Cumulative Systolic BP and Changes in Urine Albumin-to-Creatinine Ratios in Nondiabetic Participants of the Multi-Ethnic Study of Atherosclerosis

Background and objectives

Cumulative exposure to elevated systolic BP (cumSBP) may affect progression of urine albumin excretion in the absence of diabetes. The objective of this study was to examine the association between cumSBP exposure and progression of spot urine albumin-to-creatinine ratio (UACR) in a multi-ethnic cohort of adults without diabetes.

Design, setting, participants, & measurements

The analysis included 3789 participants without severely increased urine albumin excretion or diabetes in the Multi-Ethnic Study of Atherosclerosis, a cohort of 6814 adults aged 45–84 years. UACR was measured at baseline and approximately 1.6, 3.1, and 9.4 years after the baseline examination. cumSBP was calculated as the summed average systolic BP (SBP; mmHg) between two consecutive examinations multiplied by the time between the two examinations (mmHg×year) and categorized as ≤1128 (SBP<120 mmHg), 1129–1222 (SBP≥120–129 mmHg), 1223–1316 (SBP≥130–130 mmHg), and >1316 (SBP≥140 mmHg). Baseline UACR was categorized as normal, mildly increased, or moderately increased, and definite progression of UACR was defined as a persistently higher UACR category at subsequent examinations. No UACR progression was defined as remaining in the same UACR category across all examinations or regressing.

Results

In fully adjusted models, compared with cumSBP≤1128 mmHg, cumSBP 1223–1316 and >1316 mmHg was associated with a 85% and 130% significantly higher odds of definite UACR progression (95% confidence interval, 24% to 178% and 56% to 243%, respectively) versus no UACR progression. Every 100-mmHg higher level of cumSBP was associated with a 1.23-fold higher odds of definite UACR progression (95% confidence interval, 1.13 to 1.34) versus no UACR progression.

Conclusion

Exposure to higher cumSBP was associated with increased UACR progression among adults without diabetes.     

Decision making and referral from primary care for possible lung and colorectal cancer: a qualitative study of patients’ experiences

Background

The challenge for GPs when assessing whether to refer a patient for cancer investigation is that many cancer symptoms are also caused by benign self-limiting illness. UK National Institute for Health and Care Excellence (NICE) referral guidelines emphasise that the patient should be involved in the decision-making process and be informed of the reasons for referral. Research to date, however, has not examined the extent to which these guidelines are borne out in practice.

Aim

To assess the degree to which patients are involved in the decision to be referred for investigation for symptoms associated with cancer and their understanding of the referral.

Design and setting

Qualitative interview study of patients referred to secondary care for symptoms suspicious of lung and colorectal cancer. Patients were recruited from two regions of England using maximum variation sampling.

Method

Transcribed interviews were analysed thematically.

Results

The analysis was based on 34 patient interviews. Patients in both symptom pathways reported little involvement in the decision to be referred for investigation. This tended to be accompanied by a patient expectation for referral, however, to explain ongoing and un-resolving symptoms. It was also found that reasons for referral tended to be couched in non-specific terms rather than cancer investigation, even when the patient was on a cancer-specific pathway.

Conclusion

GPs should consider a more overt discussion with patients when referring them for further investigation of symptoms suspicious of cancer. This would align clinical practice with NICE guidelines and encourage more open discussion between GPs and primary care patients around cancer.     

Gut Commensal Bacteria and Regional Wnt Gene Expression in the Proximal Versus Distal Colon

Regional expression of Wingless/Int (Wnt) genes plays a central role in regulating intestinal development and homeostasis. However, our knowledge of such regional Wnt proteins in the colon remains limited. To understand further the effect of Wnt signaling components in controlling intestinal epithelial homeostasis, we investigated whether the physiological heterogeneity of the proximal and distal colon can be explained by differential Wnt signaling. With the use of a Wnt signaling-specific PCR array, expression of 84 Wnt-mediated signal transduction genes was analyzed, and a differential signature of Wnt-related genes in the proximal versus distal murine colon was identified. Several Wnt agonists (Wnt5a, Wnt8b, and Wnt11), the Wnt receptor frizzled family receptor 3, and the Wnt inhibitory factor 1 were differentially expressed along the colon length. These Wnt signatures were associated with differential epithelial cell proliferation and migration in the proximal versus distal colon. Furthermore, reduced Wnt/β-catenin activity and decreased Wnt5a and Wnt11 expression were observed in mice lacking commensal bacteria, an effect that was reversed by conventionalization of germ-free mice. Interestingly, myeloid differentiation primary response gene 88 knockout mice showed decreased Wnt5a levels, indicating a role for Toll-like receptor signaling in regulating Wnt5a expression. Our results suggest that the morphological and physiological heterogeneity within the colon is in part facilitated by the differential expression of Wnt signaling components and influenced by colonization with bacteria.One of the fundamental aspects in the development of the gastrointestinal tract is the spatiotemporal expression of signaling molecules that regulate cell fate and differentiation. Previous studies have highlighted a central role of the evolutionarily conserved Wingless/Int (Wnt) signaling pathways as key regulators of embryonic development and epithelial homeostasis in the gut.^1–3 In development, local expression patterns of Wnt signaling components play an important role in organogenesis.^4,5 Wnt signals control important biological processes required for cell proliferation, differentiation, polarity, and movement, depending on the target cell and the cellular environment.Recent reports have highlighted the importance of understanding the role of Wnt signaling in the intestinal tract. The intestinal epithelium is highly dynamic and, depending on the species and location, is actively turned over in <1 week.⁶ Wnt/β-catenin signaling regulates intestinal epithelial cell (IEC) homeostasis and proliferation by increasing β-catenin stability in crypt epithelial cells, whereas IEC migration and differentiation are believed to be in part facilitated through noncanonical (Wnt) signaling pathways independent of β-catenin.^6,7 The renewal of intestinal epithelia requires a delicate balance of signaling proteins to control epithelial cell proliferation and migration that in turn is vital for maintaining mucosal homeostasis. Interestingly, regional differences in Wnt gene expression in small versus large intestine are observed in adult mice, suggesting the importance of differential local Wnt expression in regulation of intestinal mucosal homeostasis.⁷Although the entire colon exhibits considerable morphological and physiological heterogeneity along its length,^8–11 the expression pattern of Wnt signaling components in the different regions of the adult colon remains poorly understood. Embryologically, the cecum, ascending colon, and the proximal two-thirds of the transverse colon are derived from the midgut, whereas the distal colon originates from the hindgut. Such distinct origins of the colonic segment support specific biological characteristics and suggest that distinct regulatory factors are likely to control epithelial homeostasis in the proximal versus distal colon. In addition, important contributing factors that influence Wnt/β-catenin signaling and intestinal epithelial proliferation might be microbial communities that localize in the intestine in distinct regions.^6,12 Such a delicate physiological balance of Wnt signaling and intestinal epithelial homeostasis is further perturbed in mucosal inflammatory and neoplastic diseases,^3,13 which also indicate regional differences in the proximal versus distal colonic segments.^14–17In the present study, we investigate the regional heterogeneity of Wnt genes in the proximal versus distal colon. Given the importance of luminal microbiota in influencing intestinal epithelial homeostasis¹⁸ and to determine whether the Wnt signatures are influenced by microflora colonization, we examined expression of Wnt proteins in the colonic segments of mice raised under germ-free (GF) conditions.     

Pivotal role of MUC1 glycosylation by cigarette smoke in modulating disruption of airway adherens junctions in vitro

Cigarette smoke increases the risk of lung cancer by 20‐fold and accounts for 87% of lung cancer deaths. In the normal airway, heavily O‐glycosylated mucin‐1 (MUC1) and adherens junctions (AJs) establish a structural barrier that protects the airway from infectious, inflammatory and noxious stimuli. Smoke disrupts cell–cell adhesion via its damaging effects on the AJ protein epithelial cadherin (E‐cad). Loss of E‐cad is a major hallmark of epithelial–mesenchymal transition (EMT) and has been reported in lung cancer, where it is associated with invasion, metastasis and poor prognosis. Using organotypic cultures of primary human bronchial epithelial (HBE) cells treated with smoke‐concentrated medium (Smk), we have demonstrated that E‐cad loss is regulated through the aberrant interaction of its AJ binding partner, p120‐catenin (p120ctn), and the C‐terminus of MUC1 (MUC1‐C). Here, we reported that even before MUC1‐C became bound to p120ctn, smoke promoted the generation of a novel 400 kDa glycoform of MUC1's N‐terminus (MUC1‐N) differing from the 230 kDa and 150 kDa glycoforms in untreated control cells. The subsequent smoke‐induced, time‐dependent shedding of glycosylated MUC1‐N exposed MUC1‐C as a putative receptor for interactions with EGFR, Src and p120ctn. Smoke‐induced MUC1‐C glycosylation modulated MUC1‐C tyrosine phosphorylation (TyrP) that was essential for MUC1‐C/p120ctn interaction through dose‐dependent bridging of Src/MUC1‐C/galectin‐3/EGFR signalosomes. Chemical deglycosylation of MUC1 using a mixture of N‐glycosylation inhibitor tunicamycin and O‐glycosylation inhibitor benzyl‐α‐GalNAc disrupted the Src/MUC1‐C/galectin‐3/EGFR complexes and thereby abolished smoke‐induced MUC1‐C‐TyrP and MUC1‐C/p120ctn interaction. Similarly, inhibition of smoke‐induced MUC1‐N glycosylation using adenoviral shRNA directed against N‐acetyl‐galactosaminyl transferase‐6 (GALNT6, an enzyme that controls the initiating step of O‐glycosylation) successfully suppressed MUC1‐C/p120ctn interaction, prevented E‐cad degradation and maintained cellular polarity in response to smoke. Thus, GALNT6 shRNA represents a potential therapeutic modality to prevent the initiation of events associated with EMT in the smoker's airway. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.