Bile Acid-Induced Virulence Gene Expression of Vibrio parahaemolyticus Reveals a Novel Therapeutic Potential for Bile Acid Sequestrants

Vibrio parahaemolyticus, a bacterial pathogen, causes human gastroenteritis. A type III secretion system (T3SS2) encoded in pathogenicity island (Vp-PAI) is the main contributor to enterotoxicity and expression of Vp-PAI encoded genes is regulated by two transcriptional regulators, VtrA and VtrB. However, a host-derived inducer for the Vp-PAI genes has not been identified. Here, we demonstrate that bile induces production of T3SS2-related proteins under osmotic conditions equivalent to those in the intestinal lumen. We also show that bile induces vtrA-mediated vtrB transcription. Transcriptome analysis of bile-responsive genes revealed that bile strongly induces expression of Vp-PAI genes in a vtrA-dependent manner. The inducing activity of bile was diminished by treatment with bile acid sequestrant cholestyramine. Finally, we demonstrate an in vivo protective effect of cholestyramine on enterotoxicity and show that similar protection is observed in infection with a different type of V. parahaemolyticus or with non-O1/non-O139 V. cholerae strains of vibrios carrying the same kind of T3SS. In summary, these results provide an insight into how bacteria, through the ingenious action of Vp-PAI genes, can take advantage of an otherwise hostile host environment. The results also reveal a new therapeutic potential for widely used bile acid sequestrants in enteric bacterial infections

Diabetes-Specific Nutrition Algorithm: A Transcultural Program to Optimize Diabetes and Prediabetes Care

Type 2 diabetes (T2D) and prediabetes have a major global impact through high disease prevalence, significant downstream pathophysiologic effects, and enormous financial liabilities. To mitigate this disease burden, interventions of proven effectiveness must be used. Evidence shows that nutrition therapy improves glycemic control and reduces the risks of diabetes and its complications. Accordingly, diabetes-specific nutrition therapy should be incorporated into comprehensive patient management programs. Evidence-based recommendations for healthy lifestyles that include healthy eating can be found in clinical practice guidelines (CPGs) from professional medical organizations. To enable broad implementation of these guidelines, recommendations must be reconstructed to account for cultural differences in lifestyle, food availability, and genetic factors. To begin, published CPGs and relevant medical literature were reviewed and evidence ratings applied according to established protocols for guidelines. From this information, an algorithm for the nutritional management of people with T2D and prediabetes was created. Subsequently, algorithm nodes were populated with transcultural attributes to guide decisions. The resultant transcultural diabetes-specific nutrition algorithm (tDNA) was simplified and optimized for global implementation and validation according to current standards for CPG development and cultural adaptation. Thus, the tDNA is a tool to facilitate the delivery of nutrition therapy to patients with T2D and prediabetes in a variety of cultures and geographic locations. It is anticipated that this novel approach can reduce the burden of diabetes, improve quality of life, and save lives. The specific Southeast Asian and Asian Indian tDNA versions can be found in companion articles in this issue of Current Diabetes Reports

Rheumatoid arthritis - clinical aspects: 134. Predictors of Joint Damage in South Africans with Rheumatoid Arthritis

Background: Rheumatoid arthritis (RA) causes progressive joint damage and functional disability. Studies on factors affecting joint damage as clinical outcome are lacking in Africa. The aim of the present study was to identify predictors of joint damage in adult South Africans with established RA. Methods: A cross-sectional study of 100 black patients with RA of >5 years were assessed for joint damage using a validated clinical method, the RA articular damage (RAAD) score. Potential predictors of joint damage that were documented included socio-demographics, smoking, body mass index (BMI), disease duration, delay in disease modifying antirheumatic drug (DMARD) initiation, global disease activity as measured by the disease activity score (DAS28), erythrocyte sedimentation rate (ESR), C reactive protein (CRP), and autoantibody status. The predictive value of variables was assessed by univariate and stepwise multivariate regression analyses. A p value <0.05 was considered significant. Results: The mean (SD) age was 56 (9.8) years, disease duration 17.5 (8.5) years, educational level 7.5 (3.5) years and DMARD lag was 9 (8.8) years. Female to male ratio was 10:1. The mean (SD) DAS28 was 4.9 (1.5) and total RAAD score was 28.3 (12.8). The mean (SD) BMI was 27.2 kg/m2 (6.2) and 93% of patients were rheumatoid factor (RF) positive. More than 90% of patients received between 2 to 3 DMARDs. Significant univariate predictors of a poor RAAD score were increasing age (p = 0.001), lower education level (p = 0.019), longer disease duration (p < 0.001), longer DMARD lag (p = 0.014), lower BMI (p = 0.025), high RF titre (p < 0.001) and high ESR (p = 0.008). The multivariate regression analysis showed that the only independent significant predictors of a higher mean RAAD score were older age at disease onset (p = 0.04), disease duration (p < 0.001) and RF titre (p < 0.001). There was also a negative association between BMI and the mean total RAAD score (p = 0.049). Conclusions: Patients with longstanding established RA have more severe irreversible joint damage as measured by the clinical RAAD score, contrary to other studies in Africa. This is largely reflected by a delay in the initiation of early effective treatment. Independent of disease duration, older age at disease onset and a higher RF titre are strongly associated with more joint damage. The inverse association between BMI and articular damage in RA has been observed in several studies using radiographic damage scores. The mechanisms underlying this paradoxical association are still widely unknown but adipokines have recently been suggested to play a role. Disclosure statement: C.I. has received a research grant from the Connective Tissue Diseases Research Fund, University of the Witwatersrand. All other authors have declared no conflicts of interes

BHPR research: qualitative1. Complex reasoning determines patients' perception of outcome following foot surgery in rheumatoid arhtritis

Background: Foot surgery is common in patients with RA but research into surgical outcomes is limited and conceptually flawed as current outcome measures lack face validity: to date no one has asked patients what is important to them. This study aimed to determine which factors are important to patients when evaluating the success of foot surgery in RA Methods: Semi structured interviews of RA patients who had undergone foot surgery were conducted and transcribed verbatim. Thematic analysis of interviews was conducted to explore issues that were important to patients. Results: 11 RA patients (9 ♂, mean age 59, dis dur = 22yrs, mean of 3 yrs post op) with mixed experiences of foot surgery were interviewed. Patients interpreted outcome in respect to a multitude of factors, frequently positive change in one aspect contrasted with negative opinions about another. Overall, four major themes emerged. Function: Functional ability & participation in valued activities were very important to patients. Walking ability was a key concern but patients interpreted levels of activity in light of other aspects of their disease, reflecting on change in functional ability more than overall level. Positive feelings of improved mobility were often moderated by negative self perception ("I mean, I still walk like a waddling duck”). Appearance: Appearance was important to almost all patients but perhaps the most complex theme of all. Physical appearance, foot shape, and footwear were closely interlinked, yet patients saw these as distinct separate concepts. Patients need to legitimize these feelings was clear and they frequently entered into a defensive repertoire ("it's not cosmetic surgery; it's something that's more important than that, you know?”). Clinician opinion: Surgeons' post operative evaluation of the procedure was very influential. The impact of this appraisal continued to affect patients' lasting impression irrespective of how the outcome compared to their initial goals ("when he'd done it ... he said that hasn't worked as good as he'd wanted to ... but the pain has gone”). Pain: Whilst pain was important to almost all patients, it appeared to be less important than the other themes. Pain was predominately raised when it influenced other themes, such as function; many still felt the need to legitimize their foot pain in order for health professionals to take it seriously ("in the end I went to my GP because it had happened a few times and I went to an orthopaedic surgeon who was quite dismissive of it, it was like what are you complaining about”). Conclusions: Patients interpret the outcome of foot surgery using a multitude of interrelated factors, particularly functional ability, appearance and surgeons' appraisal of the procedure. While pain was often noted, this appeared less important than other factors in the overall outcome of the surgery. Future research into foot surgery should incorporate the complexity of how patients determine their outcome Disclosure statement: All authors have declared no conflicts of interes

Molecular characterization of two patients with severe LCAT deficiency.

Lecithin:cholesterol acyltransferase (LCAT; EC2.3.1.43) is the major enzyme responsible for theesterification of cholesterol in circulating plasmalipoproteins. This is important in the human becauseunlike many other animal species, cholesterol exportedinto the plasma from the liver is largely unesterified.LCAT associates in plasma preferentially with thediscoidal apo A-I containing high-density lipoproteins(preb1-HDL), where it esterifies the free cholesterol(FC) using apo A-I as co-factor [1]. Through thisaction, LCAT plays a central role in both HDLmaturation to a-migrating spherical HDL and inreverse transport of cholesterol from peripheral tissuesto the liver, directly by interaction of the mature HDLwith the hepatic SR-BI receptor, or indirectly bytransfer of CE by cholesteryl ester transfer protein(CETP) to the VLDL and then LDL, much of which isultimately cleared by the liver via the LDL receptor [2].In addition, LCAT protein seems to have a scavengereffect toward LDL oxidation products, which isindependent of its cholesterol-esterifying activity [3].Mutations of LCAT (chr. 16q22.1, 6 exons) inhomozygous or compound heterozygous form cancause two major phenotypes: FLD (familial LCATdeficiency) and FED (Fish Eye Disease). Patients withFLD (OMIM No, 245900) have a complete loss ofboth a-LCAT activity (i.e. LCAT activity exerted onHDL) and b-LCAT activity (i.e. LCAT activity exertedon LDL), an increased proportion (>80%) of unesterifiedcholesterol in plasma. Clinical manifestationsgenerally include corneal opacification, anaemia andrenal disease with proteinuria, which progresses toterminal renal insufficiency. In FED (OMIM No.131620), there is partial loss of a-LCAT activity withnormal or slightly elevated FC in plasma and cornealopacification without renal disease [4,5]. Intermediatephenotypes have also been described. To date, morethan 60 mutations of LCAT have been identified [4\u20136];they involve all regions of the coding sequence andproduce a variety of defects, including normal secretionof LCAT with total loss of catalytic activity,reduced secretion with a partial or total loss ofcatalytic activity, secretion of an unstable or rapidlycatabolized enzyme, and complete degradation of theenzyme at its site of synthesis [4]. All subjects withFED or FLD have greatly reduced plasma HDLcholesterol concentrations (usually <0.3 mmol/l) andplasma levels of apo A-I below 50 mg/dl [6,7]; however,premature coronary artery disease is absent in mostFLD cases, but sometimes present, for unclear reasons,in some patients with FED [4,6,8]. We investigated twounrelated patients with clinical features of LCATdeficiency. Two of the three LCAT mutations foundin these patients were novel