, and handgrip strength was used to determine functional status at baseline and after the intervention. Results: After adjustment for age and gender, the intervention showed a significant effect on MNA scores (2.1, 95% [CI]: 1.0 to 3.3) (p=0.003), albumin concentration (2.0 g/L, 95% [CI]: 1.1 to 3.2) (p=0.006) and handgrip strength of the right hand in women (2.4 kg, 95% [CI]: 1.2 to 3.3) (p=0.007). The MNA scores improved in the intervention group, while albumin concentration and handgrip strength decreased in the control group.

Conclusions

Regular use of dairy- and energy-enriched berry-based snacks may improve or maintain nutritional and functional status among older people in home care.

     

Cyclic loading causes faster rupture and strain rate than static loading in medial collateral ligament at high stress

BACKGROUND: Ligaments may be subjected to higher than normal loads when one of the complementary ligament restraints of a joint or the ligament itself is injured. Damage can accumulate in a ligament due to cyclic and static loading under these increased loads, but it remains unknown whether one type of loading will cause rupture faster than the other in medial collateral ligament. METHODS: The objective of this study was to compare the time and strain behaviour of normal rabbit medial collateral ligaments under static and cyclic loading over a wide range of applied stresses, with particular emphasis on time-to-rupture. Stresses were normalized to ultimate tensile strength and selected from three regions of the stress-strain curve: two linear-region stresses (60% and 30% of the ultimate tensile strength) and one stress at the transition from the toe-region to the linear-region (15% of the ultimate tensile strength). FINDINGS: Cyclic loading caused faster rupture than static loading at all stresses. Strain-time profiles were different in that the increase in strain (strain relative to initial strain) was greater under static than cyclic loading prior to rupture. However, steady-state strain rate (when increase in strain reaches a plateau in the secondary strain stage) was greater under cyclic than static loading. INTERPRETATIONS: These results suggest that cyclic loading is more detrimental than static loading in ligaments that are subjected to higher than normal stresses following injury of a complementary restraint or the ligament itself.     

Comparison of complications,costs, and length of stay of three different lumbar interbody fusion techniques: an analysis of the Nationwide Inpatient Sample database

Background contextLumbar interbody fusion (LIF) techniques have been used for years to treat a number of pathologies of the lower back. These procedures may use an anterior, posterior, or combined surgical approach. Each approach is associated with a unique set of complications, but the exact prevalence of complications associated with each approach remains unclear.PurposeTo investigate the rates of perioperative complications of anterior lumbar interbody fusion (ALIF), posterior/transforaminal lumbar interbody fusion (P/TLIF), and LIF with a combined anterior-posterior interbody fusion (APF).Study design/settingRetrospective review of national data from a large administrative database.Patient samplePatients undergoing ALIF, P/TLIF, or APF.Outcome measuresPerioperative complications, length of stay (LOS), total costs, and mortality.MethodsThe Nationwide Inpatient Sample database was queried for patients undergoing ALIF, P/TLIF, or APF between 2001 and 2010 as identified via International Classification of Diseases, ninth revision codes. Univariate analyses were carried out comparing the three cohorts in terms of the outcomes of interest. Multivariate analysis for primary outcomes was carried out adjusting for overall comorbidity burden, race, gender, age, and length of fusion. National estimates of annual total number of procedures were calculated based on the provided discharge weights. Geographic distribution of the three cohorts was also investigated.ResultsAn estimated total of 923,038 LIFs were performed between 2001 and 2010 in the United States. Posterior/transforaminal lumbar interbody fusions accounted for 79% to 86% of total LIFs between 2001 and 2010, ALIFs for 10% to 15%, and APF decreased from 10% in 2002 to less than 1% in 2010. On average, P/TLIF patients were oldest (54.55 years), followed by combined approach (47.23 years) and ALIF (46.94 years) patients (p<.0001). Anterior lumbar interbody fusion, P/TLIF, and combined surgical costs were $75,872, $65,894, and $92,249, respectively (p<.0001). Patients in the P/TLIF cohort had the greatest number of comorbidities, having the highest prevalence for 10 of 17 comorbidities investigated. Anterior-posterior interbody fusion group was associated with the greatest number of complications, having the highest incidence of 12 of the 16 complications investigated.ConclusionsThese data help to define the perioperative risks for several LIF approaches. Comparison of outcomes showed that a combined approach is more expensive and associated with greater LOS, whereas ALIF is associated with the highest postoperative mortality. These trends should be taken into consideration during surgical planning to improve clinical outcomes.     

Prediction of tamoxifen outcome by genetic variation of CYP2D6 in post-menopausal women with early breast cancer

The question of whether genetic polymorphisms of CYP2D6 can affect treatment outcome in patients with early post-menopausal oestrogen receptor (ER)-positive breast cancer has been a matter of debate over the past few years. In this article we revisit the hypothesis of CYP2D6 being a potential tamoxifen outcome predictor and provide detailed insight into the ongoing controversy that prevented the CYP2D6 marker from being accepted by the scientific and clinical community. We summarize the available pharmacokinetic, pharmacodynamic and pharmacogenetic evidence and resolve the controversy based on the recognized methodological and statistical issues. The cumulative evidence suggests that genotyping for CYP2D6 is clinically relevant in post-menopausal women. This is important, because the clarification of this issue has the potential to resolve a clinical management question that is relevant to hundreds of thousands of women diagnosed with ER-positive breast cancer each year, who should not be denied effective endocrine therapy.