The effects of acute exercise and nutritional interventions on postprandial lipid metabolism

Raised postprandial triglycerides (TG) is an independent risk factor for cardio-metabolic disorders. This is due, in part, to the increases in circulating remnant lipoproteins after TG have been transported for storage or hydrolysis. Raised TG, are also associated with an atherogenic lipoprotein phenotype (High TG, low high-density lipoprotein cholesterol (HDL-c) and small, dense low-density lipoprotein (LDL) particles). In addition, elevated TG contribute to ectopic storage of fatty acids in liver, adipose and muscle tissues, contributing to insulin resistance in all three tissues and consequent metabolic dysregulation. It is therefore paramount to prevent frequent and prolonged exposure to raised TG in the postprandial period, particularly in groups who are at increased risk of cardio-metabolic disease.The dyslipidaemic component of cardio-metabolic health can be inferred by assessing the capacity to breakdown and clear TG from circulation after high fat ingestion using an oral fat tolerance test (OFTT). The OFTT can also be used to assess the efficacy of interventions targeting reductions in postprandial TG. Exercise and nutritional interventions have been shown to alter postprandial TG excursions and provide insight in to underlying mechanisms of postprandial lipid metabolism. However, there are several topics within this area of research that require further clarification. These topics have been addressed within this thesis.The first experimental chapter of this thesis (chapter 3) aimed to investigate the repeatability of an OFTT (75g fat, 22g carbohydrate, 14g protein) designed to meet recommendations from an expert panel statement. This study also aimed to evaluate the repeatability of the postprandial response to an OFTT preceded by 1 hour of acute moderate intensity exercise (cycling at a work rate eliciting 90% oxygen consumption anaerobic threshold). After an overnight fast, 11 healthy adult male participants consumed OFTT meals on 4 separate occasions; 2 preceded by rest and 2 preceded by exercise. TG area under the curve (AUC) was calculated for each test and compared to the repeat condition using non-parametric Bland-Altman analysis. The 4-hour OFTT was repeatable in the rest condition, with 9 of 10 repeat measurements falling within ±15% of the median TG AUC (predefined as the upper limit of acceptable error). However, in the exercise condition repeatability was poor with only 2 of 11 repeat measurements falling within 15% of the median TG AUC.Adult offspring of type 2 diabetics (OT2D) show irregular TG responses to OFTT with high or low carbohydrate content, compared to healthy controls. Prior acute aerobic exercise may favourably influence these postprandial responses in OT2D. This feasibility study (Chapter 4) aimed to investigate the effects of carbohydrate content and acute exercise on TG AUC after OFTT in OT2D. On 4 separate days, 8 adult male OT2D ingested OFTTs with low (HFLC; 75g fat, 22g carbohydrate, 14g protein) or high (HFHC; 75g fat, 95g carbohydrate, 14 g protein) carbohydrate content. Participants rested or exercised (1-hour moderate intensity; 90% oxygen consumption at anaerobic threshold) the day before each OFTT. Recruitment to the single centre was slow, but participant adherence to the study was good. There were large effect sizes for lower TG AUC and incremental AUC (iAUC) in the HFHC with prior exercise. Insulin AUC was higher in HFHC conditions and there was a large effect size for lower insulin AUC in the exercise conditions. Given the large effect sizes observed for the effects of prior acute exercise on postprandial TGs, an adequately powered multi-centre study was deemed to be relevant and feasible.Consumption of strawberries appears to be beneficial in attenuating the postprandial lipaemic response to OFTT due to the high polyphenol content within strawberries. The mechanisms of this attenuation in postprandial lipaemia appear to be different from the mechanisms involved in exercise induced reductions in postprandial lipaemia. However, the combined effects of exercise and strawberry interventions in reducing postprandial lipaemic responses to OFTT has not been investigated. The final experimental chapter (Chapter 5) aimed to evaluate the combined effects of acute exercise and strawberry consumption on postprandial responses to OFTT (73g to 74g fat, 32g to 33g carbohydrate, 11g to 12g protein). On 4 separate days, ten overweight/obese males ingested OFTTs with 25g freeze dried strawberries or a placebo. Participants rested or exercised (40 minutes submaximal high intensity exercise, HIIE) the day before each OFTT. There was a 20% reduction in TG AUC in the exercise conditions and no differences in TG AUC in the strawberry conditions.This thesis offers key contributions to postprandial lipid metabolism research. First, the OFTT recommended by an expert panel statement is repeatable. Second, the variability observed in postprandial responses to OFTT with immediate prior exercise may explain the inconsistencies within the literature. Third, acute exercise showed a substantive effect in reducing TG AUC and iAUC with high carbohydrate OFTT in adult OT2D. These improvements could be explained by acute improvements in insulin sensitivity, however, a further adequately powered study is required to support the findings of this feasibility study. Finally, acute HIIE appears to be an effective strategy to reduce postprandial TG, but strawberry intake does not appear to improve postprandial TG

CCL19-sorted mature dendritic cells have enhanced lymph node migratory capacity and function

No abstract available

Vibrational Raman Optical Activity of Carbohydrates

Vibrational Raman optical activity (ROA), measured as a small differential Raman scattering of right and left circularly polarized incident light from chiral molecules, is emerging as a powerful new chiroptical probe of the solution stereochemistry of biopolymers. Only recently with the advent of CCD detection combined with a backscattering configuration has ROA achieved the sensitivity required for the acquisition of high quality biopolymer spectra. The work presented in this thesis represents the first concerted effort to acquire, assign and interpret the ROA spectra of carbohydrates ranging from monosaccharides to polysaccharides. The opening chapter of this thesis introduces the concept of optical activity as well as describing some conventional chiroptical techniques and contrasting the two complementary forms of vibrational optical activity: vibrational circular dichroism (VCD) and ROA. The following two chapters then deal with the fundamentals of the theory of ROA and the instrumentation required to measure it. Chapter 4 concentrates on the description of those aspects of carbohydrate stereochemistry that are required to appreciate the subsequent discussion of the ROA spectra. In addition, the main conventional physical methods of establishing carbohydrate conformation are briefly reviewed and the strength and weaknesses of each method noted. The next two chapters deal exclusively with the ROA of monosaccharides. Chapter 5 consists of a detailed study of D-glucose employing deuterated analogues to assign the ROA signals to particular vibrational coordinates where possible and to relate them to stereochemical features such as anomeric configuration, hydroxymethyl-1-group conformation and relative disposition of hydroxyl groups around the ring. Chapter 6 extends the work on the monosaccharides to the ketose sugars and the results are combined with earlier ROA studies to clarify some of the old assignments and establish new ones. In chapter 7 the ROA spectra of seven disaccharides of D-glucose with a range of different linkage types and configurations are presented. It is demonstrated that their ROA spectra contain a number of new signals sensitive to the conformation of the glycosidic link as well as many signals similar to those found in D-glucose itself. The final chapter concentrates on the ROA spectra of a number of cyclodextrins and polysaccharides as well as a single glycoprotein. The interpretation of these spectra emphasise the influence of the secondary structure through ROA signals that were identified in the preceding chapter as originating in the coordinates of the glycosidic link

英語症例報告の語彙的・テキスト的特徴 : 予備調査の結果から

本稿では英文の症例報告108本を対象としたコーパス分析の結果を報告する。まず，筆者らによる医学英語カリキュラム開発のこれまでの取り組みを概観し，次に3本の症例報告を対象とした談話分析，および108本すべてのコーパスを対象とした予備的分析の結果を報告する。最後に，本研究の教育的示唆を考察する。 本稿のリサーチクエスチョンは以下の2点である。 1. 症例報告にはどのようなテキスト的特徴が見られるか。 2. 症例報告の小規模な初期コーパスから，主要な語彙項目や定型的言語表現の特定は可能か。 分析結果によれば，症例報告で用いられる医学用語は難解なものもあるが，全体的な構成や展開は極めてシンプルで，3つの主要セクション（緒言，症例提示，考察）および抄録と参考文献で構成されている。緒言では当該疾患についての概要を述べ，新しい症例の導入説明を行う。症例提示では症例の顕著な特徴を記述し，考察では関連文献を引用しつつ，その症例が興味深い理由を論述し，最後は示唆で締め括る。詳細なコーパス分析により，症例報告において広範囲かつ高頻度で出現する用語や表現の特定が可能である。例えば，非定型的症例の導入説明には，“We report a case…” のような表現が用いられる。また，考察で著者の示唆が記述される部分では，‘may’ や ‘can’ のような法助動詞とbe動詞のコロケーションが頻出する。 本稿の教育的示唆として，症例報告を読むことと実際に書くことの違いを考察する。症例報告の読解と分析は医学教育の比較的初期から開始できるが，症例報告を書くことは，学部3年生の段階では難易度が高すぎると思われる。しかしそうした学生であっても，まずは模擬患者の情報を用い，ごく一般的な症例について書く指導から始めることで，症例報告における症例提示の技能を効果的に伸長できるだろう。さらに次の段階では，実際の症例報告を書くために，研究者が自分のニーズにあった小規模コーパスの構築を行えるよう，基本的なコーパス分析の訓練を行う方法について考察する。In this article, we present our findings on an analysis of a corpus of 108 medical case reports in English. We first summarize the history of our involvement with medical English curriculum development, then present our findings from a discourse analysis of three case reports and a preliminary corpus analysis of the entire collection of articles. We conclude with a consideration of the pedagogical implications. The following research questions are addressed: 1. What textual features of medical case reports can be identified? 2. From a small initial corpus of case reports, is it possible to identify key lexical items and formulaic sequences? The results of the analyses show that although the medical terminology of case reports may be challenging, their overall organization and structure is quite simple, comprising three main sections (introduction, case presentation/report, and discussion) plus an abstract and references. The introduction describes the key area and introduces the new case. The case presentation/report narrates the salient features of the case, and the discussion involves an explanation of why the case is interesting or unusual, usually citing other literature in the area, and concluding with some suggestions. From the detailed corpus analysis a variety of terms and expressions that occur frequently and in a wide range of case reports can be identified. For example, phrases such as “We report a case . . .” are used to introduce the atypical case described in the study, and the modal verbs ‘may’ and ‘can’ often collocate with ‘be’ in the suggestions made by the authors in the discussion. In the section on pedagogical implications, we discuss the difference between reading case reports and actually writing them. While reading and analyzing case reports can start relatively early in students’ medical studies, we argue that writing case reports is too big a challenge for third-year undergraduates. However, these students could be taught first to write up usual rather than rare cases by using simulated patient information, effectively developing skills for the presentation section of a case report. For the writing of actual case reports, we consider how training in basic corpus analysis could be provided, enabling researchers to build small corpora relevant to their needs

MicroRNA-155 regulates monocyte chemokine and chemokine receptor expression in Rheumatoid Arthritis

Objectives: To test the hypothesis that miR-155 regulates monocyte migratory potential via modulation of chemokine and chemokine receptor expression in rheumatoid arthritis (RA); and thereby is associated with disease activity. Methods: miR-155 copy-number in monocytes from peripheral blood (PB) of healthy (n=22), RA (n=24), and RA synovial fluid (SF; n=11) were assessed by real time- PCR using synthetic miR-155 as quantitative standard. To evaluate the functional impact of miR-155, human monocytes were transfected with control or miR-155 mimic and the effect on transcript levels, and production of chemokines was evaluated by TLDA and multiplex assays. A comparative study evaluated constitutive chemokine receptor expression in miR-155-/- and wild-type murine (CD115+Ly6C+Ly6G-) monocytes. Results: Compared with healthy monocytes, miR-155 copy-number was higher in RA PB and SF monocytes (PB p<0.01, and SF p<0.0001). MiR-155 copy-number in RA PB monocytes were higher in ACPA positive compared with ACPA negative patients (p=0.033) and correlated (95% C.I.) with DAS28 (ESR), R=0.728 (0.460, 0.874), with tender, R=0.631 (0.306, 0.824) and swollen, R=0.503 (0.125, 0.753) joint counts. Enforced-expression of miR-155 in RA monocytes stimulated the production of CCL3, CCL4, CCL5, CCL8; up-regulated CCR7 expression and down-regulated CCR2. Conversely, miR155-/- monocytes showed down-regulated CCR7 and upregulated CCR2 expression. Conclusions: Given the observed correlations with disease activity, these data provide strong evidence that miR-155 can contribute to RA pathogenesis by regulating chemokine production and pro-inflammatory chemokine receptor expression, thereby promoting inflammatory cell recruitment and retention in the RA synovium

Immune checkpoint inhibitors: new strategies to checkmate cancer

Immune checkpoint inhibitors (ICIs) targeting Cytotoxic T-Lymphocyte-Associated protein 4 (CTLA-4) or Programmed cell Death protein 1 (PD-1) receptors have demonstrated remarkable efficacy in subsets of patients with malignant disease. This emerging treatment modality holds great promise for future cancer treatment and has engaged pharmaceutical research interests in tumour immunology. While ICIs can induce rapid and durable responses in some patients, identifying predictive factors for effective clinical responses has proven challenging. This review summarises the mechanisms of action of ICIs and outlines important pre-clinical work that contributed to their development. We explore clinical data that has led to disease-specific drug licensing, and highlight key clinical trials that have revealed ICI efficacy across a range of malignancies. We describe how ICIs have been used as part of combination therapies, and explore their future prospects in this area. We conclude by discussing the incorporation of these new immunotherapeutics into precision approaches to cancer therapy

Nuclear expression of Lyn, a Src family kinase member, is associated with poor prognosis in renal cancer patients

Background: 8000 cases of renal cancer are diagnosed each year in the UK, with a five-year survival rate of 50 %. Treatment options are limited; a potential therapeutic target is the Src family kinases (SFKs). SFKs have roles in multiple oncogenic processes and promote metastases in solid tumours. The aim of this study was to investigate SFKs as potential therapeutic targets for clear cell renal cell carcinoma (ccRCC). Methods: SFKs expression was assessed in a tissue microarray consisting of 192 ccRCC patients with full clinical follow-up. SFK inhibitors, dasatinib and saracatinib, were assessed in early ccRCC cell lines, 786-O and 769-P and a metastatic ccRCC cell line, ACHN (± Src) for effects on protein expression, apoptosis, proliferation and wound healing. Results: High nuclear expression of Lyn and the downstream marker of activation, paxillin, were associated with decreased patient survival. Conversely, high cytoplasmic expression of other SFK members and downstream marker of activation, focal adhesion kinase (FAK) were associated with increased patient survival. Treatment of non-metastatic 786-O and 769-P cells with dasatinib, dose dependently reduced SFK activation, shown via SFK (Y419) and FAK (Y861) phosphorylation, with no effect in metastatic ACHN cells. Dasatinib also increased apoptosis, while decreasing proliferation and migration in 786-O and 769-P cell lines, both in the presence and absence of Src protein. Conclusions: Our data suggests that nuclear Lyn is a potential therapeutic target for ccRCC and dasatinib affects cellular functions associated with cancer progression via a Src kinase independent mechanism

Identifying the emergence of the superficial peroneal nerve through deep fascia on ultrasound and by dissection:Implications for regional anesthesia in foot and ankle surgery

Regional anesthesia relies on a sound understanding of anatomy and the utility of ultrasound in identifying relevant structures. We assessed the ability to identify the point at which the superficial peroneal nerve (SPN) emerges through the deep fascia by ultrasound on 26 volunteers (mean age 27.85 years ± 13.186; equal male: female). This point was identified, characterized in relation to surrounding bony landmarks (lateral malleolus and head of the fibula), and compared to data from 16 formalin‐fixed human cadavers (mean age 82.88 years ± 6.964; equal male: female). The SPN was identified bilaterally in all subjects. On ultrasound it was found to pierce the deep fascia of the leg at a point 0.31 (±0.066) of the way along a straight line from the lateral malleolus to the head of the fibula (LM‐HF line). This occurred on or anterior to the line in all cases. Dissection of cadavers found this point to be 0.30 (±0.062) along the LM‐HF line, with no statistically significant difference between the two groups (U = 764.000; exact two‐tailed P = 0.534). It was always on or anterior to the LM‐HF line, anterior by 0.74 cm (±0.624) on ultrasound and by 1.51 cm (±0.509) during dissection. This point was significantly further anterior to the LM‐HF line in cadavers (U = 257.700, exact two‐tailed P < 0.001). Dissection revealed the nerve to divide prior to emergence in 46.88% (n = 15) limbs, which was not identified on ultrasound (although not specifically assessed). Such information can guide clinicians when patient factors (e.g., obesity and peripheral edema) make ultrasound‐guided nerve localization more technically challenging.PostprintPeer reviewe